Nature Summer Reads

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com/news
August 2015
NATURES SUMMER READS
NEWS FEATURE
SUMMER READS
AUGUST 2015
S
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ummer means different things to different people. It

can be a time to broaden horizons by travelling to new
places; a time to catch up on news and ideas that have
swept past this year; and of course, a time to read.
Here, Nature offers the opportunity to do all these things,
with a collection of the best and most popular stories
published in the magazines award-winning News Features
section in 2015.
The stories include something for all tastes. One
feature, on page 7, explores how advances in genetics and
developmental biology have been challenging the idea that
there is a clear distinction between the sexes, and finds that
perhaps sex should be considered as more of a spectrum.
In medicine, the collection includes a story about a largely
unrecognized, but pressing global health problem: the
astonishing rise in short-sightedness that has been taking
place over the past few decades, particularly in Asian
countries, and how it might be curbed (page 18).
Pluto was thrust into the spotlight this summer when New
Horizons reached its quarry, some 4.8 billion kilometres from
Earth. A profile in the collection (page 11) tells the story of
two scientists, a brother and sister, who have been captivated
by the planet since their youth. On page 33, a feature looks at
experiments to uncover the nature of the wavefunction the
mysterious entity that lies at the heart of quantum weirdness
and page 41 captures the excitement in the science of 2D
materials that has followed the discovery of graphene.
Natures News Features editors have enjoyed publishing
every one of these stories; we hope that your summer is
enriched by reading them.
Blood to blood
Nature Vol. 517, No. 7535, 426429 (2015).
Voices of Hubble
Nature Vol. 520, No. 7547, 282286 (2015).
Sex redefined
Nature Vol. 518, No. 7539, 288291 (2015).
Blame it on the antibodies

Nature Vol. 521, No. 7552, 274276 (2015).
The Pluto siblings (www.nature.com/pluto)

Nature Vol. 518, No. 7540, 470472 (2015).
What is really real?

Nature Vol. 521, No. 7552, 278280 (2015).
The human age

Nature Vol. 519, No. 7542, 144147 (2015).
CRISPR, the disruptor

Nature Vol. 522, No. 7554, 2024 (2015).
The myopia boom

Nature Vol. 519, No. 7543, 276278 (2015).
2D or not 2D
Nature Vol. 522, No. 7556, 274276 (2015).
Blood to blood
Megan Scudellari
Sex redefined
Claire Ainsworth
11 The Pluto siblings

Alexandra Witze
14 The human age
Richard Monastersky
18 The myopia boom

Elie Dolgin
21 The future of the postdoc

Kendall Powell
25 Voices of Hubble
Alexandra Witze
30 Blame it on the antibodies
Blood to
blood
CITING THE COLLECTION

All articles in this collection have been previously published in Nature. Please use the original
citation, which can be found below.
The future of the postdoc

Nature Vol. 520, No. 7546, 144147 (2015).
CONTENTS
Monya Baker
33 What is really real

Zeeya Merali
36 CRISPR, the disruptor

Heidi Ledford
41 2D or not 2D
Elizabeth Gibney
By splicing animals
together, scientists
have shown that young
blood rejuvenates old
tissues. Now, they
are testing whether it
works for humans.
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FEATURE NEWS
NEWS FEATURE
analysis1 showing that results in 47 of 53 landmark cancer research papers could not be
reproduced.
A few scientists who have been burned by
bad experiences with antibodies have begun to
speak up. Rimms disappointment set him on a
crusade to educate others by writing reviews,
hosting web seminars and raising the problem
in countless conference talks. He and others
are calling for the creation of standards by
which antibodies should be made, used and
described. And some half a dozen grass-roots
efforts have sprung up to provide better ways
of assessing antibody quality.
But it is too soon to call the cause a movement. There are all these resources out there,
but nobody uses them and many people arent
even aware of them, says Len Freedman, who
heads the Global Biological Standards Institute, a non-profit group in Washington DC
committed to improving biomedical research.
Most vendors have no incentive to change
whats going on right now, even though a lot of
the antibody reagents suck.
ILLUSTRATION BY GARY NEILL
ILLUSTRATION BY GARY NEILL
tremendously. A common complaint from scientists is that companies do not provide the data
required to evaluate a given antibodys specificity or its lot-to-lot variability. Companies might
DEVASTATING EFFECTS
ship a batch of antibodies with characterization
There are signs that problems with antibodies information derived from a previous batch.
are having broad and potentially devastating And the data are often derived under ideal coneffects on the research record. In 2009, one ditions that do not reflect typical experiments.
journal devoted an entire issue to assessing the Antibody companies contacted for this article
antibodies that are used to study G-proteinsaid that it is impossible to test their products
coupled receptors (GPCRs) cell-signalling across all experimental conditions, but they do
proteins that are targeted by drugs to treat variprovide reliable data and work with scientists
ous disorders, from incontinence to schizo- to improve antibody quality and performance.
phrenia. In an analysis3 of 49 commercially
Many academics use Google to find products,
available antibodies that targeted 19 signalling so optimizing search results can sometimes
receptors, most bound to more than one pro- matter more to a company than optimizing the
tein, meaning that they could not be trusted to actual reagents, says Tim Bernard, head of the
distinguish between the receptors.
biotechnology consultancy Pivotal Scientific
The field of epigenetics relies heavily on anti- in Upper Heyford, UK. Christi Bird, a Frost &
bodies to identify how proteins that regulate Sullivan analyst based in Washington DC, says
gene expression have been modified. In 2011, an that researchers are often more interested in
evaluation4 of 246 antibodies used in epigenetic how quickly reagents can be delivered than in
studies found that one-quarter failed tests for searching for antibodies with appropriate valispecificity, meaning that they often bound to dation data. Its the Amazon effect: they want it
more than one target. Four antibodies were in two or three days, with free shipping.
BUYER BEWARE
perfectly specific but to the wrong target.
Researchers who are aware of the antibody
Take the example of Ioannis Prassas, a proteoScientists often know, anecdotally, that some problem say that scientists need to be more
mics researcher at Mount Sinai Hospital in antibodies in their field are problematic, but vigilant. Antibodies are not magic reagents.
Toronto, Canada. He and his colleagues had it has been difficult to gauge the size of the You cant just throw them on your sample and
been chasing a protein called CUZD1, which problem across biology as a whole. Perhaps expect the result you get is 100% reliable withthey thought could be used to test whether the largest assessment comes from work pub- out putting some critical thinking into it, says
someone has pancreatic cancer. They bought lished by the Human Protein Atlas, a Swedish James Trimmer, head of NeuroMab at the Unia protein-detection kit and wasted two years, consortium that aims to generate antibodies versity of California, Davis, which makes anti$500,000 and thousands of patient samples
bodies for neuroscience. Like many suppliers,
before they realized that the antibody in the
NeuroMab explicitly states the types of experikit was recognizing a different cancer protein,
ment that an antibody should be used for, but
CA125, and did not bind to CUZD1 at all2. In
scientists do not always follow the instructions.
retrospect, Prassas says, a rush to get going on
Ideally, researchers would refuse to buy antia promising hypothesis meant that he and his
bodies without extensive validation dataor
would perform the validation themselves
group had failed to do all the right tests. If
someone says, Here is an assay you can use,
(see Bad antibodies). This is something that
you are so eager to test it you can forget that
Rimm is passionate about: he has developed
what has been promised is not the case.
a multistep flowchart for effective validation6,
Most scientists who purchase antibodwhich he shares with anyone who will listen.
ies believe the label printed on the vial, says
But the process is time consuming Rimm
Rimm. As a pathologist, I wasnt trained
recommends control experiments that involve
that you had to validate antibodies; I was just
engineering cell lines to both express and stop
trained that you ordered them.
expressing the protein of interest, for example.
Antibodies are produced by the immune for every protein in the human genome. It has Even he acknowledges that few labs will persystems of most vertebrates to target an invader looked at some 20,000 commercial antibodform all the steps.
such as a bacterium. Since the 1970s, scien- ies so far and found that less than 50% can be
Some scientists buy half a dozen antibodtists have exploited antibodies for research. If used effectively to look at protein distribution ies from different vendors, and then run a few
a researcher injects a protein of interest into in preserved slices of tissue5. This has led some assays to see which performs best. But they
a rabbit, white blood cells known as B cells scientists to claim that up to half of all com- may end up buying the same antibody from
will start producing antibodies against the mercially available antibodies are unreliable.
different places. The largest vendors compete
protein,
which
can
be
collected
from
the
aniBut
reliability
can
depend
on
the
experiment.
on
size, so they often buy antibodies
B
Y
M
E
G
A
N
S
C
U
D
E
L
L
A Rcatalogue
I
MEGAN SCUDELLARI
mals blood. For a more consistent product, the Our experience with commercial antibodies from smaller suppliers, relabel them and offer
fusedawith
immorapplicathem
that
the 2million
mice perch
sidefor
by sale.
side, Bernard
nibbling says
a food
pellet.
As one
wo miceBcells
perchcan
sidebebyretrieved,
side, nibbling
foodanpellet.
As oneis that they are usually okay in somewo
talized
cell
and
cultured
to
provide
a
theoretitions,
but
they
might
be
terrible
in
others,
says
antibodies
on
the
market
probably
represent
turns
to
the
left,
it
becomes
clear
that
food
is
not
all
that
turns to the left, it becomes clear that food is not all that
cally
unlimited
supply.
Mathias
Uhln
at
the
Royal
Institute
of
Tech250,000500,000
unique
core
antibodies.
they
share
their
front
and
back
legs
have
been
cinched
they share their front and back legs have been cinched
Three
needed
coordinates
researchers
rely on
and the
a neat rowByofnecessity,
sutures runsmany
the length
of their bodies,
gether, and a neat
row decades
of suturesago,
runsscientists
the lengthwho
of their
bodies,nology in Stockholm, who together,
word
of
mouth
or
the
published
literature
for
antibodies
for
their
experiments
had
to
make
Human
Protein
Atlas.
connecting
their
skin.
Under
the
skin,
however,
the
animals
are
nnecting their skin. Under the skin, however, the animals are
advice.
But that
creates
self-perpetuating
them
themselves.
by they
the late
rea-each Researchers ideally should
check
an more
joined
inthat
another,
profound
way:
they aare
pumping each
ned in another,
more
profoundBut
way:
are 1990s,
pumping
use in particular
problem, in which better-performing antibodblood.
hers blood. gent companies had started to take over the antibody has been tested for others
applications
and
tissue
types,
but
the
quality
chore.
ies that become
available
laterthat
are rarely
Parabiosis
is
a
150-year-old
surgical
technique
unitesused,
the
Parabiosis is a 150-year-old surgical technique that unites the
can vary
Today,
more
than 300
sellfrom
over theof information supplied by vendors
says Fridtjof
Lund-Johansen,
a proteomics
vasculature
of two living
animals.
(The word comes
from the
sculature of two
living
animals.
(Thecompanies
word comes
2million antibodies for research. As of 2011,
the market was worth $1.6 billion, according to
global consultancy Frost & Sullivan.
ANTIBODIES
ARE NOT
MAGIC
REAGENTS.
Blood to
blood
By splicing animals
together, scientists
have shown that young
blood rejuvenates old
tissues. Now, they
are testing whether it
works for humans.
4 2 6NATURE
| N A T COLLECTIONS
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7 | 2 2 J ASUMMER
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ll rights reserved
2015 Macmillan Publishers Limited. All rights reserved
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NEWS FEATURE
FEATURE NEWS
Greek para, meaning alongside, and bios, meaning life.) It mim- actually ate the sugar developed cavities2.
ics natural instances of shared blood supply, such as in conjoined
Clive McCay, a biochemist and gerontologist at Cornell
twins or animals that share a placenta in the womb.
University in Ithaca, New York, was the first to apply parabiosis
In the lab, parabiosis presents a rare opportunity to test what to the study of ageing. In 1956, his team joined 69 pairs of rats,
circulating factors in the blood of one animal do when they enter almost all of differing ages3. The linked rats included a 1.5-monthanother animal. Experiments with parabiotic rodent pairs have old paired with a 16-month-old the equivalent of pairing a
led to breakthroughs in endocrinology, tumour biology and 5-year-old human with a 47-year-old. It was not a pretty experiimmunology, but most of those discoveries occurred more than ment. If two rats are not adjusted to each other, one will chew
35years ago. For reasons that are not entirely clear, the technique the head of the other until it is destroyed, the authors wrote in
fell out of favour after the 1970s.
one description of their work4. And of the 69 pairs, 11 died from
In the past few years, however, a small number of labs have a mysterious condition termed parabiotic disease, which occurs
revived parabiosis, especially in the field of ageing research. By approximately one to two weeks after partners are joined, and may
joining the circulatory system of an old mouse to that of a young be a form of tissue rejection.
mouse, scientists have produced some remarkable results. In the
heart, brain, muscles and almost every other tissue examined,
the blood of young mice seems to bring new life to ageing organs,
making old mice stronger, smarter and healthier. It even makes
their fur shinier. Now these labs have begun to identify the components of young blood that are responsible for these changes.
And last September, a clinical trial in California became the first
to start testing the benefits of young blood in older people with
Alzheimers disease.
I think it is rejuvenation, says Tony Wyss-Coray, a neurologist
at Stanford University in California who founded a company that
is running the trial. We are restarting the ageing clock.
Today, parabiosis is performed carefully to reduce animal
Many of his colleagues are more cautious about making discomfort and mortality. We observe the mice at length and
such claims. Were not de-ageing animals, says Amy Wagers, have long discussions with our animal-care committee, says
a stem-cell researcher at Harvard University in Cambridge, Thomas Rando, a Stanford neurologist who has used the proceMassachusetts, who has identified a muscle-rejuvenating factor dure. We dont take this lightly. Mice of the same sex and size
in young mouse blood. Wagers argues that such factors are not are socialized with each other for two weeks before attachment,
turning old tissues into young ones, but are instead helping them and the surgery itself is done in a sterile setting with anaesthesia,
to repair damage. Were restoring function to tissues.
heating pads and antibiotics to prevent infection. Using inbred
She emphasizes that no one has convincingly shown that young lab mice, genetically matched to one another, seems to reduce
blood lengthens lives, and there is no promise that it will. Still, she the risk of parabiotic disease. Joined mice eat, drink and behave
says that young blood, or factors from it, may hold promise for normally and they can be separated successfully.
helping elderly people to heal after surgery, or treating diseases
In McCays first parabiotic ageing experiment, after old and
young rats were joined for 918 months, the older animals
of ageing.
B Y CIts
L A I very
R E A Iprovocative,
N S W O R T H says Mark Mattson, chief of the Labora- bones
sexes
becomes
even
Scientists
have
identified
many
became
similar
inblurrier.
weight and
density
to the
bones of
theirof the genes
5
involved
in the main
formsthan
of DSD,
and have
variations in
tory of Neurosciences at the US National Institute on Aging in younger
counterparts
. More
15 years
later,uncovered
in 1972, two
s a clinical
geneticist,
is accustomed
these genes
that
have subtle
effects on astudied
personsthe
anatomical
Bethesda,
Maryland,
whoPaul
has James
not been
involved in to
thediscussing
parabiosissome
researchers
at the
University
of California
lifespansor
ofphysiologiof the
most delicate
issues
with Ihis
patients.
in early
2010,
cal sex.rat
Whats
more,
new
technologies
in DNA
and cell biolwork.
It makes
you think.
Maybe
should
bankBut
some
blood
of he
oldyoung
pairs.
Older
partners
lived for
four tosequencing
five months
himself
a particularly
awkward
about
ogy
are revealing
that almostfor
everyone
is,time
to varying
degrees, a patchwork
my found
daughters
son,having
so if I start
to have any
cognitiveconversation
problems, Ill
longer
than
controls, suggesting
the first
that circulation
6
of genetically
distinct
cells,
some with
havesex.
some help, he says, only half-joking.
of young
blood might
affect
longevity
. a sex that might not match that of
A 46-year-old pregnant woman had visited his clinic at the Royal Despite
the restthese
of their
body. Some
studiesparabiosis
even suggest
sex of each cell
intriguing
findings,
fellthat
outthe
of use.
whoitshave
studiedthrough
the techniques
history
speculate
that
Melbourne
drives
behaviour,
a complicated
network
of molecular
interTHE POWERHospital
OF TWO in Australia to hear the results of an amniocentesisThose
researchers
thought
they had
learned
they could
from
it, or female,
test
to screen her
babys
abnormalities.
The baby was
actions. I
think theres
much
greateralldiversity
within
male
Physiologist
Paul
Bert chromosomes
performed the for
earliest
recorded parabiosis
or that
barisfor
gettingan
institutional
approval
parabiosis
fine
but follow-up
had
astonishing
about
andthe
there
certainly
area of overlap
wherefor
some
people cant easily
experiment
in 1864,tests
when
herevealed
removedsomething
a strip of skin
from the
define
binary structure,
says
Achermann,
flanks
of two
albino
the animals
together in
the
mother.
Her
bodyrats,
was then
built stitched
of cells from
two individuals,
probstudies
hadthemselves
become toowithin
high. the
Whatever
the reason,
the John
experiably
from
embryos
thatcirculatory
had mergedsystem
in her1.own
mothers
womb.
who
studiesThat
sex development
and endocrinology
at University
hopes
oftwin
creating
a shared
Biology
did the
ments
stopped.
is, until a stem-cell
biologist named
Irving College
And
waswound-healing
more. One setprocesses
of cells carried
chromosomes,
Londons
Institute
of Childback
Health.
rest:there
natural
joinedtwo
the X
animals
circula- the
Weissman
brought
parabiosis
to life.
complement
typically makes
person
female; theBert
otherfound
had an X
These discoveries do not sit well in a world in which sex is still defined
tory systemsthat
as capillaries
regrewaat
the intersection.
and
a Y.
Halfway
through
fifth
pregnant
terms. Few legal systems allow for any ambiguity in biological
that
fluid
injected
into aher
vein
ofdecade
one ratand
passed
easilywith
intoher
thethird
BACKinTObinary
THE SOURCE
child,
thework
woman
foran
theaward
first time
large part
of her body
sex, and
a persons
legal
rights
and social
heavily
other,
thatlearned
won him
fromthat
theaFrench
Academy
Weissman
learned
to join
mice
together
at thestatus
age ofcan
16,be
under
the influenced
was
chromosomally
by whether
birthpathologist
certificate in
says
ortown
female.
of Sciences
in 1866.male1. Thats kind of science-fiction material for
supervision
of atheir
hospital
themale
small
of Great
someone
came
in for an amniocentesis,
James.
The main
a strongwas
dichotomy
that there are interSince who
Bertsjust
initial
experiments,
the procedure says
has not
changed Falls, Montana,
in problem
1955. Hiswith
supervisor
studyingistransplanSex can
complicated
than
at first
seems. According
mediate
cases
that push
andofask
us to figurecells
out exactly
where
much.
It be
hasmuch
beenmore
performed
on hydra
itsmall
freshwater
inver- to
tation
antigens,
proteins
onthe
thelimits
surface
transplanted
or
the
simplerelated
scenario,
the presence
or absence
of a Ybut
chromosome
is what
thethat
dividing
line iswhether
betweenthey
males
females,
Arthur
tebrates
to jellyfish
frogs
and insects,
it works best
tissues
determine
areand
accepted
or says
rejected
by Arnold at
counts:
with it,
you are
male,well
andfrom
without
it, you are
But docthe University
of California,
Los Angeles,
whotracer
studies
sex
on rodents,
which
recover
the surgery.
Upfemale.
to the midthe host.
Weissman remembers
adding
a fluorescent
to biological
the
tors
have long
knownscientists
that someused
people
straddle the
boundary
differences.
Andinthats
very difficult
problem,
twentieth
century,
parabiotic
pairs
of mice
ortheir
blood
of one mouse
a pairoften
and awatching
it go back
and because
forth sex can
sex
chromosomes
say oneofthing,
but theirFor
gonads
(ovaries
orteam
testes) or
rats
to study a variety
phenomena.
example,
one
be defined
a number
of ways.
between
the animals.
It was
really amazing, he says.
ruledanatomy
out the say
ideaanother.
that dental
cavities
are with these kinds of con- He went on to spend three decades studying stem cells and
sexual
Parents
of children
regeneration
ditions
known
as intersex
conditions,
oradifferences
or disorders of
THE STARTinOFnatural
SEX parabionts, sea squirts of the species
the result
of sugar
in the blood
by using
NATURE.COM
sex
development
(DSDs)
face
difficult
about
That schlosseri.
the two sexes
are physically
is obvious,
but at the
pair
of parabiosed
rats,
ofoften
which
only
one decisions
For a podcast
on whetherBotryllus
In 1999,
Wagers,different
then a new
postdoctoral
fel- start of life,
towas
bring
theirdiet
child
a boy orThe
a girl.
now say that
it isWeissmans
not. Five weeks
into development,
embryo
has the potential
fedup
a daily
ofas
glucose.
ratsSome
had researchers
parabiosis and
low in
Stanford
lab, wanted toa human
study the
movement
2
assimilar
many as
1 person
in 100
hasowing
some form
of DSD
. visit:
to form
bothstem
malecells,
and female
anatomy.
Next to the developing
blood
glucose
levels
to their
ageing,
and fate
of blood
so Weissman
recommended
that she kidneys,
When genetics
is taken
consideration,
boundary between the
two bulgesmice
known
the gonadal ridges
emerge
alongside
shared
circulation,
yetinto
only
the rat thatthego.nature.com/berp8l
use parabiotic
andasfluorescently
label the
cells she
wantedtwo pairs of
SEX
REDEFINED
THE IDEA OF TWO SEXES IS SIMPLISTIC.
BIOLOGISTS NOW THINK THERE IS A
WIDER SPECTRUM THAN THAT.
I thought, Hey wait, theyre
sharing blood. This could
answer the question weve
been asking for years.
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NIK SPENCER/NATURE; CHART DATA: A. EGGEL & T. WYSS-CORAY SWISS MED. WKLY 144, W13914 (2014)
analysis1 showing that results in 47 of 53 land- 2million antibodies for research. As of 2011, tremendously. A common complaint from scimark cancer research papers could not be the market was worth $1.6 billion, according to entists is that companies do not provide the data
reproduced.
required to evaluate a given antibodys specificA simple surgery
ity or its lot-to-lot variability. Companies might
A veterinary surgeon will anaesthetize the animals, peel away a thin layer of skin along their sides
bad experiences with antibodies have begun to DEVASTATING
EFFECTS
shipWound-healing
a batch of antibodies
characterization
and stitch or staple the exposed surfaces together.
processes with
join the
bloodstreams
a capillary
network,
and
in one to two weeks,
the animals
are pumping
others blood.
speak up. Rimms
disappointment
set him
a There arethrough
signs that
problems
with
antibodies
information
derived
from each
a previous
batch.
Parabiotic
experiments, in which
twoon
animals
a common
were first
crusade to share
educate
othersbloodstream,
by writing reviews,
are having broad and potentially devastating And the data are often derived under ideal conthe 1860s.
connecting
hosting webattempted
seminarsin and
raisingBythe
problem effects on the research record. In 2009, one ditions that do not reflect typical experiments.
animals with different qualities or conditions,
MOUSE A
MOUSE
B article
in countless
conference
talks. He
and
others
Antibody companies contacted
for this
scientists
can investigate
how
blood
factors, journal devoted an entire issue to assessing the
Condition
proteinsof
or standards
hormones, influence
are callingsuch
for as
thecells,
creation
by antibodies that areCondition
used to study G-proteinsaid that it is impossible to
test their products
health. Inshould
recent years,
a few researchers
which antibodies
be made,
used and havecoupled receptors (GPCRs) cell-signalling across all experimental conditions, but they do
looked at heterochronic (old and young)
described. And
some
half
a
dozen
grass-roots
proteins that are targetedOld
by drugs to treat variprovide reliable data andYoung
work with scientists
mouse pairs to understand how young
helpsup
to to
repair
many better
tissues.ways
efforts haveblood
sprung
provide
Lean
Obese
But it is too
soon to call theon
cause
a moveavailable antibodies that
targeted 19 signalling so optimizing search results
can sometimes
Publications
parabiosis
Parabiosis
popularity during
the 1960s
ment. There
are all gained
these resources
out there,
1970s,
eventually
fell out of
wide practice.
but nobodyand
uses
thembut
and
many people
arent
Sedentary
Active
even aware80
of them, says Len Freedman, who distinguish between
the receptors.
biotechnology consultancy
Pivotal Scientific
heads the Global Biological Standards InstiThe field of epigenetics relies heavily on anti- in Upper Heyford, UK. Christi Bird, a Frost &
tute, a non-profit group in Washington DC bodies to identify how proteins that regulate Sullivan analyst based in Washington DC, says
Non-irradiated
Irradiated
committed 60
to improving biomedical research. gene expression have
been modified. In 2011, an that researchers are often more interested in
4
Most vendors have no incentive to change evaluation of 246 antibodies used in epigenetic how quickly reagents can be delivered than in
whats going40on right now, even though a lot of studies found that
one-quarter failed tests for searching for antibodies with
appropriate valiFluorescent
Non-fluorescent
specificity, meaning that they often bound to dation data. Its the Amazon effect: they want it
20
BUYER BEWARE
Mutant
Wild type
Take the example
of
Ioannis
Prassas,
a
proteoScientists
often
know,
anecdotally,
that
some
problem
say that scientists
need to be more
0
mics researcher
at
Mount
Sinai
Hospital
in
antibodies
in
their
field
are
problematic,
but
vigilant.
Antibodies
are
not magic reagents.
1860
1950
1970
1990
2010
someone has
pancreatic
bought
lished
by the Human
a Swedish
James
Trimmer,
head
of NeuroMab
at the Unito track
in onecancer.
animalThey
of a pair.
Wagers
experiments
led toProtein
two Atlas,
Instead,
members
of the
original
research
team branched
a protein-detection
and wasted
years, andconsortium
that
aims
to generate
antibodies
versity
California,
Davis,
which
antirapid-firekit
discoveries
on two
the nature
migration of
blood
stem
out into
separate efforts
to of
determine
what
exactly
in makes
the blood
7,8
$500,000 and
of patient
samples neighbours.
bodies
for neuroscience.
manyIrina
suppliers,
cellsthousands
. It also inspired
her Stanford
is responsible for the
rejuvenating
effects. Like
In 2008,
and
before they realized
the
antibody
in the
explicitly states
the typesBerkeley,
of experiIn 2002,that
Irina
Conboy,
a postdoctoral
fellow in Randos lab, Michael Conboy, by NeuroMab
then at the University
of California,
presented
one of Wagers
papers at a journal-club meeting. linked10 muscle rejuvenation
kit was recognizing
a different
cancer protein,
ment thattoan
should
be used
for, but
theantibody
activation
of Notch
signalling
CA125, and
did notConboy,
bind to CUZD1
at all2. In
do not
always
follow
the instructions.
Michael
Irinas husband
and a postdoc in the same lab, which promotes scientists
cell division
or
to the
deactivation
of the
retrospect,was
Prassas
says,
rush
to get
going
on room.
Ideally,(TGF)-
researchers
wouldwhich
refuseblocks
to buy cell
antidozing
inathe
back
of the
meeting
transforming growth factor
pathway,
11
a promising hypothesis
meant
that he mice
and his
bodies
without
extensive
dataor
The mention
of stitching
together jolted him awake. We division. Then, in 2014,
they
identified
one ofvalidation
the age-defying
perform
the avalidation
themselves
group hadhad
failed
to in
dodiscussion
all the right
been
fortests.
yearsIf
that ageing seems to be all cells factors circulating inwould
the blood:
oxytocin,
hormone best
known
someone says,
Here
is that
an assay
you can
use,to
go to hell in a handbasket for its involvement in(see
Bad antibodies).
This
is something
that
in the
body,
all tissues
seem
childbirth
and bonding,
and
already a drug
you are so together,
eager to test
you can forget
that
saysit Michael.
Yet they
had been unable to think of a approved by the US Food
Rimmand
is passionate
about: he has
Drug Administration
for developed
inducing
what has been
promised
is not the
case.
to investigate what coordinates labour in pregnant women.
a multistep
flowchart
for decline
effectivewith
validation
realistic
experiment
with
which
Oxytocin
levels
age in 6,
Most scientists
who purchase
antibodwhich
shares
with systemically
anyone whointo
willolder
listen.
ageing throughout
the body.
both men and women,
and he
when
injected
ies believe the
printed
the theyre
vial, says
But the
process
consuming
Rimm
I label
thought,
Heyon
wait,
sharing blood, says Michael. mice, the hormone quickly
withinisa time
couple
of weeks regenRimm. AsThis
a pathologist,
I wasnt
trainedweve been asking for years. erates muscles by activating
recommends
control
that involve
could answer
that question
muscle
stem experiments
cells.
that you had
antibodies;
I was he
justran up to Irina and Rando. He
At to
thevalidate
end of the
presentation,
even finished
trained thathad
younot
ordered
them. his pitch before Rando said: Lets do it.
ALL THE ORGANS expressing the protein of interest, for example.
AntibodiesThe
areresearchers
produced by
the immune
for every
in thethe
human
genome.
has Even
that
few at
labs
will perteamed
up with Wagers,
whoprotein
performed
Wagers
wasItfollowing
uphe
onacknowledges
the anti-ageing
work
Harvard,
systems of most
vertebrates
to target
an invader
looked
at some
20,000the
commercial
antibodform
thelab
steps.
oldyoung
pairings
for the
experiment
and taught
Michael
where she
had started
her all
own
in 2004. She recruited the help
such as a bacterium.
Since
the 1970s,
scieniesRando
so far and
that
than
50% can
be
Some systems
scientiststobuy
dozen
antibodtechnique (see
Share
and share
alike).
saysfound
that he
didless of
experts
in various
organ
helphalf
herato
evaluate
the
tists have exploited
antibodies
for research.
If butused
effectively
to look
at protein
distribution
ies from
different
vendors,
and With
then run
a few
not expect
the experiment
to work,
it did.
Within five
weeks,
impact
of young blood
on their
respective
tissues.
neuroa researcher
protein
of interest
into
in preserved
slices
ofmice,
tissue5. This
has led
someFranklin
assaysattothe
seeUniversity
which performs
best. ButUK,
they
theinjects
youngablood
restored
muscle
and liver
cells in the
older
scientist
Robin
of Cambridge,
9
a rabbit, white
blood
cells known
as B cells to start
may young
end upblood
buying
the samerepair
antibody
from
scientists
to claim
up toher
halfteam
of allshowed
com- 12 that
notably
by causing
aged stem
dividing
againthat
. The
promotes
of damwill start producing
antibodies
against
theresulted
mercially
availablegrowth
antibodiesaged
are unreliable.
different
places.
largest
vendors compete
team also found
that young
blood
in enhanced
spinal cords in older
mice.
WithThe
Harvard
neuroscientist
Lee
protein, which
cancells
be collected
fromalthough
the ani- the work
But reliability
canofdepend
the experiment.
on catalogue
size,sparks
so they
buy antibodies
of brain
in old mice,
was left out
their onRubin,
she found13 that
young blood
theoften
formation
of new
mals blood.2005
For paper
a moredescribing
consistent the
product,
theAll in
Our
experience
with commercial
antibodies
smaller suppliers,
relabel
and offer
results.
all, the
results suggested
neurons
in the brainfrom
and olfactory
system. And
withthem
cardiologist
Bcells can that
be retrieved,
fused with
immoris that
theythat
arecoordinate
usually okay in
some applicathemand
for Womens
sale. Bernard
says in
that
the 2million
blood contains
the an
elusive
factor or
factors
Richard
Lee at Brigham
Hospital
Boston,
Mas14
talized cellageing
and cultured
to provide
a theoretitions, but they might be terrible
in others,she
says
antibodies
on the market
probably
represent
in different
tissues.
sachusetts,
found
that it reverses
age-related
thickening
of
cally unlimited
supply.
Mathias
Uhln
at the
Royal Institute
250,000500,000 unique core antibodies.
After
the team published its results,
Randos
phone
started
the wallsofofTechthe heart.
Three decades
scientists
who
nology
Stockholm,
who coordinates
the began
By necessity,
many
researchers
rely on
ringingago,
incessantly.
Some
of needed
the calls were
from in
mens
health magWith Lee, Wagers
screening for
proteins
that were particword of
mouth
literature
for
antibodiesazines
for their
experiments
to make
Atlas.
looking
for wayshad
to build
muscle;Human
others Protein
were from
people ularly abundant in young
blood
but or
notthe
oldpublished
blood. One
leapt out
advice. Butfactor
that creates
a self-perpetuating
them themselves.
Butbybythe
the
late 1990s,
reaResearchers
ideally should
checkgrowth
that andifferentiation
fascinated
prospect
of forestalling
death. They wanted
to at them:
11, or GDF11.
Wagers and
14
antibody
beenthe
tested
use showed
in particular
gent companies
had started
toblood
take over
the lifespan.
problem,
in which
better-performing
antibodknow whether
young
extended
Buthas
despite
hintsfor Lee
that direct
infusions
of GDF11
alone were sufficient
applications
and tissue
types,tobut
the quality
chore.
that
become
available
are rarely
used,
that this was true from the 1970s, no one
has yet properly
tested
physically
increaseiesthe
strength
and
staminalater
of muscles,
as well
of information
supplied by vendors
can vary
Today, more
thanIt 300
companies
sell over
says Fridtjof
proteomics
the idea.
would
be an expensive,
labour-intensive
experiment.
as to reverse
DNA damage
insideLund-Johansen,
muscle stem cells.a No
mouse
ANTIBODIES
ARE NOT
MAGIC
REAGENTS.
4 2 8NATURE
| N A T COLLECTIONS
7 | 2 2 J ASUMMER
N U A R Y READS
2015
2 1 M A Y 2 0 1 5 | V O L 5 2 1 | N A T U R E | 2 75 5
NEWS FEATURE
FEATURE NEWS
studies outside of Wagers lab have yet replicated the finding, but young plasma in the treatment of different types of dementia and
a similar protein in fruit flies extends lifespan and prevents mus- age-related conditions.
All the caution over young blood is justified, given the history
cular degeneration15.
It is perhaps fitting that parabiosis newfound popularity has of dashed hopes in the anti-ageing field. In the past two decades,
spread among labs with close ties. Wyss-Coray, who worked in researchers have identified the anti-ageing properties of numerthe room next to Randos lab, had previously discovered prom- ous treatments, including calorie-restricted diets; resveratrol,
inent changes in levels of proteins and growth factors in the a chemical found in the skin of grapes; telomerase, an enzyme
blood of ageing humans and people with Alzheimers disease. that protects the integrity of chromosomes (see Books & Arts,
Following up on Randos unpublished brain results, he used old
young mouse pairs to show16 that old mice exposed to young
blood did indeed have increased neuron growth, and that young
mice exposed to old blood had reduced growth. Plasma alone
had the same effects. We didnt have to exchange the whole
blood, says Wyss-Coray. It acts like a drug. Next, the team
looked at overall changes in the brain, and found that young
plasma activates brain plasticity and memory formation in older
mice, and increases learning and memory. We could not believe
that this worked, says Wyss-Coray.
Neither could the reviewers. The first time Wyss-Coray submit- page 436); rapamycin, an immune-suppressing drug that extends
ted the work to a journal, it was rejected, he says, responding that lifespan in mice; and stem cells, which decline in function and
it was too good to be true. So his team spent a year repeating the number as people age.
experiments at the University of California, San Francisco a
Only two of these caloric restriction and rapamycin have
different facility with different staff, instruments and tools. The been shown to reliably slow or reverse the effects of ageing across
researchers got the same results. After that, I was really reas- many mammalian tissue types, but neither has turned into an
anti-ageing treatment. The former has produced conflicting
sured, says Wyss-Coray. Im convinced it works.
His research, published last May17, caught the attention of a results in primates; the latter has toxic side effects.
company in Hong Kong owned by a family with a history of AlzYoung blood, by contrast, seems to turn back the effects of ageheimers disease, which is characterized by neuron loss. One family ing, potentially with few known safety concerns in humans and,
members condition had reportedly temporarily improved after so far, with corroborated results from parabiotic ageing studies in
they received a plasma transfusion. So the company put forward multiple labs. But scientists and ethicists still worry about the treatthe initial funding to translate Wyss-Corays approach to human ment being tried in people outside approved clinical trials before
clinical trials. Wyss-Coray formed a start-up company, Alkahest evidence on its safety and effectiveness is in. Unlicensed stem-cell
in Menlo Park, California, and in September 2014 it began a rand- transplants are already a booming industry, warns Mattson, and
omized, placebo-controlled, double-blind trial at Stanford, testing unlicensed transfusion of young blood would be even easier.
the safety and efficacy of using young plasma to treat Alzheimers
You often have these lucrative markets emerge on a slender
disease. Six out of a planned 18 people with Alzheimers, all aged foundation of credible work, says Leigh Turner, a bioethicist at
50 or above, have already begun to receive plasma harvested from the University of Minnesota in Minneapolis who has studied the
B Ymen
C L Aaged
I R E A30
I Nor
S Wyounger.
O R T H In addition to monitoring disease symp- anti-ageing
sexes becomes
field. even blurrier. Scientists have identified many of the genes
involved
in claims
the main
forms
of DSD,
have uncovered
variations in
toms, the researchers are looking for changes in brain scans and
For
now, any
that
young
bloodand
or plasma
will extend
s a biomarkers
clinical geneticist,
Paul James is accustomed to discussing some
these
effects
on a persons
anatomical
or physiologiblood
of the disease.
lifespan
aregenes
false:that
thehave
datasubtle
are just
not there.
An experiment
to test
of the most delicate issues with his patients. But in early 2010, he
sex. would
Whatstake
more,
new technologies
sequencing
and cell biolsuchcal
claims
upwards
of six yearsin
DNA
first waiting
for the
himself having a particularly awkward conversation about
are then
revealing
that almost
everyonethen
is, toanalysing
varying degrees,
BADfound
BLOOD?
miceogy
to age,
for them
to die naturally,
the data.a patchwork
sex. is eager to see the results, but she worries that a failure If weofhad
genetically
cells,
a sex
that says
might
not match that of
Wagers
fundingdistinct
to do this,
Idsome
do it.with
But we
dont,
Michael
would
be difficult
to interpret
andhad
so could
whole
field
A 46-year-old
pregnant
woman
visitedset
histhe
clinic
at the
Royal
the rest
ofhe
their
body.
Somethat
studies
even suggest
that the
Conboy.
Still,
adds,
I hope
someone,
somewhere
is.sex
of each cell
Melbourne
Hospital
Australia to donor
hear the
results
an amniocentesis
drives its behaviour, through a complicated network of molecular interback. Plasma
from in
a 30-year-old
may
not of
contain
factors
test
to screentoher
babyswith
chromosomes
forfor
abnormalities.
The
baby was
actions.
I think
much
greater
diversity
within male or female,
beneficial
patients
Alzheimers,
example. She,
Rando
Megan
Scudellari
is atheres
science
journalist
based
in Boston,
Massachusetts.
fine
but follow-up
teststo
had
something
about
and there is certainly an area of overlap where some people cant easily
andothers
would prefer
seerevealed
testing for
a specificastonishing
blood factor
the
Her of
body
wasfactors
built ofsynthesized
cells fromin
two
prob- define themselves within the binary structure, says John Achermann,
or mother.
combination
known
theindividuals,
lab, for which
1. Bert, P. J. Anatomie Physiologie 1, 6987 (1864).
ably
twin embryos
that
had merged
in her own mothers womb.
who studies sex development and endocrinology at University College
thefrom
mechanism
of action
is fully
understood.
2. Kamrin, B. B. J. Dent. Res. 33, 824829 (1954).
AndThere
thereare
wasalso
more.
One set
of cells as
carried
two Xactivating
chromosomes,
Londons
Institute
of Child
lingering
concerns
to whether
stem the
3. McCay,
C. M., Pope,
F., Lunsford,
W.,Health.
Sperling, G. & Sambhavaphol, P.
1, 717 (1957).
complement
that
typically
makesblood
a person
female;
the other
had
These discoveries
do not sit well in a world in which sex is still defined
cells which
is what
the young
most
often seems
to do
an X Gerontologia
4. McCay,
C. M., terms.
Pope, F. Few
& Lunsford,
W. Bull. New
Yorkfor
Acad.
32,
and
a Y.
Halfway
through
fifth result
decade
her third
in binary
legal systems
allow
anyMed.
ambiguity
in biological
over
a long
period
of timeher
would
inand
too pregnant
much cellwith
division.
91101 (1956).
child,
woman
for the
first timewith
thatanything
a large part
of her body
sex,
and
a
persons
legal
rights
and
social
status
can
be
heavily
influenced
My the
suspicion
is learned
that chronic
treatments
plasma,
5. Horrington, E. M., Pope, F., Lunsford, W. & McCay, C. M. Gerontologia 4,
was
chromosomally
male1cells
. Thats
kind
of science-fiction
material
by whether
drugs
that rejuvenate
in old
animals
is going to lead
to an for 2131
(1960). their birth certificate says male or female.
F. C.main
& Elashoff,
R. M. Trans
New
York Acad.
Sci. 34, 582587
(1972).
someone
just came
inRando.
for an amniocentesis,
says
James.
The
problem
with
a strong
dichotomy
is that
there are interincreasewho
in cancer,
says
Even if we learn
how
to make 6. Ludwig,
7. Wright,
D. E.,cases
Wagers,
A. J.,
Gulati,
P., Johnson,
F. L. us
& Weissman,
L. exactly where
Sex can
be much
more complicated
it at
first seems.
mediate
that
push
theA.limits
and ask
to figure I.out
cells
young,
its something
well wantthan
to do
judiciously.
According to
Science 294, 19331936 (2001).
Michael
Conboythe
is concerned
another
he has seen
the simple
scenario,
presence orfor
absence
of areason:
Y chromosome
is what
the dividing
line isR.between
malesJ.and
females, I.says
Arthur Arnold at
8. Wagers,
A. J., Sherwood,
I., Christensen,
L. & Weissman,
L. Science
counts:
it, you
are
and without
it, you
female.about
But doc- 297,
the22562259
University
of California, Los Angeles, who studies biological sex
enoughwith
paired
mice
diemale,
of parabiotic
disease
to beare
cautious
(2002).
9. Conboy,
I. M. et al.And
Nature
433, often
760764
(2005).
tors
haveitlong
known that
somebe
people
the boundary
their
differences.
thats
a very
difficult problem, because sex can
trying
in humans.
I would
leerystraddle
of any trial
in which sig10. Carlson, M. E., Hsu, M. & Conboy, I. M. Nature 454, 528532 (2008).
sex
chromosomes
thing,
but theirwere
gonads
(ovaries into
or testes)
be defined a number of ways.
nificant
amountssay
ofone
blood
or plasma
transfused
an or
11. Elabd, C. et al. Nature Commun. 5, 4082 (2014).
sexual
say another.
Parents
of children
these kinds
of conolderanatomy
person regularly,
he says.
Alkahests
chiefwith
executive,
Karoly
12. Ruckh, J. M. et al. Cell Stem Cell 10, 96103 (2012).
ditions
known
as intersex
conditions,
differences
or disorders
THE STARTL.OF
SEX
Nikolich,
says that
he understands
theor
safety
concerns,
but he of
13. Katsimpardi,
et al.
Science 344, 630634 (2014).
14. Loffredo,
F. S.two
et al.
Cell 153,
828839 (2013).
sex
development
of
often
face
difficult
decisions
abouthave
whether
That the
sexes
are physically
different is obvious, but at the start of life,
emphasizes
that(DSDs)
millions
blood
and
plasma
transfusions
15. Demontis, F., Patel V. K., Swindell, W. R. & Perrimon, N. Cell Rep. 7,
outchild
safely
humans.
tobeen
bringcarried
up their
asin
a boy
or a girl. Some researchers now say that
it
is
not.
Five
weeks
into
development,
a human embryo has the potential
14811494 (2014).
as many
as 1 person
in 100
hasissome
formtoofconclude
DSD2. by the end of 16.Villeda,
to form
male and
anatomy. Next to the developing kidneys,
The initial
Alkahest
study
expected
S. A.both
et al. Nature
477,female
9094 (2011).
17. Villeda,
S. A. et al.
Nature Med.
20,
659663ridges
(2014).emerge alongside two pairs of
When
genetics
taken intoplans
consideration,
the boundary
two bulges
known
as the
gonadal
this
year,
and theiscompany
to initiate further
studiesbetween
testing the
SEX
REDEFINED
BIOLOGISTS
NOW these
THINKlucrative
THERE IS A
You
often have
markets emerge on a slender
foundation of credible work.
NATURE
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NEWS FEATURE
reproduced.
DEVASTATING EFFECTS
BUYER BEWARE
Ideally, researchers
wouldmany
refuse
buy
antiB Yretrospect,
C L A I R E A IPrassas
N S W O Rsays,
T H a rush to get going on
sexes becomes even blurrier. Scientists
have identified
ofto
the
genes
a promising hypothesis meant that he and his
bodies
without
extensive
validation
dataor
involved in the main forms
of DSD,
and have
uncovered
variations
in
perform
the
validation
themselves
group
had failed
to do all
the
rightistests.
If
s a clinical
geneticist,
Paul
James
accustomed
to discussing some these genes that have subtlewould
effects on
a persons
anatomical
or physiologisomeone
says, Here
is an
assay
you
use, But in early 2010, he cal sex. Whats more, new technologies
(see Bad antibodies).
This is something
that
of the most
delicate
issues
with
hiscan
patients.
in DNA sequencing
and cell biolyoufound
are sohimself
eager tohaving
test itayou
can forget
that conversation about ogy are revealing that almost
Rimm
is passionate
about:
he has
developed
particularly
awkward
everyone
is, to varying
degrees,
a patchwork
what
has been promised is not the case.
multistep
for effective
validation
sex.
of genetically distinct cells,asome
with aflowchart
sex that might
not match
that of 6,
scientists
who purchase
antibodheeven
shares
withthat
anyone
who
AMost
46-year-old
pregnant
woman had
visited his clinic at the Royal the rest of their body. Somewhich
studies
suggest
the sex
ofwill
eachlisten.
cell
ies believeHospital
the labelinprinted
ontothe
vial,
Buta the
process isnetwork
time consuming
Rimm
Melbourne
Australia
hear
thesays
results of an amniocentesis drives its behaviour, through
complicated
of molecular interRimm.
Asher
a pathologist,
I wasntfor
trained
recommends
control within
experiments
that
involve
test
to screen
babys chromosomes
abnormalities. The baby was actions. I think theres much
greater diversity
male or
female,
thatyou
to validate
I was
just
engineering
linessome
to both
express
stop
fine
buthad
follow-up
testsantibodies;
had revealed
something
astonishing about and there is certainly an area
of overlapcell
where
people
cantand
easily
binary structure,
says
John Achermann,
trained
thatHer
youbody
ordered
expressing
the protein
of interest,
for example.
the
mother.
wasthem.
builtof cells from two individuals, prob- define themselves within the
are produced
by merged
the immune
for mothers
every protein
in thewho
human
genome.
It has Even
heendocrinology
acknowledges at
that
few labsCollege
will perablyAntibodies
from twin embryos
that had
in her own
womb.
studies
sex development
and
University
systems
most
vertebrates
invader
at some 20,000
commercial
antibodall the steps.
And
thereofwas
more.
One settooftarget
cells an
carried
two Xlooked
chromosomes,
the Londons
Institute
of Childform
Health.
such as a bacterium.
Since
the 1970s,
scienfar and
than
50% can do
be not sitSome
halfsex
a dozen
antibodcomplement
that typically
makes
a person
female;ies
thesoother
hadfound
an X that less
These
discoveries
well inscientists
a world inbuy
which
is still defined
tists
have
exploited
antibodies
fordecade
research.
used effectively
to lookin
atbinary
proteinterms.
distribution
ies fromallow
different
vendors,
and then
run a few
and
a Y.
Halfway
through
her fifth
andIfpregnant
with her third
Few legal systems
for any
ambiguity
in biological
child,
the woman
learned
for theoffirst
time that
part of her
bodyof tissue
a researcher
injects
a protein
interest
intoa large
in preserved
slices
. This
has led some
assays
see status
whichcan
performs
best.
But they
sex,5and
a persons
legal rights
and to
social
be heavily
influenced
1
a rabbit,
white blood
cells
known
as of
B cells
may end
upmale
buying
the same antibody from
scientists
to claim
upwhether
to half of
all birth
com-certificate
was
chromosomally
male
. Thats
kind
science-fiction
material
forthatby
their
says
or female.
will start
producing
against the says
mercially
unreliable.
different
The largest
someone
who
just cameantibodies
in for an amniocentesis,
James.available antibodies
Theare
main
problem with
a strongplaces.
dichotomy
is thatvendors
there arecompete
interprotein,
which
can
be collected
from
theitaniBut reliability
can
on the
experiment.
catalogue
size,
they often
buy antibodies
Sex can be
much
more
complicated
than
at first seems.
According
todepend
mediate
cases
that push theon
limits
and ask
us so
to figure
out exactly
where
mals
blood.
For a more
consistent
thea Y chromosome
Our experience
with commercial
from
smaller
suppliers,
relabel
them
and offer
the
simple
scenario,
the presence
or product,
absence of
is what
the dividingantibodies
line is between
males
and females,
says
Arthur
Arnold
at
Bcells with
can be
fusedand
with
an immoris that
theyBut
aredocusuallythe
okay
in some applicathem
forAngeles,
sale. Bernard
says that
the 2million
counts:
it,retrieved,
you are male,
without
it, you are
female.
University
of California,
Los
who studies
biological
sex
talized
cultured
provide
a theoretibut they
terrible in others,
says often
antibodies
on the market
probably
tors
have cell
longand
known
that to
some
people
straddle thetions,
boundary
might
their bedifferences.
Andthats
a very difficult
problem,
becauserepresent
sex can
sex
chromosomes
say one thing, but their gonads (ovaries
testes)ator
cally
unlimited supply.
Mathiasor
Uhln
the Royal
Institute
of Tech250,000500,000
unique core antibodies.
be defined
a number
of ways.
Three
decades
ago, scientists
neededwithnology
in Stockholm,
who coordinates the
By necessity, many researchers rely on
sexual
anatomy
say another.
Parentswho
of children
these kinds
of conword of mouth or the published literature for
antibodies
for their
experiments
had toor
make
Human
Protein Atlas.
ditions
known
as intersex
conditions,
differences
or disorders
of THE START OF SEX
advice.
But that
createsbut
a self-perpetuating
them
themselves.
But by
the late
1990s,
rea-decisions
Researchers
ideallyThat
should
check
that
sex
development
(DSDs)
often
face
difficult
about whether
the two
sexes
arean
physically
different
is obvious,
at the start of life,
antibody
hassay
been
use
in weeks
particular
companies
hadas
started
to atake
the
problem, inawhich
antibodtogent
bring
up their child
a boy or
girl.over
Some
researchers
now
thattested
it isfor
not.
Five
into development,
humanbetter-performing
embryo has the potential
and tissuetotypes,
quality
aschore.
many as 1 person in 100 has some form of DSD2applications
ies that
become
available
later are rarely
used,
.
form but
boththe
male
and female
anatomy.
Next
to the developing
kidneys,
of information
bybulges
vendors
can vary
When
genetics
is taken
consideration,
the boundary
betweensupplied
the two
Today,
more than
300into
companies
sell over
says Fridtjof
proteomics
known
as the gonadal
ridges Lund-Johansen,
emerge alongsideatwo
pairs of
SEX
REDEFINED
ANTIBODIES
ARE NOT
MAGIC
REAGENTS.
2 8 8NATURE
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ILLUSTRATION BY JONNY WAN
ducts, one of which can form the uterus and Fallopian tubes, and the other
the male internal genital plumbing: the epididymes, vas deferentia and
seminal vesicles. At six weeks, the gonad switches on the developmental
pathway to become an ovary or a testis. If a testis develops, it secretes
testosterone, which supports the development of the male ducts. It also
makes other hormones that force the presumptive uterus and Fallopian
tubes to shrink away. If the gonad becomes an ovary, it makes oestrogen,
and the lack of testosterone causes the male plumbing to wither. The sex
hormones also dictate the development of the external genitalia, and they
come into play once more at puberty, triggering the development of secondary sexual characteristics such as breasts or facial hair.
Changes to any of these processes can have dramatic effects on an
individuals sex. Gene mutations affecting gonad development can
result in a person with XY chromosomes developing typically female
characteristics, whereas alterations in hormone signalling can cause XX
individuals to develop along male lines.
For many years, scientists believed that female development was the
default programme, and that male development was actively switched
on by the presence of a particular gene on the Y chromosome. In 1990,
researchers made headlines when they uncovered the identity of this
gene3,4, which they called SRY. Just by itself, this gene can switch the
gonad from ovarian to testicular development. For example, XX individuals who carry a fragment of the Y chromosome that contains SRY
develop as males.
By the turn of the millennium, however, the idea
of femaleness being a passive default option had
NATURE.COM
been toppled by the discovery of genes that actively For a podcast on the
promote ovarian development and suppress the tes- sex spectrum, see:
ticular programme such as one called WNT4. go.nature.com/xowzq5
8
XY individuals with extra copies of this gene can develop atypical genitals and gonads, and a rudimentary uterus and Fallopian tubes5. In 2011,
researchers showed6 that if another key ovarian gene, RSPO1, is not working normally, it causes XX people to develop an ovotestis a gonad with
areas of both ovarian and testicular development.
These discoveries have pointed to a complex process of sex determination, in which the identity of the gonad emerges from a contest between
two opposing networks of gene activity. Changes in the activity or
amounts of molecules (such as WNT4) in the networks can tip the balance
towards or away from the sex seemingly spelled out by the chromosomes.
It has been, in a sense, a philosophical change in our way of looking at
sex; that its a balance, says Eric Vilain, a clinician and the director of
the Center for Gender-Based Biology at the University of California, Los
Angeles. Its more of a systems-biology view of the world of sex.
BATTLE OF THE SEXES
According to some scientists, that balance can shift long after development is over. Studies in mice suggest that the gonad teeters between being
male and female throughout life, its identity requiring constant maintenance. In 2009, researchers reported7 deactivating an ovarian gene called
Foxl2 in adult female mice; they found that the granulosa cells that support
the development of eggs transformed into Sertoli cells, which support
sperm development. Two years later, a separate team showed8 the opposite: that inactivating a gene called Dmrt1 could turn adult testicular cells
into ovarian ones. That was the big shock, the fact that it was going on
post-natally, says Vincent Harley, a geneticist who studies gonad development at the MIMR-PHI Institute for Medical Research in Melbourne.
The gonad is not the only source of diversity in sex. A number of DSDs
are caused by changes in the machinery that responds to hormonal
1 NATURE
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THE SEX SPECTRUM
analysis1 showing that results in 47 of 53 land- 2million antibodies for research. As of 2011, tremendously. A common complaint from scimale
variations
DSD
mark cancer research papers could not be theTypical
market
was worth Subtle
$1.6 billion,
according to Moderate
entists isvariations
that companies46,XY
do not
provide the data
reproduced.
required to evaluate a given antibodys specificXY
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scientists
burned by
ity or its lot-to-lot variability. Companies might
A typical
male
has XY who have been
Chromosomes
chromosomes,
and a with
typical
Testes
Testes
Testes
bad experiences
antibodies have begun to DEVASTATING
EFFECTSTestes
ship a batch of antibodies
with characterization
female has XX. But owing to
Gonads
speak
up.
Rimms
disappointment
set
him
on
a
There
are
signs
that
problems
with
antibodies
information
derived
from
a previous batch.
Often
ambiguous
Male
internal
and
Male
internal
Male
external
genetic variation or chance
Genitals
genitals
external
withdata are often derived under ideal concrusade
to educatesome
others by writing
reviews, areand
having
broad andexternal
potentially
devastating genitals
And the
events
in development,
The hormonal disorder
genitals
people
do not
fit seminars
neatly into and raising the problem
hosting
web
effects
on the research
record.
In 2009, one anatomical
ditions that do not reflect
typicalMllerian
experiments.
Other
persistent
Subtle
differences
variations such as
either category. Some are
characteristics/
Male devoted an entire
duct syndrome
results
in countless
journal
assessing the urethral
Antibody
companies
contacted
for this
article
such issue
as lowto
sperm
opening
on
classed
as havingconference
differences ortalks. He and others
examples
in male
external
secondary that are used
production.
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of it
penis.
are calling
the creation of standards
by antibodies
to study
G-protein- underside
said that
is impossible
to test
their products
disorders
of sex for
development
sexual
genitals
and
testes,
caused by variation
(DSDs),
in antibodies
which their sex
which
should be made, used and coupled
receptors (GPCRs)
cell-signalling Affects
across
all experimentalbut
conditions,
butand
they do
characteristics
also a womb
in sex-development
1 in
chromosomes do not match
Fallopian
genes.
described.
And
some
half
a
dozen
grass-roots
proteins
that
are
targeted
by drugs to treat vari- 250400
provide
reliable data and
worktubes.
with scientists
births.
their sexual anatomy.
efforts have sprung up to provide better ways ous disorders, from incontinence to schizo- to improve antibody quality and performance.
Butfrom
it is too
toand
callother
the cause
a moveantibodies
19 signalling
optimizing
search
canissometimes
signals
the soon
gonads
glands.
Completeavailable
androgen
insensi- thatistargeted
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typical male,sobut
if most cells
are X,results
the result
a female
ment.
There are
thesefor
resources
out
there,
to more
than onecalled
pro- Turners
matter more
to a company
the
tivity
syndrome,
orall
CAIS,
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cellsbound
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tendsoptimizing
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butto
nobody
uses
them andusually
many people
arent
tein, meaning
that theyrestricted
could not height
be trusted
actual reagents,
says Tim
head of the
deaf
male sex
hormones,
because
the receptors
that respond
andto
underdeveloped
ovaries.
This Bernard,
kind of mosaicism
rare, affecting about 1 inbiotechnology
15,000 people.consultancy Pivotal Scientific
aware of them,
says
Len Freedman,
who CAIS
distinguish
between theisreceptors.
toeven
the hormones
are not
working.
People with
have Ychromoheadsand
theinternal
Global Biological
Instiof epigenetics
relies
heavilyofonsex-chromosome
anti- in Upper mosaicism
Heyford, UK.
Christi
Frost &
somes
testes, but Standards
their external
genitaliaThe
arefield
female,
and
The effects
range
fromBird,
the aprosaic
tute,
a non-profit
group
in Washington DC bodies to identify howto
proteins
that regulateA few
Sullivan
based
in Washington
DC, says
they
develop
as females
at puberty.
the extraordinary.
cases analyst
have been
documented
in which
a
committed
improving
biomedical
research.
gene
expression
have been
modified.
2011, anbecame
thataresearchers
are types
often
more
interested
Conditionsto
such
as these meet
the medical
definition
of DSDs,
in which
mosaic
XXYIn
embryo
mix of two cell
some
with twoin
vendors
have no incentive
of 246 antibodies
used in epigenetic
reagents
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thaninin
anMost
individuals
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sex seems to
to change
be at odds evaluation
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withquickly
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a Y can
andbethen
split early
whats
on right
now,
even
a lot of about
studies
found
failed12.tests
searching
for antibodies
with appropriate
somal
orgoing
gonadal
sex. But
they
arethough
rare affecting
1 in
4,500that
peo-one-quarter
development
Thisfor
results
in identical
twins of different
sexes. vali9
specificity,
meaning
they often
boundway
to indation
is a second
whichdata.
a person
canAmazon
end up with
dif- it
the
antibody
reagentsnow
suck.
that the definition should
Its the
effect:cells
theyofwant
ple
. Some
researchers
say
be widened
to that There
more than in
one
target.ferent
Four chromosomal
antibodies were
two orpatient
three days,
free shipping.
include subtle variations of anatomy such as mild hypospadias,
which
sexes.in
Jamess
was awith
chimaera:
a person who
BUYERurethral
BEWAREopening is on the underside of his penis
perfectly
to the wrong
Researchers
whousually
are aware
of the
a mans
ratherspecific
than at the butdevelops
fromtarget.
a mixture of two
fertilized eggs,
owing
to aantibody
merger
Take
example
of Ioannis
Prassas,
a proteoScientists
know,between
anecdotally,
that some
problem
say This
that kind
scientists
need to be
more
tip.
Thethe
most
inclusive
definitions
point
to the figure of
1 in 100often
people
embryonic
twins in
the womb.
of chimaerism
resultmics some
researcher
atDSD,
Mount
Hospital
antibodies in their field
are
but rare,
vigilant.
Antibodies
are1%
not
reagents.
having
form of
saysSinai
Vilain
(see Theinsex spectrum).
ing
inproblematic,
a DSD is extremely
representing
about
ofmagic
all DSD
cases.
Toronto,
Canada.
He and
hisbecolleagues
But beyond
this, there
could
even morehad
variation.
Since
thedifficult
1990s, to gauge
it has
been
the form
size of
You cant
just throw
themknown
on yourtosample
and
Another
ofthe
chimaerism,
however,
is now
be wideproblem
acrossand
biology
as a whole.
Perhaps
spread.
Termed
microchimaerism,
happens
stem reliable
cells from
a
been chasing
called
CUZD1,
expect theitresult
you when
get is 100%
withresearchers
havea protein
identified
more
than 25which
genes involved
in DSDs,
they thought could
be used to in
testthe
whether
the largest
assessment
fromthe
work
pub-intoout
some
critical
thinking
says
next-generation
DNA sequencing
past few years
has uncovered
a comes
fetus cross
placenta
theputting
mothers
body,
and vice
versa. into
It wasit,first
someone
has
pancreatic
cancer.
They
Human Protein
Atlas,
a Swedish
Trimmer,
head of NeuroMab
thetwo
Uniwide
range of
variations
in these
genes
thatbought
have mildlished
effectsby
onthe
individuidentified
in the
early 1970sJames
but
the big surprise
came more at
than
a protein-detection
and wasted
two years,
consortium that aims to generate antibodies decades
versitylater,
of California,
Davis, which
makeshow
antials,
rather than causingkitDSDs.
Biologically,
its
when researchers
discovered
a spectrum,
saysthousands
Vilain.
$500,000 and
of patient samples
bodies
neuroscience.
Like many
long
thesefor
crossover
cells survive,
evensuppliers,
though
before
realized
that adrenal
the antibody
in the
NeuroMab
explicitly
states
types
of experiA DSDthey
called
congenital
hyperplasia
they
are foreign
tissue that
thethe
body
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in
kit wasfor
recognizing
a different
cancer
protein,
mentreject.
that an
should
be used
for, but
(CAH),
example, causes
the body
to produce
theory,
Aantibody
study in 1996
recorded
women
2
CA125, and
did not
at allXX
. In
scientists
doin
not
always
follow
the instructions.
excessive
amounts
of bind
male to
sexCUZD1
hormones;
with
fetal cells
their
blood
as many
as 27 years
13
individuals
thissays,
condition
born
with
retrospect,with
Prassas
a rush are
to get
going
on
researchers
would
refuse
buy antiafter Ideally,
giving birth
; another
found
thattomaternal
ambiguous
genitalia
(an enlarged
clitoris
a promising
hypothesis
meant that
he andand
his
bodies
without
extensive
validation14dataor
cells
remain
in children
up to adulthood
. This
would
perform
the validation
group
had
failed
to doa scrotum).
all the right
If
fused
labia
that
resemble
It istests.
usually
type
of work
has further
blurred the themselves
sex divide,
someone
says, Here
is anin
assay
you can
use,
(see Bad
antibodies).
something
that
caused
by a severe
deficiency
an enzyme
called
because
it means
that menThis
ofteniscarry
cells from
you are so eager
test it you
can forget
that
Rimm
is passionate
about:
hasbeen
developed
21-hydroxylase.
Buttowomen
carrying
mutations
their
mothers,
and women
whohe
have
pregwhat
hasin
been
promised
is notdevelop
the case.anona multistep
flowchart
forcarry
effective
validation
that
result
a milder
deficiency
nant
with a male
fetus can
a smattering
of 6,
Mostform
scientists
who
purchase
antibodhe shares
classical
of CAH,
which
affects about
1 in
itswhich
discarded
cells. with anyone who will listen.
ies believe
the label
printed
the vial,facial
says
But the process iscells
timehave
consuming
Rimm
1,000
individuals;
they may
haveon
male-like
Microchimaeric
been found
in
Rimm.
As irregular
a pathologist,
wasnt
trained
recommends
experiments
that involve
and
body hair,
periodsIor
fertility
probmany
tissues. Incontrol
2012, for
example, immunolothat
you
validate
was just at all. Another gene, gist Lee Nelson and her team
engineering
cell lines
both express
stop
lems
or had
theyto
might
haveantibodies;
no obviousI symptoms
at the University
ofto
Washington
inand
Seattle
trainedisthat
you ordered
them.
expressing
theofprotein
of interest,
NR5A1,
currently
fascinating
researchers
because variations in it cause a found XY cells in post-mortem
samples
womens
brains15. for
Theexample.
oldest
are10produced
by the immune
every
protein in thewoman
humancarrying
genome.male
It hasDNA
Even
few labs
perwideAntibodies
range of effects
, from underdeveloped
gonads for
to mild
hypospadias
washe
94 acknowledges
years old. Otherthat
studies
havewill
shown
of most
vertebrates
to target
invader looked at some 20,000that
commercial
antibodform
thethey
steps.
insystems
men, and
premature
menopause
in an
women.
these immigrant
cells are
notall
idle;
integrate into their new envisuch
a bacterium.
Since the
1970s,
scien-unless
iesthey
so far
andhelp
found
less than
50%
can be
Somefunctions,
scientistsincluding
buy half (in
a dozen
antibodManyaspeople
never discover
their
condition
seek
for that
ronment
and
acquire
specialized
mice at
least)
tists haveorexploited
for research.
If used
effectivelyLast
to lookforming
at protein
distribution
ies16from
different
run a few
infertility,
discoverantibodies
it through some
other brush
with medicine.
neurons
in the brain
. But what
is notvendors,
known isand
howthen
a peppering
5
a researcher
injects
a protein
of interest
intohad been
in preserved
slices
. This
has
some or assays
to see
which
best. But they
year,
for example,
surgeons
reported
that they
operating
on of
a tissue
of male
cells
inled
a female,
vice versa,
affects
the performs
health or characteristics
11
a rabbit,
bloodthey
cells
known asthat
B cells
may enditup
buying
same
antibody
from
hernia
in a white
man, when
discovered
he had scientists
a womb .to
claim
to halfoffor
allexample,
com- whether
The
manthatofup
a tissue
makes
thethe
tissue
more
susceptible
will
against the mercially available antibodies
was
70,start
and producing
had fatheredantibodies
four children.
are more
unreliable.
different
places.
The
largest
vendors
compete
to diseases
common in
the opposite
sex.
I think
thats
a great
quesprotein, which can be collected from the aniBut reliability can depend
theNelson,
experiment.
catalogue
size, sounaddressed.
they often buy
tion,on
says
and it ison
essentially
entirely
Inantibodies
terms of
human behaviour,
the consensus
is that asuppliers,
few male micro
mals blood.
antibodies
from smaller
relabelchimaeric
them andcells
offer
CELLULAR
SEXFor a more consistent product, the Our experience with commercial
the in
brain
seem
unlikely to
havefor
a major
effect onsays
a woman.
Bcellsof
can
be retrieved,
fused
immoris that they
usuallyin
okay
some
applicathem
sale. Bernard
that the 2million
Studies
DSDs
have shown
thatwith
sex an
is no
simple dichotomy.
Butare
things
talizedeven
cell and
cultured
to provide
a theoretithey
in others,
says
antibodies
probably
represent
become
more
complex
when scientists
zoomtions,
in tobut
look
at might
indi- be terrible
Scientists
are now
finding
that XX on
andthe
XYmarket
cells behave
in different
cally cells.
unlimited
supply. assumption that every cell
Mathias
Uhln
at the Royal
Techunique
antibodies.
vidual
The common
contains
the same
ways,Institute
and thatof
this
can be 250,000500,000
independent of the
actioncore
of sex
hormones.
Three
ago,
scientists
in Stockholm,
who
theits actually
By necessity,
many researchers
set of
genesdecades
is untrue.
Some
peoplewho
haveneeded
mosaicism:nology
they develop
from To
tellcoordinates
you the truth,
kind of surprising
how big anrely
effecton
mouth
orthe
published
for
for their
to make of Human
Protein
Atlas. of sex chromosomes weveword
a antibodies
single fertilized
eggexperiments
but become had
a patchwork
cells with
different
beenofable
to see,
says
Arnold. literature
He and his
advice.
But of
that
creates a self-perpetuating
them themselves.
Butcan
by the
late 1990s,
reaResearchers
ideallycolleagues
should check
an 17 that
genetic
make-ups. This
happen
when sex
chromosomes
are doled
havethat
shown
the dose
X chromosomes
in a mouses
18
antibody has
been tested
forcan
use affect
in particular
gent
companies
had dividing
started to
take
over the
problem,
whichin
better-performing
out
unevenly
between
cells
during
early embryonic
developbody
its metabolism,
andinstudies
a lab dish suggestantibodthat
tissueXX
types,
chore.
ies that become
available later
used,
ment.
For example, an embryo that starts off as XYapplications
can lose a Yand
chroandbut
XYthe
cellsquality
behave differently
on a molecular
level,are
forrarely
example
supplied
by different
vendors can
vary responses
Today,
more
than 300
sellcells
overendof
says Fridtjof
Lund-Johansen,
a proteomics
mosome
from
a subset
of itscompanies
cells. If most
upinformation
as XY, the result
with
metabolic
to stress.
The next challenge,
says
SURGEONS
ANTIBODIES
DISCOVERED THAT THE
ARE
NOT
MAN HAD A WOMB.
MAGIC
HE WAS 70.
REAGENTS.
2 9 0NATURE
| N A T COLLECTIONS
8 | 1 9 F ESUMMER
B R U A R READS
Y 2015
2 1 M A Y 2 0 1 5 | V O L 5 2 1 | N A T U R E | 2 79 5
NEWS FEATURE
FEATURE NEWS
SEX
REDEFINED
Chromosomes
Ovotesticular DSD
46,XX testicular DSD
Moderate variations
Subtle variations
Typical female
XX, XY or mix of both
XX
XX
XX
XX
Small testes
Ovaries
Ovaries
Ovaries
Female internal and

external genitals
Female internal and

external genitals
Variations in sex
development such as
premature shutdown of
ovaries. Some caused
by variation in
sex-development genes.
Subtle differences
such as excess male
sex hormones or
polycystic ovaries.
Female internal
and external
genitals
Gonads
Both ovarian and

testicular tissue
Genitals
Ambiguous
Other
characteristics/
examples
Rare reports of
predominantly XY
people conceiving
and bearing a
healthy child.
Male external
genitals
Usually caused by
presence of male
sex-determining
gene SRY.

Arnold, is to uncover the mechanisms. His team is studying the handful

of X-chromosome genes now known to be more active in females than
in males. I actually think that there are more sex differences than we
know of, says Arnold.
BEYOND THE BINARY
Biologists may have been building a more nuanced view of sex, but society has yet to catch up. True, more than half a century of activism from
members of the lesbian, gay, bisexual and transgender community has
softened social attitudes to sexual orientation and gender. Many societies are now comfortable with men and women crossing conventional
societal boundaries in their choice of appearance, career and sexual
partner. But when it comes to sex, there is still intense social pressure to
conform to the binary model.
This pressure has meant that people born with clear DSDs often
undergo surgery to normalize their genitals. Such surgery is controversial because it is usually performed on babies, who are too young
to consent, and risks assigning a sex at odds with the childs ultimate
gender identity their sense of their own gender. Intersex advocacy
groups have therefore argued that doctors and parents should at least
wait until a child is old enough to communicate their gender identity,
which typically manifests around the age of three, or old enough to
decide whether they want surgery at all.
B Y CThis
L A I Rissue
E A I Nwas
S W Obrought
R T H into focus by a lawsuit filed in South Carolina
in May 2013 by the adoptive parents of a child known as MC, who
a clinical
PaulDSD,
Jamesaiscondition
accustomed
discussing
some
wassborn
withgeneticist,
ovotesticular
thattoproduces
ambiguthe most
delicate
with ovarian
his patients.
But in early
2010,
he
ousof
genitalia
and
gonadsissues
with both
and testicular
tissue.
When
having
a particularly
awkward
conversation
about
MCfound
was 16himself
months
old, doctors
performed
surgery
to assign the
child
sex. but MC, who is now eight years old, went on to develop a
as female
A 46-year-old
pregnant
woman
had
hisatclinic
at the
Royal
male
gender identity.
Because
he was
in visited
state care
the time
of his
treatMelbourne
Hospitalalleged
in Australia
to hear
an amniocentesis
ment, the lawsuit
not only
that the results
surgeryofconstituted
medical
test
to screen her
chromosomes
for abnormalities.
The baby
wasto
malpractice,
butbabys
also that
the state denied
him his constitutional
right
fine
but
follow-up
tests
hadtorevealed
something
astonishing
about
bodily
integrity
and his
right
reproduce.
Last month,
a court decision
the
mother.the
Herfederal
bodycase
was from
built going
of cells
twoa individuals,
probprevented
to from
trial, but
state case is ongoing.
ablyThis
from is
twin
embryosa that
had merged
in her
own mothers
womb.
potentially
critically
important
decision
for children
born
And
was traits,
more. says
OneJulie
set ofGreenberg,
cells carried
two X chromosomes,
the
withthere
intersex
a specialist
in legal issues relatcomplement
that
makes aJefferson
person female;
theLaw
other
had Diego,
an X
ing to gender
andtypically
sex at Thomas
School of
in San
and
a Y. Halfway
through
her fifth encourage
decade anddoctors
pregnant
with
her third
California.
The suit
will hopefully
in the
United
States
child,
the woman
learned foroperations
the first time
that a large
ofwhen
her body
to refrain
from performing
on infants
withpart
DSDs
there
was
. Thatsnecessity,
kind of science-fiction
material
for
arechromosomally
questions about male
their 1medical
she says. It could
raise awaresomeone
whothe
justemotional
came in forand
an amniocentesis,
says
James. people are
ness about
physical struggles
intersex
Sex can
muchbecause
more complicated
thantoithelp
at first
According
to
forced
tobe
endure
doctors wanted
usseems.
fit in, says
Georgiann
the
simple
scenario, the
presence
absence
of a Y chromosome
is what
Davis,
a sociologist
who
studiesorissues
surrounding
intersex traits
and
counts:
you are male,
and without
it, you
are
female.
But docgenderwith
at theit,University
of Nevada,
Las Vegas,
who
was
born with
CAIS.
torsDoctors
have long
known
that are
some
people straddle
theconcerns,
boundary
the
their
and
scientists
sympathetic
to these
but
MC
sex
chromosomes
say one
thing,
their they
gonads
(ovaries
or testes)
orto
case
also makes some
uneasy
but
because
know
how much
is still
sexual
anatomy
say the
another.
Parents
withthat
thesechanging
kinds of mediconbe learned
about
biology
of sexof19children
. They think
ditions
known
as intersex
or differences
disorders
of
cal practice
by legal
ruling isconditions,
not ideal, and
would like or
to see
more data
sex
development
(DSDs)such
often
face difficult
decisions
whether
collected
on outcomes
as quality
of life and
sexual about
function
to help
todecide
bring up
child asofaaction
boy orfor
a girl.
Some
researchers
now say that
thetheir
best course
people
with
DSDs something
that
asresearchers
many as 1 person
in 100tohas
are starting
do.some form of DSD2.
When
geneticsofisDSDs
taken into
consideration,
the boundary
the
Diagnoses
once
relied on hormone
tests,between
anatomical
210
Female
secondary
sexual
characteristics
inspections and imaging, followed by painstaking tests of one gene at a

time. Now, advances in genetic techniques mean that teams can analyse
multiple genes at once, aiming straight for a genetic diagnosis and making the process less stressful for families. Vilain, for example, is using
whole-exome sequencing which sequences the protein-coding regions
of a persons entire genome on XY people with DSDs. Last year, his
team showed20 that exome sequencing could offer a probable diagnosis
in 35% of the study participants whose genetic cause had been unknown.
Vilain, Harley and Achermann say that doctors are taking an increasingly circumspect attitude to genital surgery. Children with DSDs are
treated by multidisciplinary teams that aim to tailor management and
support to each individual and their family, but this usually involves raising a child as male or female even if no surgery is done. Scientists and
advocacy groups mostly agree on this, says Vilain: It might be difficult
for children to be raised in a gender that just does not exist out there. In
most countries, it is legally impossible to be anything but male or female.
Yet if biologists continue to show that sex is a spectrum, then society
and state will have to grapple with the consequences, and work out
where and how to draw the line. Many transgender and intersex activists
dream of a world where a persons sex or gender is irrelevant. Although
some governments are moving in this direction, Greenberg is pessimistic about the prospects of realizing this dream in the United States, at
least. I think to get rid of gender markers altogether or to allow a third,
sexes
becomes even
blurrier.
Scientists
identified
many of the genes
indeterminate
marker,
is going
to behave
difficult.
So if the
lawmain
requires
thatofaDSD,
person
is male
or female, should
thatin
sex
involved
in the
forms
and
have uncovered
variations
these
genes thatbyhave
subtle effects
on a persons
or physiologibe assigned
anatomy,
hormones,
cells oranatomical
chromosomes,
and what
calshould
sex. Whats
more,
newclash?
technologies
in DNA
sequencing
and cell
biolbe done
if they
My feeling
is that
since there
is not
one
ogy
are revealing
that almost
everyone
to varying
a patchwork
biological
parameter
that takes
overis,every
other degrees,
parameter,
at the end
ofofgenetically
distinct
cells, some
with
a sex
might
not match
that of
the day, gender
identity
seems
to be
thethat
most
reasonable
parameter,
the
restVilain.
of theirInbody.
studies
suggest
thatwhether
the sex ofsomeone
each cellis
says
otherSome
words,
if youeven
want
to know
drives
through
a complicated
maleits
orbehaviour,
female, it may
be best
just to ask. network of molecular interactions. I think theres much greater diversity within male or female,
and
thereAinsworth
is certainlyisan
area of overlap
some
people cant
Claire
a freelance
writer where
based in
Hampshire,
UK.easily
define themselves within the binary structure, says John Achermann,
1. James, P. A., Rose, K., Francis, D. & Norris, F. Am. J. Med. Genet. A 155, 2484
who2488
studies
sex development and endocrinology at University College
(2011).
Londons
Institute
of ChildD.Health.
2. Arboleda,
V. A., Sandberg,
E. & Vilain, E. Nature Rev. Endocrinol. 10, 603615
(2014).
These
discoveries do not sit well in a world in which sex is still defined
Sinclair, A. H. et al. Nature 346, 240244 (1990).
in3.
Few legal
4.binary
Berta, terms.
P. et al. Nature
348, systems
448450 allow
(1990).for any ambiguity in biological
sex,
a persons
rights
social
status can(2001).
be heavily influenced
5. and
Jordan,
B. K. et al.legal
Am. J.
Hum. and
Genet.
68, 11021109
Tomaselli,their
S. et al.
PLoScertificate
ONE 6, e16366
by6.whether
birth
says(2011).
male or female.
7. Uhlenhaut, N. H. et al. Cell 139, 11301142 (2009).
The main problem with a strong dichotomy is that there are inter8. Matson, C. K. et al. Nature 476, 101104 (2011).
mediate
cases
push
the limits
to figure out exactly
where
9. Hughes,
I. A.,that
Houk,
C., Ahmed,
S. F.,and
Lee, ask
P. A. us
& LWPES1/ESPE2
Consensus
Group Arch.
Dis.isChild.
91, 554563
the dividing
line
between
males (2006).
and females, says Arthur Arnold at
10. El-Khairi, R. & Achermann, J. C. Semin. Reprod. Med. 30, 374381 (2012).
the
University of California, Los Angeles, who studies biological sex
11. Sherwani, A. Y. et al. Int. J. Surg. Case Rep. 5, 12851287 (2014).
differences.
thatsReprod.
often 29,
a very
difficult(2014).
problem, because sex can
12. Tachon, G.And
et al. Hum.
28142820
Bianchi,aD.number
W., Zickwolf,
G. K., Weil,
be13.
defined
of ways.
G. J., Sylvester, S. & DeMaria, M. A. Proc. Natl
Acad. Sci. USA 93, 705708 (1996).
14. Maloney, S. et al. J. Clin. Invest. 104, 4147 (1999).
THE
OFF. SEX
15.START
Chan, W.
N. et al. PLoS ONE 7, e45592 (2012).
16. Zeng,
X. X.sexes
et al. Stem
Cells Dev. 19,
18191830
(2010. but at the start of life,
That
the two
are physically
different
is obvious,
Link,Five
J. C., weeks
Chen, X.,
Arnold,
A. P. & Reue,aK.human
Adipocyte
2, 7479
(2013).
it 17.
is not.
into
development,
embryo
has
the potential
18. Penaloza, C. et al. FASEB J. 23, 18691879 (2009).
to19.
form
both
male
and2,female
anatomy.
Warne,
G. L.
Sex Dev.
268277
(2008). Next to the developing kidneys,
two
the Endocrinol.
gonadal ridges
emerge
alongside
two pairs of
20.bulges
Baxter, R.known
M. et al.as
J. Clin.
Metab. 100,
E333E344
(2014).
1NATURE
V O L 5 1 8SUMMER
| N A T UREADS
RE | 291
FEATURE NEWS
NEWS FEATURE
reproduced.
DEVASTATING EFFECTS
BUYER BEWARE
mics researcher at Mount Sinai Hospital in antibodies in their field are
Antibodies are not magic reagents.
Theproblematic,
Youngs andbut
othervigilant.
Pluto researchers
Leslie and Eliot Young have gauge
Toronto, Canada. He and his colleagues had it has been difficult towill
the sizeupofover
thetheYou
just throw
be gearing
nextcant
few months
as them on your sample and
problem
across biology
as aHorizons
whole. Perhaps
been chasing a proteinspent
called CUZD1,
which
expect
the result
you get is 100% reliable withNew
finally nears
its quarry,
4.8biltheir
lives
studying
they thought could be used to test whether the largest assessment comes
from work
pubputting some
critical thinking into it, says
kilometres
from
Earth.out
A telescope
on the
Pluto. Now they are gearing lion
someone has pancreatic cancer. They bought lished by the Human Protein
Atlas,
a Swedish
James
Trimmer,
head of NeuroMab at the Unispacecraft
has
already begun
capturing
fuzzy
a protein-detection kitup
and wasted
two years,
consortium
thatof
aims to
generate
antibodies
of California,
pictures
of Pluto,
which willversity
grow sharper
as the Davis, which makes antifor the
biggest
event
$500,000 and thousands of patient samples
bodies
for neuroscience.
Like many suppliers,
probe closes in. And when New
Horizons
passes
their careers.
NeuroMab
explicitly
within 12,500 kilometres of
Pluto on 14July,
it states the types of experikit was recognizing a different cancer protein,
ment
anworlds
antibody should be used for, but
will provide the first close-up
lookthat
at the
scientists
always follow the instructions.
icy surface, and the best chance
yetdo
to not
answer
Ideally,ofresearchers
major questions about the evolution
the outer would refuse to buy antia promising hypothesis meant that he and his B Y A L E X A N D R A W I T Z E Solar System.(see page 468).
wouldmilestone
perform the
The fly-by will mark a major
in validation themselves
someone says, Here is an assay you can use, n a spare conference both the personal and the(see
professional
lives This is something that
Bad antibodies).
you are so eager to test it you can forget that room in Boulder, Colo- of the Youngs, who occupy
adjoining
offices about: he has developed
Rimm
is passionate
Institute in
Boul- for effective validation6,
flowchart
rado, planetary scientists at the Southwest Researcha multistep
of a century,
their
Most scientists who purchase antibod- Leslie and Eliot Young der. Over the past quarterwhich
he shares
with anyone who will listen.
ies believe the label printed on the vial, says quiz a graduate stu- careers have intersected with
But Pluto
the process
scienceisattime consuming Rimm
Rimm. As a pathologist, I wasnt trained dent to prepare him for key points, from helping torecommends
discover the control
dwarf experiments that involve
that you had to validate antibodies; I was just his upcoming exams. planets atmosphere to making
engineering
cellfirst
lines to both express and stop
some of the
They take their task detailed maps of its enigmatic
expressing
theWhatprotein of interest, for example.
surface.
Antibodies are produced
by interrupting
the immuneoftenfor
protein
in theever
human
It has
Even
hewill
acknowledges
that few labs will perseriously,
as every
he answers
quesNewgenome.
Horizons
finds this
year
build in
systems of most vertebrates
targetPluto
an invader
looked
at some
20,000large
commercial
antibodall the steps.
tionstoabout
and Neptunes
moon
Triton.
part on work
done byform
the siblings.
Leslie
technical ies
comment
about
the that less
such as a bacterium. Since
themakes
1970s,ascienso far and
found
thanhad
50%some
can be
Some how
scientists
Weve
ideas about
Plutobuy half a dozen antibodfor distribution
decades now,ies
says
Eliot.
Well
tists have exploited antibodies
for research.
If distant
used effectively
to lookworks
at protein
from
different
vendors, and then run a few
light reflecting
off those
worlds. Then,
5
a researcher injects a protein
of interest
into and
in Triton
preserved
slices
. This
someare right.
assays
Eliot notes
that Pluto
may
haveof tissue
finally
findhas
outled
if they
to see which performs best. But they
a rabbit, white blood cells
known
as Bsimilar
cells toscientists
started
out very
one another
in thethat up to half of all com- may end up buying the same antibody from
to claim
will start producing antibodies
the mercially
early Solar against
System before
evolving down
dif-antibodies
available
unreliable.
FAMILY are
ORBIT
protein, which can be collected
from
the
ani- caseBut
can depend
on Eliot
the experiment.
on catalogue
so they often buy antibodies
ferent paths.
Its
a classic
of reliability
nature versus
When
and Leslie were
growingsize,
up in
Newton, Massachusetts,
life revolved
mals blood. For a morenurture,
consistent
the areOur
experience
with commercial
antibodies family
from smaller
suppliers, relabel them and offer
heproduct,
says. They
siblings.
Bcells can be retrieved, fused

with are
an immoris that
usuallyaround
okay intheir
somefather,
applicafora sale.
Bernard says that the 2million
So, too,
the Youngs.
Eliotthey
andare
Leslie
Larry them
Young,
legendary
grew
up as the
oldest children
of they
an astrotalized cell and cultured
to provide
a theoretitions, but
might beresearcher
terrible in others,
says antibodies
on theof
market probably represent
at theMassachusetts
Institute
cally unlimited supply. nautics researcher, and their
Mathias
Uhln
at the Royal
Institute
of Tech250,000500,000
unique core antibodies.
mutual
interests
Technology
(MIT)
in Cambridge.
Young speThree decades ago, scientists
needed
nology
in Stockholm,
who coordinates
the effects
By of
necessity,
many researchers rely on
convergedwho
on one
dwarf planet.
They
are the cializes
in the biological
weightlessword
mouth
or the published literature for
antibodies for their experiments
had to make
Human
Protein
Atlas. ness, and he trained to fly on
only brothersister
Pluto team
in the
Solar Systheofspace
shuttle
advice.
them themselves. But tem,
by the
lateAlan
1990s,
rea-a planetary
Researchers
should check
thatwent
an into
says
Stern,
scientist ideally
and although
he never
orbit. But
Eliot,that
Leslie
antibody
been tested
useyounger
in particular
gent companies had started
to take
over the
in which better-performing antibodprincipal
investigator
of NASAs
Newhas
Horizons
andfor
their
brother,problem,
Robert, sometimes
and tissueplayed
types,poker
but the
quality
chore.
ies that become available later are rarely used,
mission, which has beenapplications
hurtling towards
with
visiting astronauts.
of information supplied by
vendors
Larry
Youngcan
wasvary
also a passionate
skierLund-Johansen,
who
Today, more than 300
companies
sellnine
overyears.
says Fridtjof
a proteomics
Pluto
for the past
The Pluto
siblings
ANTIBODIES
ARE NOT
MAGIC
REAGENTS.
SUMMER
4 7 0NATURE
| N A T COLLECTIONS
8 | 26 FE
B R U A R READS
Y 2015
2 1 M A Y 2 0 1 5 | V O L 5 2 1 | N A T U R E | 2 11
75
NEWS FEATURE
FEATURE NEWS
SEX
REDEFINED
Leslie and Eliot
Young at the
SommersBausch
Observatory in
Boulder, Colorado.
BARRY GUTIERREZ

studied skiing injuries. On most winter week- object. And by noting whether the light dims spacecraft had visited Uranus in 1986, and
B Yends,
C L A Ihis
R E Afamily
I N S W Otook
R T H a long car trip to New abruptly or gradually, they
sexes
blurrier.
Scientists
haveitidentified
many
of the but
genes
canbecomes
deduce even
whether
three
years later
swept past
Neptune
did
involved
in the
main
forms
ofgo
DSD,
have
uncovered
variations
in
Hampshire that was filled with brain games and that object has an atmosphere.
Pluto
is so
small
not
nearand
Pluto.
Researchers
knew
little about
s a clinical
geneticist, Paul James is accustomed(about
to discussing
some
these
genes that
haveand
subtlethat
effects
on a persons
anatomical
or physiologichatter
about mathematics.
two-thirds
the size
of Earths
Moon)
world,
other than
that its surface
seemed
to be mostlyinice,
rather
than rock,
it was
of theismost
issues
his patients.
in early
2010, he
more,
new technologies
DNA
sequencing
andand
cell biolLarry
not delicate
surprised
thatwith
his two
oldest But
far away
(between
aboutcal
30sex.
andWhats
50 times
farther
accompanied
byvarying
a moon,
Charon,
which was
foundpursued
himself science,
having abut
particularly
conversation
aboutEarth
ogyis)are
revealing
that almost
everyone is, to
degrees,
a patchwork
children
he never awkward
imag- from
the Sun than
that
astronomers
techniquedistinct
they can
of genetically
cells,half
some
might
notitself.
match
that was
of
inedsex.
them both studying the same dwarf planet need to use every creative
thewith
sizeaofsex
thethat
dwarf
planet
(Pluto
A the
46-year-old
pregnant
woman
visited
clinicofattothe
Royal
the rest of their body. Somedemoted
studies even
that the
of each cell
in
distant reaches
of the
Solarhad
System.
I histhink
tease
out information.
fromsuggest
planet status
in sex
2006.)
think its the
closest
could
doing
Melbourne
Hospital
in they
Australia
toget
heartothe
results of an amniocentesis drives its behaviour, through Helped
a complicated
network
of molecular
interby her keen
coding
skills, Leslie
went
test
to screen
herand
babys
The baby was actions. I think theres much
male or female,
science
fiction
stillchromosomes
earn a living,for
heabnormalities.
says. SKYWATCH
on togreater
make adiversity
series of within
major discoveries
as part
fine
butended
follow-up
had revealed
somethingOne
astonishing
about
there
is certainly
an area
of overlap
where
some people
cantmethane
easily
(Robert
up intests
software
development.)
night in June
1988,and
several
members
of the
of the
MIT team,
including
spotting
2
define
themselves
within
binary structure,
says
John
Achermann,
the mother.
bodyofwas
built
of As
cells
from twoMIT
individuals,
probEliot feltHer
the pull
Pluto
first.
a gradugroup took
off from
Honolulu,
Hawaii,
in the
in Plutos
atmosphere
and
nitrogen
ice on
3
its surface
ably
twin
embryos
merged
in her own
womb. Observatory,
who studiesasex
development
and endocrinology
at University
College
ate from
student
at MIT
in thethat
latehad
1980s,
he worked
the mothers
Kuiper Airborne
telescope. If somebody
asks me whats
my
And
there
more.
of cells carried
two Xcarrying
chromosomes,
the flew
Londons
Institute
of Childfavourite
Health. colour, she says, I say 2.15 microns
with
Jim was
Elliot
and One
Ted set
Dunham,
who were
plane that
above the
obscuring
complement
that typically
makes a person
female;effects
the other
had anatmosphere.
X
TheseAstronomers
discoveries do
sitthe
wellwavelength
in a world in
sexabsorbed
is still defined
building instruments
for airborne
astronomy
of Earths
at not
ofwhich
the light
by the
frozen nitrogen
Plutos
surface.
and
a Y. Halfway
through
fifthPluto.
decade
and
withsuspected
her third thatinPluto
binaryhad
terms.
Few legal systems
allow foron
any
ambiguity
in biological
missions,
including
ones her
to study
But
hispregnant
the time
an atmoschild,
woman
for the
first time
that a large
partbut
of no
herone
body
sex, and
a persons
and
can be heavily
sister,the
three
yearslearned
his junior,
quickly
followed.
phere,
had ever
spotted
it. legal rightsIn
thesocial
yearsstatus
that followed,
Leslieinfluenced
developed
1
was
chromosomally
male
. Thats
kind
of science-fiction
fornotby
their
birth certificate
saysmodels
male ortofemale.
One
day, she stopped
in at
his lab to
show
him
Lesliematerial
Young was
yetwhether
a graduate
student,
computer
describe how the surface
someone
just came
in for
anhad
amniocentesis,
James.
problem
a strong
dichotomy
is that
thereBecause
are intera piece ofwho
computer
coding
she
done. Even says
but she
was on the plane toThe
helpmain
with the
meas- with
and
atmosphere
of Pluto
interact.
the
Sex canshe
be was
much
more
complicated than
it at first seems.
According
to mediate
casesthe
that
push theorbit
limits
ask usplanet
to figure
out exactlystretched
where
though
still
an undergraduate
at nearby
urements.
She distinctly
remembers
exciteof and
the dwarf
is extremely
the
simple scenario,
theJim
presence
or absence
of a Y chromosome
is what
the dividing
line is and
between
males
and
females, ellipse,
says Arthur
Arnold atof
Harvard
University,
Elliot was
impressed
ment as the stars
light dimmed
gradually,
out
in an
elongated
the amount
1
reachingwho
its surface
changes markcounts:
it, you
male,
and without
it, you are
female.
But doc-atmosphere
the University
of California,
Los Angeles,
studies biological
sex
enoughwith
to offer
herare
a job
working
on software.
Plutos
long-sought
was revealed
. sunlight
edlya very
throughout
Pluto because
year, which
lasts
torsThe
haveMIT
longteam
known
that someinpeople
straddle
boundary
their
differences.
And thats often
difficultthe
problem,
sex can
specialized
studying
dis- theThe
discovery,
supported
by ground-based
248Earth
years. When Plutos orbit carries it
sex
chromosomes
oneoccultations
thing, but their
gonads (ovaries
or testes)
be defined
a number
of ways.
tant
worlds usingsay
stellar
when
measurements
ofor
the same
occultation,
made
sexual
anatomy
say another.
children
these kindsheadlines.
of con- When her brother Rob- closer to the Sun, methane, nitrogen and other
an object
of interest
movesParents
betweenofEarth
andwithfront-page
ert asked
how it felt
rewritten
the text- ices on the surface sublimate and form a tenuditions
known star.
as intersex
or disorders
of to have
THE START
OF SEX
a background
By conditions, or differences
measuring
how
much often
sex
development
(DSDs)
face difficult decisions
about
whether
thegood,
two sexes
physically
different is obvious,
butone
at the
start of life,
NATURE.COM
books,
I told
him it feltThat
pretty
she are
says.
ous atmosphere,
roughly
millionth
the
thickness of
Earths.embryo
Some researchers
argue
tothe
bring
updims,
theirplanetary
child as a boyForormore
a girl.
say thata fuzzy
it isdot
not.on
Five
weeks
a human
has the potential
light
on Some
Pluto, researchers
Plutonow
remained
a map
ofinto
the development,
asscientists
many as 1can
person
in 100 hassee:
some form of DSD2outer
.
toas
form
both
maleplanand female
Nextfarther
to the developing
kidneys,
determine
Solar System, even
other
distant
thatanatomy.
as Pluto gets
away from the
Sun in
When
is taken intonature.com/pluto
consideration, the boundary
two bulges
as the gonadal
ridges
emerge
alongside
pairs of
the
sizegenetics
of the blocking
ets werebetween
coming the
into focus.
NASAsknown
Voyager2
the coming
years,
the gases
in thetwo
atmosphere
212
2NATURE
V O L 5 1 8SUMMER
| N A T UREADS
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FEATURE NEWS
1
analysis
showing
that
in 47 of
53 landwill
refreeze
and drop
toresults
the surface,
although
mark latest
cancer
research
papers
not be
Leslies
models
suggest
thatcould
the atmosreproduced.
phere
never completely disappears4.
5,6
Occultation
studies
A few scientists
who
have been
indicate
thatburned
the den-by
badofexperiences
with antibodies
have
begun to
sity
Plutos atmosphere
doubled
between
1988
and
anddisappointment
has stayed pretty
much
speak
up.2002
Rimms
set him
on a
crusadesince
to educate
others
byNew
writing
reviews,
constant
then. So
one of
Horizons
hosting
web
raising
major
goals
at seminars
Pluto is toand
unravel
thethe
icyproblem
interplay
between the
surface and
theHe
atmosphere.
in countless
conference
talks.
and others
which
antibodies should be made, used and
FACE
OF PLUTO
described.
Andwho
some
half
a dozen
The
big brother
got
Leslie
into grass-roots
Pluto has
efforts
sprung
up to and
provide
ways
made
hishave
own mark.
During
after better
his graduassessing
antibody
ateofstudies,
Eliot
worked quality.
to map the face of Pluto
But itadvantage
is too soon
call the cause
a moveby taking
of atogeometric
coincidence.
ment. There
are all
these
out there,
Between
1985 and
1990,
theresources
orbital planes
of
Pluto
and Charon
tilted
that
the two
but nobody
uses them
andsuch
many
people
arent
even aware
of them,
says
Len of
Freedman,
who
worlds
regularly
passed
in front
one another
the Global
Standards Instiasheads
seen from
Earth,Biological
allowing astronomers
to
tute,aaseries
non-profit
group
in Washington
DC
watch
of mutual
eclipses.
By measuring
committed
to improving
how
Plutos face
dimmed asbiomedical
sections of itresearch.
disapMostfrom
vendors
no incentive
to change
peared
view,have
researchers
could work
out
whats
going
ondark
rightand
now,
evenwere
though
lotaof
which
areas
were
which
lighta
the antibody
suck.was
one of several
property
calledreagents
albedo. Eliot
scientists piecing together these mosaics to proBUYER
BEWARE
duce
maps
of the dwarf planets surface7.
Take
the example
Ioannis
Prassas,
proteoThe maps
were faroffrom
perfect:
Thearesolumics
researcher
at with
Mount
Sinaiglasses
Hospital
tion
is like
somebody
a strong
pre-in
Toronto,
Canada.
Heand
andgoing
his colleagues
had
scription
getting
drunk
to look at the
beenchasing
a protein
called
CUZD1,
which
Moon,
says Eliot.
But they
provided
some
of
they
could be
used
to test
the
firstthought
real knowledge
about
what
Plutowhether
might
someone
haswas
pancreatic
cancer.information
They bought
look
like. It
foundational
a protein-detection
andPluto,
wasted
twoMarc
years,
that
got people excitedkit
about
says
$500,000
thousands
samples
Buie,
a Plutoand
astronomer
nowofatpatient
the Southwest
before they
realized
that the antibody
in to
the
Research
Institute.
He competed
with Eliot
kit was recognizing
a different
cancer
generate
the Pluto maps,
and gives
himprotein,
credit
2
CA125,
and didHe
not came
bind to
at all
. In
for
inventiveness.
upCUZD1
with some
ways
Prassas
rush towould
get going
ofretrospect,
tackling the
data says,
that Ia never
haveon
a promising
meant
he and his
thought
of in ahypothesis
million years,
saysthat
Buie.
Since then,
the Hubble
hasIf
group
had failed
to do Space
all theTelescope
right tests.
someonetosays,
Here
is an images
assay you
use,
managed
make
sharper
of can
Plutos
you areBy
soaround
eager toMay
testthis
it you
can
forget
that
surface.
year,
New
Horiwhat
hasbebeen
promised
theto
case.
zons
will
close
enough is
tonot
Pluto
capture
Most
scientists
who purchase
images
better
than Hubbles,
and theantiboddwarf
ies believe
the label
printed
on the
says
planet
will finally
begin
to come
intovial,
focus.
As a pathologist,
I wasnt
trained
InRimm.
the highest-resolution
pictures,
scientists
should
be had
ableto
tovalidate
pick outantibodies;
details as small
as
that you
I was just
trained
that
youYork
ordered
Park.
the
lakes in
New
Citysthem.
Central
Antibodies
produced
byhis
themapping
immune
Eliot
is perhapsare
best
known for
systems
most
vertebrates
targetcontribuan invader
work,
butofsays
that
his mostto
useful
such
as a bacterium.
thefor
1970s,
sciention
to Pluto
science is aSince
method
modelling
antibodies
for research.
occultation
light curves.
He is happiest
at theIf
interface
between
technology
space scia researcher
injects
a proteinand
of interest
into
a rabbit,
white
cells
known
as B cells
ence,
especially
if ablood
healthy
dose
of hardware
is
will start
producing
antibodies
the
involved.
I may
still be an
engineer atagainst
heart, he
protein,
whichnow
canat
beLowell
collected
from the anisays.
Dunham,
Observatory
in
mals blood.
For aremembers
more consistent
product,his
the
Flagstaff,
Arizona,
Eliot building
Bcells
can be retrieved,
fused
with
an immorown
computers
and housing
them
in cardboard
talized
cellinand
cultured
to provide a theoretiboxes
while
graduate
school.
cally
unlimited
In recent
years,supply.
Eliot has spent less time on
Three
decades
ago, scientists
who
needed
Pluto
and more
on pushing
technical
boundaantibodies
forfrontier
their experiments
hadscience
to make
ries
in another
of Solar System
themselves.
But byEarths
the late
1990s, reathem
sending
balloons above
atmosphere
companies
started toHis
takepropenover the
togent
make
planetary had
observations.
chore.
sity
for technical tinkering has served him in
Today, more
than
300
over
his favourite
hobby,
too.
Hecompanies
developedsell
a new
timing
system
for races
a ski resort
2million
antibodies
for at
research.
As ofnear
2011,
the market
washe
worth
$1.6abillion,
Boulder,
where
coaches
team. according to
global
consultancy
Frost & Sullivan.
Eliot and
Leslies mother,
Jody Williams, is
not surprised that the siblings have ended up
working
closelyEFFECTS
together. During their childDEVASTATING
There
aretosigns
problemswhere
with antibodies
hood
trips
Newthat
Hampshire,
they had
having broad
anddistractions,
potentially devastating
noare
television
or other
Eliot and
effects on the research record. In 2009, one
journal devoted an entire issue to assessing the
antibodies that are used to study G-proteincoupled receptors (GPCRs) cell-signalling
proteins that are targeted by drugs to treat various disorders, from incontinence to schizophrenia. In an analysis3 of 49 commercially
available antibodies that targeted 19 signalling
receptors, most bound to more than one protein, meaning that they could not be trusted to
The field of epigenetics relies heavily on antibodies to identify how proteins that regulate
gene expression have been modified. In 2011, an
evaluation4 of 246 antibodies used in epigenetic
studies found that one-quarter failed tests for
specificity, meaning that they often bound to
more than one target. Four antibodies were
Scientists often know, anecdotally, that some
antibodies in their field are problematic, but
it has been difficult to gauge the size of the
problem across biology as a whole. Perhaps
the largest assessment comes from work published by the Human Protein Atlas, a Swedish
consortium
that their
aimsparents
to generate
antibodies
Eliot
and Leslie with
in 1967.
ANTIBODIES
ARE NOT
MAGIC
REAGENTS.
Leslie would play for hours, building small

towns and fantasy worlds with shared rules.
Now, Williams says, every time Eliot runs into
a problem, he calls Leslie, and she never lets
him down.
Today, Eliot retains a measure of his bigbrother status: he is the gregarious one who
often speaks for both of them and is known
more widely among planetary astronomers.
Leslie, more reserved, sometimes gets noticed
initially because she is his sibling. They learn
Im his sister and they figure Im worth listening to, she says.
Yet the siblings clearly revel in their close
relationship.
Bothin
usually
workgenome.
some menfor every protein
the human
It has
looked
at some
20,000
commercial
antibodtion
of each
other into
professional
discussions
ies so minutes,
far and found
that constantly
less than 50%
can be
within
and they
ricochet
usedbetween
effectively
look atoffices.
proteinThey
distribution
ideas
eachtoothers
know
in preserved
slices
of any
tissue
. This
haseither
led some
each
other better
than
of5us
know
of
scientists
to claim that up to half of all comthem,
says Stern.
mercially available antibodies are unreliable.
ButFRENZY
reliability can depend on the experiment.
FLY-BY
experience
commercial
antibodies
AsOur
Pluto
scientists with
approach
peak excitement
is that
arewill
usually
okay intosome
applicathis
year,they
Eliot
be helping
coordinate
a tions,
cadrebut
of amateur
they mightastronomers
be terrible inacross
others,the
says
MathiasHemisphere
Uhln at thewho
Royal
Institute
of TechSouthern
will
try to capture
in Stockholm,
who
coordinates
the
a nology
major occultation
as Pluto
passes
in front of
Protein
Atlas.
a Human
particularly
bright
star on 29 June. It is the
ideally
check
that an
last Researchers
of these events
beforeshould
the New
Horizons
antibody
been data
tested
for use
in particular
fly-by,
and ahas
crucial
point
in the
series of
applications
and tissue
types,
occultation
studies
dating
backbut
to the
the quality
midof information
bymeasurements
vendors can vary
1980s
the onlysupplied
long-term
of
4 7 2NATURE
| N A T COLLECTIONS
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8 | 2 6 F ESUMMER
B R U A R READS
Y 2015
tremendously.
A common
how
Plutos atmosphere
has complaint
changed. from scientists
thatmove
companies
do not control
provide the
data
Leslieiswill
to mission
at the
Johns
Hopkins
University
Applied Physics
required
to evaluate
a given antibodys
specificLaboratory
in Laurel,
Maryland,
to prepare
ity or its lot-to-lot
variability.
Companies
might
ship
a batch
of gathering.
antibodies She
withischaracterization
for
intense
data
a deputy proinformation
derived
from a previous
batch.
ject
scientist for
New Horizons
and the chief
And theof
data
oftenof
derived
undera ideal
conarchitect
theare
details
the fly-by,
job that
ditions that
do not
reflect
typical experiments.
involves
a steady
diet
of teleconferences
and
Antibody companies
contacted
this article
spreadsheets
to coordinate
what for
observation
said
it isbyimpossible
to test their
products
will
bethat
made
what instrument
at what
time.
across
all experimental
conditions,
but they
The
mission
team has carried
out several
drydo
provide
and work
withtoscientists
runs
of thereliable
entire data
encounter,
trying
anticito improve
antibodyinquality
andbe
performance.
pate
every possibility
what will
an actionMany
academics
use Google
findafter
products,
packed
few
days leading
up totoand
the
closest
approach.search
Ive been
working
for the
so optimizing
results
can sometimes
matter
to a company
optimizing
the
future
formore
15 years,
and the than
pay-off
is coming
actual
reagents,
Tim Bernard, head of the
this
summer,
sayssays
Leslie.
biotechnology
Scientific
Among otherconsultancy
things, she Pivotal
has developed
alternative
trajectories
the spacecraft
to&
in Upper Heyford,
UK.for
Christi
Bird, a Frost
Sullivan
Washington
DC, says
divert
to ifanalyst
it seemsbased
to bein
heading
for a particuthatdusty
researchers
often
more
larly
patch ofare
space.
With
theinterested
spacecraftin
how quickly
reagents
be delivered
moving
at nearly
50,000can
kilometres
per than
hour,in
searching
for dust
antibodies
with
appropriate
collisions
with
particles
could
endangervaliit
data.
Its the Amazon effect: they want it
ordation
damage
instruments.
inCathy
two or
threeatdays,
with free shipping.
Olkin
the Southwest
ResearchInstiwho
are aware
the group
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NEWS FEATURE
2 1 M A Y 2 0 1 5 | V O L 5 2 1 | N A T U R E | 213
75
The
human
age
Momentum is building to
establish a new geological epoch
that recognizes humanitys
impact on the planet. But there is
fierce debate behind the scenes.
lmost all the dinosaurs have vanished from the National

Museum of Natural History in WashingtonDC. The fossil
hall is now mostly empty and painted in deep shadows as
palaeobiologist Scott Wing wanders through the cavernous room.
Wing is part of a team carrying out a radical, US$45-million redesign
of the exhibition space, which is part of the Smithsonian Institution. And
when it opens again in 2019, the hall will do more than revisit Earths
distant past. Alongside the typical displays of Tyrannosaurus rex and
Triceratops, there will be a new section that forces visitors to consider
the species that is currently dominating the planet.
We want to help people imagine their role in the world, which is
maybe more important than many of them realize, says Wing.
This provocative exhibit will focus on the Anthropocene the slice
of Earths history during which people have become a major geological
force. Through mining activities alone, humans move more sediment
than all the worlds rivers combined. Homo sapiens has also warmed the
planet, raised sea levels, eroded the ozone layer and acidified the oceans.
Given the magnitude of these changes, many researchers propose
that the Anthropocene represents a new division of geological time.
The concept has gained traction, especially in the past few years and
not just among geoscientists. The word has been invoked by archaeologists, historians and even gender-studies researchers; several museums
14

ILLUSTRATION BY JESSICA FORTNER
BY RICHARD MONASTERSKY
FEATURE NEWS
around the world have exhibited art inspired by the Anthropocene; and
the media have heartily adopted the idea. Welcome to the Anthropocene, The Economist announced in 2011.
The greeting was a tad premature. Although the term is trending,
the Anthropocene is still an amorphous notion an unofficial name
that has yet to be accepted as part of the geological timescale. That
may change soon. A committee of researchers is currently hashing out
whether to codify the Anthropocene as a formal geological unit, and
when to define its starting point.
But critics worry that important arguments
against the proposal have been drowned out by
popular enthusiasm, driven in part by environmentally minded researchers who want to highlight how destructive humans have become.
Some supporters of the Anthropocene idea
have even been likened to zealots. Theres a
similarity to certain religious groups who are
extremely keen on their religion to the extent
that they think everybody who doesnt practise
their religion is some kind of barbarian, says one
geologist who asked not to be named.
The debate has shone a spotlight on the typically unnoticed process by which geologists
carve up Earths 4.5 billion years of history. Normally, decisions about the geological timescale
are made solely on the basis of stratigraphy the
evidence contained in layers of rock, ocean sediments, ice cores and other geological deposits.
But the issue of the Anthropocene is an order of magnitude more complicated than the stratigraphy, says Jan Zalasiewicz, a geologist at the
University of Leicester, UK, and the chair of the Anthropocene Working
Group that is evaluating the issue for the International Commission on
Stratigraphy (ICS).
and marine sediments around the world, allowing geologists to precisely

identify the start of the Holocene elsewhere.
Even as the ICS was finalizing its decision on the start of the Holocene, discussion was already building about whether it was time to end
that epoch and replace it with the Anthropocene. This idea has a long
history. In the mid-nineteenth century, several geologists sought to
recognize the growing power of humankind by referring to the present
as the anthropozoic era, and others have since made similar proposals, sometimes with different names. The idea
has gained traction only in the past few years,
however, in part because of rapid changes in the
environment, as well as the influence of Paul
Crutzen, a chemist at the Max Plank Institute
for Chemistry in Mainz, Germany.
Crutzen has first-hand experience of how
human actions are altering the planet. In the 1970s
and 1980s, he made major discoveries about the
ozone layer and how pollution from humans could
damage it work that eventually earned him a
share of a Nobel prize. In 2000, he and Eugene
Stoermer of the University of Michigan in Ann
Arbor argued that the global population has gained
so much influence over planetary processes that
the current geological epoch should be called
the Anthropocene2. As an atmospheric chemist,
Crutzen was not part of the community that adjudicates changes to the geological timescale. But the
idea inspired many geologists, particularly Zalasiewicz and other members of the Geological Society of London. In 2008,
they wrote a position paper urging their community to consider the idea3.
Those authors had the power to make things happen. Zalasiewicz
happened to be a member of the Quaternary subcommission of the ICS,
the body that would be responsible for officially considering the suggestion. One of his co-authors, geologist Phil Gibbard of the University of
Cambridge, UK, chaired the subcommission at the time.
Although sceptical of the idea, Gibbard says, I could see it was
important, something we should not be turning our backs on. The next
year, he tasked Zalasiewicz with forming the Anthropocene Working
Group to look into the matter.
The geologic
timescale,
in my view,
is one of
the great
achievements
of humanity.
WRITTEN IN STONE
For geoscientists, the timescale of Earths history rivals the periodic table
in terms of scientific importance. It has taken centuries of painstaking
stratigraphic work matching up major rock units around the world
and placing them in order of formation to provide an organizing
scaffold that supports all studies of the planets past. The geologic timescale, in my view, is one of the great achievements of humanity, says
Michael Walker, a Quaternary scientist at the University of Wales Trinity
St David in Lampeter, UK.
Walkers work sits at the top of the timescale. He led a group that
helped to define the most recent unit of geological time, the Holocene
epoch, which began about 11,700 years ago.
The decision to formalize the Holocene in 2008 was one of the most
recent major actions by the ICS, which oversees the timescale. The commission has segmented Earths history into a series of nested blocks, much
like the years, months and days of a calendar. In geological time, the 66
million years since the death of the dinosaurs is known as the Cenozoic
era. Within that, the Quaternary period occupies the past 2.58 million
years during which Earth has cycled in and out of a few dozen ice ages.
The vast bulk of the Quaternary consists of the Pleistocene epoch, with the
Holocene occupying the thin sliver of time since the end of the last ice age.
When Walker and his group defined the beginning of the Holocene,
they had to pick a spot on the planet that had a signal to mark that boundary. Most geological units are identified by a specific change recorded in
rocks often the first appearance of a ubiquitous fossil. But the Holocene is so young, geologically speaking, that it permits an unusual level
of precision. Walker and his colleagues selected a
climatic change the end of the last ice ages final
NATURE.COM
cold snap and identified a chemical signature To hear more about
of that warming at a depth of 1,492.45metres in a the Anthropocene,
core of ice drilled near the centre of Greenland1. A visit:
similar fingerprint of warming can be seen in lake go.nature.com/vybhfu
A NEW BEGINNING
Since then, the working group has been busy. It has published two large
reports (They would each hurt you if they dropped on your toe, says
Zalasiewicz) and dozens of other papers.
The group has several issues to tackle: whether it makes sense to
establish the Anthropocene as a formal part of the geological timescale;
when to start it; and what status it should have in the hierarchy of the
geological time if it is adopted.
When Crutzen proposed the term Anthropocene, he gave it the suffix
appropriate for an epoch and argued for a starting date in the late eighteenth century, at the beginning of the Industrial Revolution. Between
then and the start of the new millennium, he noted, humans had chewed
a hole in the ozone layer over Antarctica, doubled the amount of methane in the atmosphere and driven up carbon dioxide concentrations by
30%, to a level not seen in 400,000 years.
When the Anthropocene Working Group started investigating, it
compiled a much longer long list of the changes wrought by humans.
Agriculture, construction and the damming of rivers is stripping away
sediment at least ten times as fast as the natural forces of erosion. Along
some coastlines, the flood of nutrients from fertilizers has created
oxygen-poor dead zones, and the extra CO2 from fossil-fuel burning
has acidified the surface waters of the ocean by 0.1pH units. The fingerprint of humans is clear in global temperatures, the rate of species
extinctions and the loss of Arctic ice.
The group, which includes Crutzen, initially leaned towards his
idea of choosing the Industrial Revolution as the beginning of the

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45
Humans at the helm
Researchers are studying whether the geological timescale should be modified to include the Anthropocene,
a unit of time during which humans became a major force on the planet. Some support starting the
Anthropocene in the mid-twentieth century, whereas others propose much earlier dates.
Holocene
The Anthropocene
could be added as a
new epoch on top of
the Holocene. Or the
timescale could
remain unchanged,
in which case the
Anthropocene would
function as an
informal time unit.
Radioactive fallout
from nuclear blasts
peaked in the
mid-twentieth century,
leaving a signal visible
in sediments that has
been proposed as a
marker for the start of
the Anthropocene.
WATER USE
1950
200
20
10
0
1750
1900
Million tonnes
30
Thousand km3
Dams (thousands)
FERTILIZER USE
1950
1950
3
2
1
0
1750
2010
1900
2010
150
100
50
0
1750
1900
2010
2.0
Pu fallout (PBq)
781,000 ya
~3,000 years ago (ya)

Expansion in mining
Human impacts on
the environment
surged in the
mid-twentieth century,
a trend visible in many
records. That time has
been called the Great
Acceleration.
LARGE DAMS
239+240
Anthropocene
LATEANTHROPOCENE
PROPOSAL
1.5
1.0
0.5
0
1950
1960
1970
1980
1990
2000
Pleistocene
Calabrian
5,0007,000 ya
Expansion in
agriculture
EARLYANTHROPOCENE
PROPOSAL
One potential
stratigraphic marker
is a rise in the
atmospheric
concentration of
methane millennia
ago, which is
recorded in glacial ice.
This could reflect
increases in farming
and animal herding.
Years of intensive land use based on model estimates

>5,000 years
5,0002,000 years
2,0001,000 years
1,000250 years
<250 years
CH4 (parts per billion)
11,700 ya
Upper Pleistocene
2.6 million ya
Gelasian
1.8 million ya
Humans began
transforming the land
surface thousands of
years ago, through
agriculture and other
activities. That has led
some researchers to
propose an early start
date for the
Anthropocene.
750
700
650
600
550
11
Anthropocene. But other options were on the table.

Some researchers have argued for a starting time that coincides
with an expansion of agriculture and livestock cultivation more than
5,000years ago4, or a surge in mining more than 3,000 years ago (see
Humans at the helm). But neither the Industrial Revolution nor those
earlier changes have left unambiguous geological signals of human
activity that are synchronous around the globe.
This week in Nature, two researchers propose that a potential marker
1 16
4 6 | N A T U R E | V O L 5 1 9 | 1 2 M A R C H 2 0 1 5
10
6
5
4
Thousand years ago
for the start of the Anthropocene could be a noticeable drop in atmospheric CO2 concentrations between 1570 and 1620, which is recorded
in ice cores (see page 171). They link this change to the deaths of some
50 million indigenous people in the Americas, triggered by the arrival of
Europeans. In the aftermath, forests took over 65 million hectares of abandoned agricultural fields a surge of regrowth that reduced global CO2.
In the working group, Zalasiewicz and others have been talking
increasingly about another option using the geological marks left
SOURCES: DAMS/WATER/FERTILIZER, IGBP; FALLOUT, REF. 5; MAP, E. C. ELLIS

PHIL. TRANS. R. SOC. A 369,10101035 (2011); METHANE, REF. 4
Mid-twentieth century
Industrial Revolution
Middle
126,000 ya Holocene
Upper
NEWS FEATURE
FEATURE NEWS
by the atomic age. Between 1945 and 1963, when the Limited Nuclear
Test Ban Treaty took effect, nations conducted some 500 above-ground
nuclear blasts. Debris from those explosions circled the globe and created
an identifiable layer of radioactive elements in sediments. At the same
time, humans were making geological impressions in a number of other
ways all part of what has been called the Great Acceleration of the
modern world. Plastics started flooding the environment, along with
aluminium, artificial fertilizers, concrete and leaded petrol, all of which
have left signals in the sedimentary record.
In January, the majority of the 37-person working group offered its
first tentative conclusion. Zalasiewicz and 25 other members reported5
that the geological markers available from the mid-twentieth century
make this time stratigraphically optimal for picking the start of the Anthropocene, whether or not it
is formally defined. Zalasiewicz calls it a candidate
for the least-worst boundary.
The group even proposed a precise date: 16July
1945, the day of the first atomic-bomb blast. Geologists thousands of years in the future would be able
to identify the boundary by looking in the sediments for the signature of long-lived plutonium
from mid-century bomb blasts or many of the other
global markers from that time.
Zalasiewicz takes pains to make it clear that the working group has
not yet reached any firm conclusions.We need to discuss the utility of
the Anthropocene. If one is to formalize it, who would that help, and to
whom it might be a nuisance? he says. There is lots of work still to do.
Any proposal that the group did make would still need to pass a series
of hurdles. First, it would need to receive a supermajority 60% support in a vote by members of the Quaternary subcommission. Then it
would need to reach the same margin in a second vote by the leadership
of the full ICS, which includes chairs from groups that study the major
time blocks. Finally, the executive committee of the International Union
of Geological Sciences must approve the request.
At each step, proposals are often sent back for revision, and they
sometimes die altogether. It is an inherently conservative process, says Martin Head, a marine
stratigrapher at Brock University in St Catharines,
Canada, and the current head of the Quaternary
subcommission. You are messing around with a
timescale that is used by millions of people around
the world. So if youre making changes, they have to
be made on the basis of something for which there
is overwhelming support.
Some voting members of the Quaternary subcommission have told Nature that they have not
been persuaded by the arguments raised so far in
favour of the Anthropocene. Gibbard, a friend of
Zalasiewiczs, says that defining this new epoch will
not help most Quaternary geologists, especially
those working in the Holocene, because they tend
not to study material from the past few decades or
centuries. But, he adds: I dont want to be the person who ruins the party, because a lot of useful stuff
is coming out as a consequence of people thinking
about this in a systematic way.
If a proposal does not pass, researchers could continue to use the name
Anthropocene on an informal basis, in much the same way as archaeological terms such as the Neolithic era and the Bronze Age are used today.
Regardless of the outcome, the Anthropocene has already taken on a life
of its own. Three Anthropocene journals have started up in the past two
years, and the number of papers on the topic is rising sharply, with more
than 200 published in 2014.
By 2019, when the new fossil hall opens at the Smithsonians natural
history museum, it will probably be clear whether the Anthropocene
exhibition depicts an official time unit or not. Wing, a member of the
working group, says that he does not want the stratigraphic debate to
overshadow the bigger issues. There is certainly a broader point about
human effects on Earth systems, which is way more important and also
more scientifically interesting.
As he walks through the closed palaeontology hall, he points out how
much work has yet to be done to refashion the exhibits and modernize
the museum, which opened more than a century ago. A hundred years
is a heartbeat to a geologist. But in that span, the human population
has more than tripled. Wing wants museum visitors to think, however
briefly, about the planetary power that people now wield, and how that
fits into the context of Earths history. If you look back from 10 million
years in the future, he says, youll be able to see what we were doing
today. SEE EDITORIAL P.129
Its
become a
political
statement.
Thats what
so many
people
want.
A MANY-LAYERED DEBATE
The push to formalize the Anthropocene upsets

some stratigraphers. In 2012, a commentary published by the Geological Society of America6 asked:
Is the Anthropocene an issue of stratigraphy or pop
culture? Some complain that the working group
has generated a stream of publicity in support of the
concept. Im frustrated because any time they do
anything, there are newspaper articles, says Stan
Finney, a stratigraphic palaeontologist at California State University in
Long Beach and the chair of the ICS, which would eventually vote on any
proposal put forward by the working group. What you see here is, its
become a political statement. Thats what so many people want.
Finney laid out some of his concerns in a paper7 published in 2013.
One major question is whether there really are significant records of
the Anthropocene in global stratigraphy. In the deep sea, he notes, the
layer of sediments representing the past 70 years would be thinner than
1millimetre. An even larger issue, he says, is whether it is appropriate
to name something that exists mainly in the present and the future as
part of the geological timescale.
Some researchers argue that it is too soon to make a decision it will
take centuries or longer to know what lasting impact humans are having
on the planet. One member of the working group, Erle Ellis, a geographer
at the University of Maryland, Baltimore County, says that he raised the
idea of holding off with fellow members of the group. We should set a
time, perhaps 1,000 years from now, in which we would officially investigate this, he says. Making a decision before that would be premature.
That does not seem likely, given that the working group plans to
present initial recommendations by 2016.
Some members with different views from the majority have dropped
out of the discussion. Walker and others contend that human activities
have already been recognized in the geological timescale: the only difference between the current warm period, the Holocene, and all the
interglacial times during the Pleistocene is the presence of human societies in the modern one. Youve played the human card in defining the
Holocene. Its very difficult to play the human card again, he says.
Walker resigned from the group a year ago, when it became clear that
he had little to add. He has nothing but respect for its members, he says,
but he has heard concern that the Anthropocene movement is picking up
speed. Theres a sense in some quarters that this is something of a juggernaut, he says. Within the geologic community, particularly within the
stratigraphic community, there is a sense of disquiet.
Richard Monastersky is a features editor for Nature in

WashingtonDC.
Walker, M. et al. J. Quat. Sci. 24, 317 (2009).
Crutzen, P. J. & Stoermer, E. F. IGBP Newsletter 41, 1718 (2000).
Zalasiewicz. J. et al. GSA Today 18(2), 48 (2008).
Ruddiman, W. F. Ann. Rev. Earth. Planet. Sci. 41, 4568 (2013).
Zalasiewicz, J. et al. Quatern. Int. http://dx.doi.org/10.1016/j.quaint.2014.11.045
(2015).
6. Autin, W. J. & Holbrook, J. M. GSA Today 22(7), 6061 (2012).
7. Finney, S. C. Geol. Soc. Spec. Publ. 395, 2328 (2013).
1.
2.
3.
4.
5.

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IMAGINECHINA/CORBIS
NEWS FEATURE
THE MYOPIA BOOM

SHORT-SIGHTEDNESS IS REACHING EPIDEMIC PROPORTIONS.
SOME SCIENTISTS THINK THEY HAVE FOUND A REASON WHY.
BY ELIE DOLGIN
he southern city of Guangzhou has long held the largest eye

hospital in China. But about five years ago, it became clear
that the Zhongshan Ophthalmic Center needed to expand.
More and more children were arriving with the blurry
distance vision caused by myopia, and with so many needing eye tests
and glasses, the hospital was bursting at the seams. So the centre began
adding new testing rooms and to make space, it relocated some of
its doctors and researchers to a local shopping mall. Now during the
summer and winter school holidays, when most diagnoses are made,
thousands and thousands of children pour in every day, says ophthalmologist Nathan Congdon, who was one of those uprooted. You
literally cant walk through the halls because of all the children.
218
7 6 | N A T U R E | V O L 5 1 9 | 1 9 M A R C H 2 0 1 5
East Asia has been gripped by an unprec- Glasses have become the
edented rise in myopia, also known as short- rule, not the exception, in
sightedness. Sixty years ago, 1020% of the Chinese universities.
Chinese population was short-sighted.
Today, up to 90% of teenagers and young adults are. In Seoul, a whopping 96.5% of 19-year-old men are short-sighted.
Other parts of the world have also seen a dramatic increase in the
condition, which now affects around half of young adults in the United
States and Europe double the prevalence of half a century ago. By
some estimates, one-third of the worlds population 2.5 billion people could be affected by short-sightedness by the end of this decade. We are going down the path of having a myopia epidemic, says
FEATURE NEWS
Padmaja Sankaridurg, head of the myopia programme at the Brien
Holden Vision Institute in Sydney, Australia.
The condition is more than an inconvenience. Glasses, contact lenses
and surgery can help to correct it, but they do not address the underlying
defect: a slightly elongated eyeball, which means that the lens focuses
light from far objects slightly in front of the retina, rather than directly
on it. In severe cases, the deformation stretches and thins the inner parts
of the eye, which increases the risk of retinal detachment, cataracts,
glaucoma and even blindness. Because the eye grows throughout childhood, myopia generally develops in school-age children and adolescents.
About one-fifth of university-aged people in
East Asia now have this extreme form of myopia, and half of them are expected to develop
irreversible vision loss.
This threat has prompted a rise in research
to try to understand the causes of the disorderand scientists are beginning to find
answers. They are challenging old ideas that
myopia is the domain of the bookish child and
are instead coalescing around a new notion:
that spending too long indoors is placing children at risk. Were really trying to give this
message now that children need to spend more time outside, says Kathryn Rose, head of orthoptics at the University of Technology, Sydney.
accommodate the incoming light and focus close-up images squarely

on the retina.
Attractive though the idea was, it did not hold up. In the early 2000s,
when researchers started to look at specific behaviours, such as books
read per week or hours spent reading or using a computer, none seemed
to be a major contributor to myopia risk5. But another factor did. In
2007, Donald Mutti and his colleagues at the Ohio State University
College of Optometry in Columbus reported the results of a study that
tracked more than 500 eight- and nine-year-olds in California who
started out with healthy vision6. The team examined how the children
spent their days, and sort of as an afterthought at the time, we asked about sports
and outdoorsy stuff , says Mutti.
It was a good thing they did. After five
years, one in five of the children had developed myopia, and the only environmental
factor that was strongly associated with risk
was time spent outdoors6. We thought it
was an odd finding, recalls Mutti, but it
just kept coming up as we did the analyses.
A year later, Rose and her colleagues arrived
at much the same conclusion in Australia7.
After studying more than 4,000 children at Sydney primary and secondary schools for three years, they found that children who spent less
time outside were at greater risk of developing myopia.
Roses team tried to eliminate any other explanations for this link
for example, that children outdoors were engaged in more physical
activity and that this was having the beneficial effect. But time engaged
in indoor sports had no such protective association; and time outdoors
did, whether children had played sports, attended picnics or simply
read on the beach. And children who spent more time outside were
not necessarily spending less time with books, screens and close work.
We had these children who were doing both activities at very high
levels and they didnt become myopic, says Rose. Close work might
still have some effect, but what seemed to matter most was the eyes
exposure to bright light.
SORT OF A S A N
AF T E RTH OU G H T, WE
ASK ED A B OU T SP ORTS
AND O U TDOOR SY STU FF.
VISION QUEST
For many years, the scientific consensus held that myopia was largely
down to genes. Studies in the 1960s showed that the condition was
more common among genetically identical twins than non-identical
ones, suggesting that susceptibility is strongly influenced by DNA1.
Gene-finding efforts have now linked more than 100 regions of the
genome to short-sightedness.
But it was obvious that genes could not be the whole story. One of
the clearest signs came from a 1969 study of Inuit people on the northern tip of Alaska whose lifestyle was changing2. Of adults who had
grown up in isolated communities, only 2 of 131 had myopic eyes. But
more than half of their children and grandchildren had the condition.
Genetic changes happen too slowly to explain this rapid change or
the soaring rates in myopia that have since been documented all over
the world (see The march of myopia). There must be an environmental effect that has caused the generational difference, says Seang
Mei Saw, who studies the epidemiology and genetics of myopia at the
National University of Singapore.
There was one obvious culprit: book work. That idea had arisen more
than 400 years ago, when the German astronomer and optics expert
Johannes Kepler blamed his own short-sightedness on all his study. The
idea took root; by the nineteenth century, some leading ophthalmologists were recommending that pupils use headrests to prevent them
from poring too closely over their books.
The modern rise in myopia mirrored a trend for children in many
countries to spend more time engaged in reading, studying or more
recently glued to computer and smartphone screens. This is particularly the case in East Asian countries, where the high value placed
on educational performance is driving children to spend longer in
school and on their studies. A report last year3 from the Organisation
for Economic Co-operation and Development showed that the average
15-year-old in Shanghai now spends 14 hours per week on homework,
compared with 5 hours in the United Kingdom and 6 hours in the
United States.
Researchers have consistently documented a strong association
between measures of education and the prevalence of myopia. In the
1990s, for example, they found that teenage boys in Israel who attended
schools known as Yeshivas (where they spent their days studying religious texts) had much higher rates of myopia than did students who
spent less time at their books4. On a biological level, it seemed plausible
that sustained close work could alter growth of the eyeball as it tries to
SEE THE LIGHT
Some researchers think that the data to support the link need to be
more robust. Most epidemiological studies have estimated childrens
time outdoors from questionnaires but Christine Wildsoet, an
optometrist at the University of California, Berkeley, says that such
data should be treated with caution. In a small, pilot study of wearable
light sensors8, she found that peoples estimates often do not match up
with their actual exposure. And Ian Flitcroft, a myopia specialist at
Childrens University Hospital in Dublin, questions whether light is the
key protective factor of being outdoors. He says that the greater viewing
distances outside could affect myopia progression, too. Light is not the
only factor, and making it the explanation is a gross over-simplification
of a complex process, he says.
Yet animal experiments support the idea that light is protective.
Researchers first demonstrated this in chicks, a common lab model
for studying vision. By fitting chicks with goggles that alter the resolution and contrast of incoming images, it is possible to induce the
development of myopia while raising the birds under controlled conditions in which only light intensity is changed. In 2009, Regan Ashby,
Arne Ohlendorf and Frank Schaeffel from the University of Tbingens
Institute for Ophthalmic Research in Germany showed that high illumination levels comparable to those encountered outside slowed
the development of experimentally induced myopia in chicks by about
60% compared with normal indoor lighting conditions9. Researchers elsewhere have found similar protective effects in tree shrews and
rhesus monkeys10.
But what scientists really needed was a mechanism: something to
explain how bright light could prevent myopia. The leading hypothesis is that light stimulates the release of dopamine in the retina, and

1 9 M A R C H 2 0 1 5 | V O L 5 1 9 | N A T U R E | 219
77
Estimated prevalence
in 20-year-olds
this neurotransmitter in turn blocks the elongation of the eye during

extremely difficult. Saw and her colleagues learned this when they
development. The best evidence for the lightdopamine hypothesis
trialled a 9-month programme to teach parents in Singapore about the
comes again from chicks. In 2010, Ashby and Schaeffel showed
importance of outdoor time in order to prevent myopia. They provided
that injecting a dopamine-inhibiting drug called spiperone into chicks
step-counters, organized outdoor weekend activities for families and
eyes could abolish the protective effect of bright light11.
even offered cash prizes for cooperation. But by the end of the trial,
Retinal dopamine is normally produced on a diurnal cycle rampthe time spent outdoors was not statistically different from that for a
ing up during the day and it tells the
control group with no such campaign13.
eye to switch from rod-based, nightIn some places, children cannot get
time vision to cone-based, daytime
any more outdoor light: there are too
THE MARCH OF MYOPIA
East Asian countries have seen a steep rise in short-sightedness
vision. Researchers now suspect that
few hours of daylight, the sun is too
over the past 50 years. The condition is caused by a slightly
under dim (typically indoor) lightfierce, or the cold too intense. Animal
elongated eyeball, which means that light is focused just in
ing, the cycle is disrupted, with conseresearch10 has suggested that powerful
front of the retina instead of on it.
quences for eye growth. If our system
indoor lights could do the trick instead:
does not get a strong enough diurnal
light boxes currently sold to treat seasonal affective disorder, for example,
rhythm, things go out of control, says
can deliver up to 10,000 lux illuminaAshby, who is now at the University of
Retina
tion, but their effects on myopia have
Canberra. The system starts to get a bit
noisy and noisy means that it just grows
not been tested extensively in humans.
Light
in its own irregular fashion.
Meanwhile, researchers have been
working on ways to prevent myopia
from worsening. Sankaridurg and
TIME OUT
her colleagues have developed speBased on epidemiological studies,
Ian Morgan, a myopia researcher at
cial glasses and contact lenses that can
the Australian National University in
alter eye growth by focusing light from
100
Canberra, estimates that children need
distant images across the entire field
Hong Kong
of view, rather than just at the centre,
to spend around three hours per day
Taiwan
80
as standard lenses do. Other research
under light levels of at least 10,000 lux
Singapore
South Korea
groups have shown that nightly eye
to be protected against myopia. This is
drops with a neurotransmitter-blockabout the level experienced by someone
60
under a shady tree, wearing sunglasses,
ing drug called atropine can also help to
on a bright summer day. (An overcast
control myopia progression14, although
40
day can provide less than 10,000 lux and
the mechanism remains unclear. We
a well-lit office or classroom is usually
want to take a holistic approach to tack20
no more than 500lux.) Three or more
ling myopia, Sankaridurg says.
hours of daily outdoor time is already
But eye drops and light boxes do not
0
the norm for children in Morgans native
have quite the appeal of sending chil1930
1950
1970
1990
2010
Australia, where only around 30% of
dren outside to play, which has plenty of
17-year-olds are myopic. But in many
other benefits besides those for the eyes.
parts of the world including the United States, Europe and East
It probably also increases physical activity, which decreases likelihood
Asia children are often outside for only one or two hours.
of obesity and enhances mood, Rose says. I can only see it as a win
In 2009, Morgan set out to test whether boosting outdoor time would
and its free.
help to protect the eyesight of Chinese children. He and a team from the
More than a century ago, Henry Edward Juler, a renowned British
Zhongshan Ophthalmic Center (where Morgan also works) launched
eye surgeon, offered similar advice. In 1904, he wrote in A Handbook
a three-year trial in which they added a 40-minute outdoor class to the
of Ophthalmic Science and Practice that when the myopia had become
end of the school day for a group of six- and seven-year-olds at six ranstationary, change of air a sea voyage if possible should be predomly selected schools in Guangzhou; children at six other schools had
scribed. As Wildsoet points out: Weve taken a hundred years to go
no change in schedule and served as controls. Of the 900-plus children
back to what people were intuitively thinking was the case.
who attended the outside class, 30% developed myopia by age nine or
ten compared with 40% of those at the control schools. The study is
Elie Dolgin is a science writer in Somerville, Massachusetts.
being prepared for publication.
1. Sorsby, A. & Leary, G. A. Refraction and its components in twins. Special Report
A stronger effect was found at a school in southern Taiwan, where
Series no. 303 (Medical Research Council, 1962).
teachers were asked to send children outside for all 80 minutes of their
2. Young, F. A. et al. Am. J. Optom. Arch. Am. Acad. Optom. 46, 676685 (1969).
daily break time instead of giving them the choice to stay inside. After
3. Salinas, D. Does Homework Perpetuate Inequities in Education? (OECD, 2014).
Available at http://doi.org/2sd
one year, doctors had diagnosed myopia in 8% of the children, com4. Zylbermann, R., Landau, D. & Berson, D. J. Pediatr. Ophthalmol. Strabismus 30,
pared with 18% at a nearby school12.
319322 (1993).
Morgan is buoyed by the preliminary findings, but thinks that he can
5. Saw, S. M., Carkeet, A., Chia, K. S., Stone, R. A. & Tan, D. T. Ophthalmology 109,
20652071 (2002).
do even better. Weve got proof of principle that increasing the amount
6. Jones, L. A. et al. Invest. Ophthalmol. Vis. Sci. 48, 35243532 (2007).
of time children spend outside actually works, he says. The question
7. Rose, K. A. et al. Ophthalmology 115, 12791285 (2008).
then is how do we make this work in practice at a level that would have
8. Alvarez, A. A. & Wildsoet, C. F. J. Mod. Opt. 60, 12001208 (2013).
9. Ashby, R., Ohlendorf, A. & Schaeffel, F. Invest. Ophthalmol. Vis. Sci. 50, 5348
a significant impact? He recognizes that many schools do not have
5354 (2009).
the flexibility to add time outdoors. So last year, in collaboration with
10. Siegwart J. T., Ward, A. H. & Norton, T. T. Invest. Ophthalmol. Vis. Sci. 53, 3457
Congdon, he began piloting the idea of teaching kids in a classroom
(2012).
11. Ashby, R. S. & Schaeffel, F. Invest. Ophthalmol. Vis. Sci. 51, 52475253 (2010).
made of glass to let in more natural light. This glass classroom idea is
12. Wu, P.-C., Tsai, C.-L., Wu, H.-L., Yang, Y.-H. & Kuo, H.-K. Ophthalmology 120,
quite applicable for whole swathes of China, Congdon says.
10801085 (2013).
Rose points out that additional outdoor time has to be mandated
13. Ngo, C. S. et al. Ophthalmic Physiol. Opt. 34, 362368 (2014).
14. Chia, A. et al. Ophthalmology 119, 347354 (2012).
through the schools, because getting parents to voluntarily do this is
220
7 8 | N A T U R E | V O L 5 1 9 | 1 9 M A R C H 2 0 1 5

SOURCE: IAN MORGAN, AUSTRALIAN NATL UNIV.
NEWS FEATURE
FEATURE NEWS
NEWS FEATURE
reproduced.

DEVASTATING EFFECTS
There are signs that problems with antibodies

are having broad and potentially devastating
consortium that aims to generate antibodies
information derived from a previous batch.
And the data are often derived under ideal conditions that do not reflect typical experiments.
Antibody companies contacted for this article
said that it is impossible to test their products
across all experimental conditions, but they do
provide reliable data and work with scientists
to improve antibody quality and performance.
so optimizing search results can sometimes
matter more to a company than optimizing the
actual reagents, says Tim Bernard, head of the
in Upper Heyford, UK. Christi Bird, a Frost &
Sullivan analyst based in Washington DC, says
that researchers are often more interested in
how quickly reagents can be delivered than in
searching for antibodies with appropriate validation data. Its the Amazon effect: they want it
in two or three days, with free shipping.
problem say that scientists need to be more
vigilant. Antibodies are not magic reagents.
You cant just throw them on your sample and
expect the result you get is 100% reliable without putting some critical thinking into it, says
James Trimmer, head of NeuroMab at the University of California, Davis, which makes antibodies for neuroscience. Like many suppliers,
NeuroMab explicitly states the types of experiment that an antibody should be used for, but
Ideally, researchers would refuse to buy antibodies without extensive validation dataor
which he shares with anyone who will listen.
But
the process
is time
consuming
Rimm
for
many
years and,
in a small
but significant
recommends
control
experiments
proportion,
never
leaving
them. Ofthat
the involve
more
engineering
lines toinboth
express
stop
than
40,000 UScell
postdocs
2013,
almostand
4,000
expressing
of interest,
example.
had
been sothe
forprotein
more than
6 yearsfor
(see
The
Even hepile-up).
acknowledges that few labs will perpostdoc
form
the steps.
This all
problem
is felt acutely in the large US
Some scientists buy
half a dozen
biomedical-sciences
workforce,
but theantibodtrends
iessimilar
from different
and thenand
rundisa few
are
in manyvendors,
other countries
assays
to and
see which
performs
best. are
Buttoo.
they
ciplines
the economic
drivers
may end
up buying
same antibody
from
Postdoc
salaries
have the
remained
lowoften
less
than the
stipend
and tuition
costs
of a
different
places.
The largest
vendors
compete
graduate
student.
hadoften
the incentives
all
on catalogue
size,We
so they
buy antibodies
wrong,
says Paula
Stephan,
an economist
at
from smaller
suppliers,
relabel
them and offer
them for
sale.
Bernard says
that the
2million
Georgia
State
University
in Atlanta
who
studon the markets.
market probably
represent
iesantibodies
research labour
We made
post250,000500,000
unique core
antibodies.
docs
so cheap that principal
investigators
had
necessity,tomany
researchers
rely on
lots By
of incentives
hire them.
word
of mouth
or the
literature
for
Discussion
about
thepublished
postdoc problem
has
advice.
But that creates
self-perpetuating
grown
increasingly
loud. InaDecember
2014, a
problem, convened
in which better-performing
committee
by the US NationalantibodAcadies that
becomea available
later are
rarely used,
emies
released
report aimed
at highlighting
andFridtjof
improving
the postdocsaplight.
The
says
Lund-Johansen,
proteomics
THE FUTURE OF THE
POSTDOC
BUYER BEWARE
Take the example of Ioannis Prassas, a proteomics researcher at Mount Sinai Hospital in
Toronto, Canada. He and his colleagues had
been chasing a protein called CUZD1, which
they thought could be used to test whether
someone has pancreatic cancer. They bought
a protein-detection kit and wasted two years,
kit was recognizing a different cancer protein,
Most scientists who purchase antibodies believe
the
label
printed
on the vial, says
y the
time
Sophie
Thuault-Restituito
Rimm.reached
As a pathologist,
wasnt
her twelfth Iyear
as atrained
postfellow, she
had finally
had
that youdoctoral
had to validate
antibodies;
I was
just
trained enough.
that you She
ordered
them.
had completed
her first
Antibodies
by the
immune
postdocare
inproduced
London, then
moved
to
systemsNew
of most
vertebrates
to(NYU)
target anininvader
York
University
2004
a bacterium.
Sinceand
thetwo
1970s,
scientosuch
start as
a second.
Eight years
laboratotists
have
exploited
foreffectively
research. If
ries
later,
she
was still antibodies
there and still
researcher
injects a dependent
protein of interest
into
a apostdoc,
precariously
on outside
a rabbit,
whiteand
blood
known
as BHer
cells
grants
to secure
paycells
for her
position.
will start
the
research
on producing
Alzheimersantibodies
disease wasagainst
not makprotein,
can be collected
thewas
aniing
it intowhich
high-profile
journals,from
so she
mals blood.
For a more
consistentpositions
product,in
the
unable
to compete
for academic
Bcells
canStates
be retrieved,
fused
anscience
immorthe
United
or Europe.
Shewith
loved
talized
cell and cultured
to provide
a theoretiand
had immense
experience,
but with
two
cally unlimited
young
children atsupply.
home, she knew she needed
Three decades
ago, scientists
who needed
something
more secure.
My motivation
was
antibodies
for their
experiments
had
tosays.
make
gone.
I was done
with doing
research,
she
them
But by the late
1990s,into
reaSo inthemselves.
2013, Thuault-Restituito
moved
companies
had started to take
over the
a gent
job as
a research-laboratory
operations
chore. at NYU, where she coordinates buildmanager
more than
companies
sell over
ing Today,
renovations
and 300
fosters
collaboration
There is a growing number of postdocs

and few places in academia for them to go.
But change could be on the way.
ANTIBODIES
ARE NOT
MAGIC
REAGENTS.
BY KENDALL POWELL
between labs. She enjoys the fact that her staff

position has set hours, as well as better pay
and benefits. But at the time of the move, she
mourned the loss of a research career and she
for every
protein
in thepursuing
human one.
genome.
It has
regrets
the years
wasted
I stayed
looked
some
20,000
commercial
five
yearsat
more
than
I should
have, sheantibodsays.
ies
so far and found that
than
can be
Thuault-Restituito
is theless
face
of a50%
postdocused
effectively
look atThese
protein
distribution
toral
system
that istobroken.
highly
skilled
in preserved
tissue5driving
. This has
led some
scientists
are aslices
majorofengine
scientific
scientistsyettothey
claim
up poorly
to half rewarded
of all comresearch,
arethat
often
mercially
antibodies
are unreliable.
and
have noavailable
way to progress
in academia.
The
number
of postdocs
science
But reliability
canin
depend
onhas
theballooned:
experiment.
experience
commercial
inOur
the United
Stateswith
alone,
it jumpedantibodies
by 150%
is that they
areand
usually
applicabetween
2000
2012.okay
But in
thesome
number
of
tions, but
might
be terrible
in others,
says
tenured
andthey
other
full-time
faculty
positions
Mathias
Uhln
at the
Royalplaces,
Institute
ofeven
Techhas
plateaued
and,
in some
it is
shrinking
Nature 472,
2011).
nology in(see
Stockholm,
who276279;
coordinates
the
Many
postdocs
Human
Proteinmove
Atlas.on to fulfilling careers
Researchers
ideally
thatinan
elsewhere,
but those
whoshould
want tocheck
continue
antibody
has
been
tested forthwarted.
use in particular
research
can
find
themselves
They
applications
tissue types, but
themultiquality
end
up trappedand
as permadocs:
doing
ofpostdoc
information
supplied
can vary
ple
terms,
stayingby
invendors
these positions
1 4 4NATURE
| N A T COLLECTIONS
0 | 9 A P SUMMER
R I L 2 0 1 READS
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2 1 M A Y 2 0 1 5 | V O L 5 2 1 | N A T U R E | 221
75
NEWS FEATURE
FEATURE NEWS
ILLUSTRATION BY VIKTOR KOEN
SEX
REDEFINED
sexes becomes even blurrier. Scientists have identified many of the genes
involved in the main forms of DSD, and have uncovered variations in
s a clinical geneticist, Paul James is accustomed to discussing some these genes that have subtle effects on a persons anatomical or physiologiof the most delicate issues with his patients. But in early 2010, he cal sex. Whats more, new technologies in DNA sequencing and cell biolfound himself having a particularly awkward conversation about ogy are revealing that almost everyone is, to varying degrees, a patchwork
sex.
of genetically distinct cells, some with a sex that might not match that of
A 46-year-old pregnant woman had visited his clinic at the Royal the rest of their body. Some studies even suggest that the sex of each cell
scientists than we
haveitsplaces
for, but
Melbourne
in Australia
hear thefrom
results more
of an amniocentesis
drives
behaviour,
through
a complicated
network
ofand
molecular
intercommitteeHospital
called for
a hike into
salaries,
whats
best for that
postdoc
whats best
for
andwas
strainsactions.
were not
harmful
in much
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recommended
starting for
salary
of the stresses
test
screen her
babys chromosomes
abnormalities.
The baby
I think
theres
greater
postdocs
as diversity
a whole?within male or female,
US$42,840
to $50,000,
5-year limit
on the
fine
but follow-up
testsand
hadarevealed
something
astonishing
about
and there
is certainly
an areaMicoli
of overlap
some limits
peoplecombat
cant easily
way they are
now, says
Shirley
Tilghman,
sayswhere
that term
two
define themselves
within
binary structure,
says John
Achermann,
the
Her
body was
builtscientists
of cells from
individuals,
prob-of Princeton
themother.
length of
postdocs.
Senior
in thetwopresident
emerita
University
in the
problematic
phenomena.
The first
is the just
ably
fromStates,
twin embryos
had
merged
in her own
mothers
who studies
sex development
endocrinology
at University
College
United
who havethat
been
urging
reforms
New
Jersey, womb.
who has studied
the workforce
oneand
more
year, experiment
or paper
synAnd
was more.
One set ofascells
carried
two Xproblem.
chromosomes,
Londons
Institute
of Child
Health.in which postdocs feel that they must
for there
the scientific
workforce
a whole,
have
Some the
changes
will have
to happen.
drome,
complement
that
typically
makes aas
person
the other had an X
These discoveries do notendlessly
sit well inbuild
a world
inacademic
which sexCV
is still
defined
identified the
postdoc
oversupply
one offemale;
the
their
before
movand
a Y.urgent
Halfway
through
her fifth
decade
allow
for any
in biological
most
issues
(B. Alberts
et al.
Proc.and
Natlpregnant with her third in binary terms. Few legal systems
ing on. The
second
is ambiguity
the permadoc
who stays
child,
woman
learned
for the first
time that a large part of her body sex, and a persons legal rights
on indefinitely,
eventually
runs into
his or her
and social status
can be heavily
influenced
Acad.the
Sci.
USA 112,
19121913;
2015).
was Experts
chromosomally
male1. that
Thats
kind will
of science-fiction
for by whether their
birth certificate
says
male or female.
acknowledge
change
be In 2008,material
while Thuault-Restituito
was there,
advisers
retirement
and is stranded without
NYUs
School of Medicine
decided
to try a with
someone
who
in forAcademies
an amniocentesis,
James.
The
main problem
a strong
dichotomy
is that himself
there areencouninterhard; after
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National
made says
a job,
a situation
that Micoli
Sex canrecommendations
be much more complicated
at first seems.
According
to itmediate
cases thatapush
limitsHaving
and askaus
to figure
outforces
exactlypostdocs
where
similar
15 yearsthan
agoitwith
tough-love
approach:
began enforcing
rule thetered.
hard
deadline
little
effect.
But some
institutions
and counthe
simple
scenario,
the presence
or absence
of a Y chromosome
is what
dividing
line isfor
between
and females,
says
Arthur
Arnold
at
that researchers
couldthe
hold
a postdoc
a tomales
make career
decisions
and
people
are better
counts:
withstarted
it, youto
areaddress
male, and
without
it, you are
female. But
doc- the University
California,
LosheAngeles,
whopostdocs
studies who
biological
sexin
tries have
the issue.
Several
maximum
of 5 yearsincluding
time of
spent
at for it,
says. Of the
left NYU
tors
long known
that
some people
straddle
boundary
their
differences.
And thats
a very
difficult
problem,
because
sex can
UShave
universities
have
enforced
5-year
term theother
institutions.
In 2014,
35 of the roughly
400 often
2014,
Micoli
says that
roughly
equal numbers
sex
chromosomes
say one
thing, but their
gonads (ovaries
testes)
gotfaculty positions and left academia.
be defined
a number
limits,
New Zealand
inadvertently
narrowed
postdocsorthere
leftorbecause
their time
was up.of ways.
sexual
anatomywhen
say another.
Parents
childrenofwith these
kindslimit
of conthe pipeline
it slashed
the of
number
The time
can be painful for people who
Other major research universities, such as
ditions
known
as intersex
conditions,
or differences
or disorders
of Keith
THEMicoli,
START chairman
OF SEX of the University of California system and the
postdocs
available,
and some
laboratories
are feel forced
out, says
University
ofisNorth
Carolina,
Hill
sex
development
(DSDs)
often
face
difficult decisions
aboutofwhether
That
the two sexes
are physically
different
obvious,
but at theChapel
start of life,
moving
permadocs
into
stable,
better-paid
the board
the National
Postdoctoral
Associ(UNC), have
also implemented
5-year
term
topositions.
bring up Other
their child
as a boy
a girl.
researchers
now
say that
is not.School
Five weeks
into development,
a human
embryo has the
potential
scientists
whoorare
keenSome
to help
ation and
director
of theitNYU
of Medilimits.
But the
limits
are
not always
strictly
aspostdocs
many as 1are
person
in 100
has
somewith
forminterof DSD2cine
.
to formPeople
both male
and female
anatomy.
Next
to the
developing
kidneys,
watching
the
results
postdoctoral programme.
coming
enforced.
Postdocs
their advisers
When
genetics
is taken
consideration,
the boundary
between
as the gonadal
ridges
emergeand
alongside
two pairs can
of
est.
Weve
always
beeninto
at risk
of producing
up against
it putthe
me intwo
an bulges
ethicalknown
quandary:
BY CLAIRE AINSWORTH
THE FIXED-TERM POSTDOC
222
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9 A
P R I L 2 0 1 5 || NATURES
V O L 5 2 0SUMMER
| N A T UREADS
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FEATURE NEWS
NEWS FEATURE
1
analysis
showing
results
in 47 postdocs
of 53 landoften
request
a sixththat
year
and some
mark
cancer
could
not be
are
moved
intoresearch
positionspapers
that are
postdocs
inreproduced.
everything but name. When ThuaultA few scientists
who
have the
been
burned
Restituito
bumped up
against
5-year
ruleby
experiences with
begunitto
inbad
2006before
the antibodies
universityhave
enforced
speak
up. Rimms disappointment
him on a
more
strictlyshe
was promoted toset
associate
crusadescientist
to educate
others
by writing
reviews,
research
, a staff
position
that brought
hosting
web seminars
andpay
raising
thesecurity.
problem
better
benefits,
but no extra
or job
in countless
conference
talks. Heonand
others
Her
position was
still contingent
outside
are calling
the was
creation
of standards
grant
funding,for
which
far from
guaranteed.by
which
antibodies
should
be and
made,
used
and
At
the end
of the day,
my job
what
I was
described.
somechange
half a dozen
doing
in the And
lab didnt
at all,grass-roots
she says.
efforts
sprungThompkins,
up to provide
better
ways
Sibby have
Anderson
who
directs
the
affairs
office at UNC, says
of postdoctoral
assessing antibody
quality.
is too soonpostdocs
to call thethere
cause
a movethatBut
the itmost-recent
embrace
ment.
are allenter
thesewith
resources
outfind
there,
the
termThere
limit. They
a plan to
a
but nobody
uses them
andthe
many
people
arent
career
path quickly
and exit
postdoc
early
if
aware of them,
Len Freedman,
who
aneven
opportunity
arises. says
Anderson
Thompkins,
heads
thesat
Global
Biological
Standards
Instiwho
also
on the
2014 National
Acadtute, report
a non-profit
groupsays
in Washington
DC
emies
committee,
that this type
to improving
biomedical
ofcommitted
planning should
begin in
graduate research.
school,
Most vendors
have no incentive
to change
alongside
raised awareness
of the academic
bottleneck
that
will
face.
Whereas
whats going
ontrainees
right now,
even
though
a lot of
the antibody
reagents
suck. continue into a
about
65% of US
PhD-holders
postdoc, only 1520% of those move into tenBUYER BEWARE
ure-track
academic posts. The European situTakeisthe
example
of Ioannis Prassas,
proteoation
even
more competitivein
theaUnited
mics researcher
at Mount
Kingdom,
for example,
aboutSinai
3.5% Hospital
of sciencein
Toronto, Canada.
He and his colleagues
had
doctorates
become permanent
research staff
chasing a protein called CUZD1, which
atbeen
universities.
they
couldalso
be used
test whether
Termthought
limits have
beentotested
in the
someone
has pancreatic
cancer.
They where
bought
United
Kingdom,
France and
Germany,
a protein-detection
kit and of
wasted
labour
laws limit the number
years two
that years,
aca$500,000
and thousands
of patient
samples
demic
researchers
can remain
on short-term
before they
realized
in the
contracts
before
they that
mustthe
be antibody
hired permakit was
recognizing
differentthese
cancer
protein,
nently.
But
it is unclearawhether
laws
help
and didthere
not bind
to CUZD1
at all2. In
orCA125,
hurt, because
are often
ways around
them.
aIn
promising
hypothesis
meant
thatoriginally
he and his
Germany,
for example,
a law
intended
to curb
contracts
aboutIf
group had
failedpostdoc
to do all
the righttotests.
says,
Here is an
assay
you
can use,
sixsomeone
years after
completing
a PhD
was
altered
so
youscientists
are so eager
to test itonyou
can forget
that
that
can remain
short-term
conwhatashas
been
promised
is notby
theancase.
tracts
long
as they
are funded
external
Most
who purchase
antibodgrant
and scientists
not paid directly
by the university.
iesresult
believe
the label
printed
the vial,
says
The
is that
scientists
surf on
endlessly
from
Rimm.
Astoaanother:
pathologist,
I wasnt
trained
one
postdoc
There
are unlimited
that youofhad
to validate
antibodies;
was just
numbers
short-term
contracts,
saysI Sibylle
traineda that
you ordered
Anderl,
German
postdoc them.
in astronomy
at the
Antibodies
arefor
produced
the immune
Grenoble
Institute
PlanetarybySciences
and
systems of most
vertebrates
target
an invader
Astrophysics
in France.
Thetoreal
problem
for
such aspostdocs
a bacterium.
thehave
1970s,
scienGerman
is thatSince
we dont
enough
permanent
positions antibodies
available. for research. If
a researcher injects a protein of interest into
a rabbit, white blood cells known as B cells
will start producing antibodies against the
protein,dont
which
can
aniPostdocs
have
tobe
becollected
forced outfrom
of thethe
pipemals
blood. For
more
consistent
product,
the
line
if, instead,
theyaare
never
let in. That
was the
Bcells
can be
retrieved,
fusedZealand
with angovernimmorresult
when,
in 2010,
the New
talized
cell and
cultured
to provide
ment
decided
to axe
a scheme
that hada theoretifunded
cally unlimited
supply.
roughly
90 postdoc
slotseliminating nearly
Threeofdecades
ago, in
scientists
who needed
one-third
its postdocs
one fell swoop.
antibodies
experiments
hadsalaries
to make
Before this,for
thetheir
government
covered
them
themselves.
But
by the late
1990s,who
reafor
a huge
chunk of the
countrys
postdocs,
gentsalaries
companies
had started
toequivalent
take over to
the
enjoy
and benefits
nearly
chore.
those
starting permanent academic positions.
more
than 300
sell over
For Today,
most labs,
postdocs
arecompanies
too expensive
to
THE ELITE POSTDOC
2million
antibodies
for research.
ofgov2011,
fund
from research
grants.
So whenAs
the
the market
was worth
$1.6 billion, accordingato
ernment
funding
disappearedmainly
global consultancy
Frost & Sullivan.
money-saving
decisionso
too did many
postdoc spots.
DEVASTATING
EFFECTS
Lara Shepherd
got caught in the squeeze
There
are signs vanished
that problems
when
fellowships
in herwith
fieldantibodies
of evoluare having
broad
potentially
tionary
biology
andand
she reached
the devastating
end of her
effects
on the
research
record.
In 2009,
one
first
postdoc,
at the
Museum
of New
Zealand
devoted aninentire
issue toShe
assessing
the
Tejournal
Papa Tongarewa
Wellington.
secured
antibodies
thatatare
used University
to study G-proteina second
postdoc
Massey
in Palmcoupled
receptors
cell-signalling
erston
North,
using(GPCRs)
a grant to pay
half of her
proteins
are targeted
by drugs
to treat
varisalary
andthat
working
part time
to cover
the rest.
ous
to schizoBut
shedisorders,
could not from
land aincontinence
coveted academic
posi3
phrenia.
In an analysis
of 49
commercially
tion.
New Zealand
is so small
there
are very
available
that targeted
signalling
few
jobs inantibodies
your particular
area of19
expertise,
receptors,
she
says. most bound to more than one protein, meaning that they could not be trusted to
I THINK THE GOAL IS

TO MAKE THE POSTDOC
SOMETHING SPECIAL.
IT SHOULD BE HARD TO
GET A POSTDOC
HARDER THAN GETTING
INTO GRADUATE
ANTIBODIES
SCHOOL.
ARE NOT
MAGIC
REAGENTS.
Shepherd eventually found a temporary

research position back at the Museum of New
Zealand, and scored an early-career grant from
the Royal Society of New Zealand, which she
leveraged into a permanent position. She now
oversees genetic analyses of plant, animal and
fossil samples. Without the early-career fellowship, she says, I would have been looking
for every
proteinin the human genome. It has
outside
of science.
looked
at some 20,000
commercial
Many principal
investigators
(PIs) antibodin New
ies so far
found with
that less
than 50% With
can be
Zealand
areand
unhappy
the situation.
effectively
to look
at they
protein
distribution
noused
postdocs
to help
them,
struggle
with
inmanagement
preserved slices
tissue5. Thisand
hasthey
led some
lab
andofmentoring,
say
that
labs have
dependent
onof
graduate
scientists
to become
claim that
up to half
all commerciallyAll
available
antibodies
are unreliable.
students.
weve done
is to outsource
our
postdocs,
says Shaun
Hendy,
a physicist
at
But reliability
can depend
on the
experiment.
Our
experience
with commercial
antibodies
the
University
of Auckland.
Weve removed
a
is thatofthey
are researchers
usually okayfrom
in some
applicacohort
young
our system
tions,
but they
might
be terrible
in others,less says
and
replaced
them
with
even younger,
Mathias Uhln
at the Royal
Institute of Techexperienced
researchers.
nology
in Stockholm,
who coordinates
the
Once trained,
the countrys
best PhD stuHuman
dents
tendProtein
to headAtlas.
out of science or to postdocs
Researchers
shouldacheck
that an
overseas.
One lab ideally
head describes
top marineantibody
has been
tested forno
useprospect
in particular
biology
graduate
whowith
of a
applications
and tissue
types, but
quality
postdoc
or academic
jobended
upthe
driving
a
of information
suppliedlanding
by vendors
can vary
forklift
before eventually
a position
in
1 4 6NATURE
| N A T COLLECTIONS
0 | 9 A P SUMMER
R I L 2 0 1 READS
5
tremendously.
A common
complaint
from scithe
countrys statistics
bureau.
Hendy predicts
entists
is that companies
notin
provide
the data
that
the postdoc
void will do
result
lower-qualrequired
to evaluate
a givenprojects.
antibodys
specificity,
less-complex
research
Im
sure
ity orwill
its lot-to-lot
variability.
might
there
be productivity
hits Companies
down the line.
ship
a batch
ofhead
antibodies
characterization
Simon
Davy,
of the with
school
of biological
information
derived University
from a previous
batch.
sciences
at the Victoria
of WellingAnd
thethat
datathe
areresearch
often derived
under
ideal conton,
says
culture
of university
ditions that loses
do notvibrancy
reflect typical
experiments.
departments
without
any postAntibody
companies contacted
for this
article
docs.
His department
of 35 research
groups
saidfewer
that itthan
is impossible
to test
hosts
10 postdocs.
Histheir
ownproducts
lab has
across
all experimental
conditions,
been
lucky
enough to have
a couplebut
of they
themdo
dataand
andhework
scientists
inprovide
the pastreliable
56 years
sayswith
that this
has
to improve
antibody
quality and performance.
tripled
his groups
productivity.
Googlewand
to find
products,
IfMany
Davy academics
could waveuse
a magic
and
bring
so optimizing
search results can
sometimes
back
the government-funded
postdoctoral
matter more
to a companysothan
optimizing
the
positions,
he wouldand
would
560 of the
actual reagents,
says
TiminBernard,
head of the
countrys
scientists,
who,
2011, collectively
biotechnology
consultancy
Pivotalminister,
Scientific
sent
a letter of protest
to the science
in Upper
Heyford,
UK. Christi
Bird,
Frost &
among
other
government
leaders.
Ivea strugSullivan
analyst
based infrom
Washington
DC, says
gled
to think
of positives
our experience,
that researchers
are often more interested
Hendy
says. Science-development
managerin
howBerryman,
quickly reagents
canNew
be delivered
Anne
from the
Zealandthan
Min-in
searching
for antibodies
with
valiistry
of Business,
Innovation
andappropriate
Employment,
dation
data. Itsto
thecut
Amazon
effect:
want it
says
the decision
postdocs
wasthey
designed
two or threegovernment
days, with free
shipping.
toinreprioritize
support
towards
who
arecontends
aware ofthat
the antibody
laterResearchers
career stages,
and
there is
that scientists
need to
be more
noproblem
evidencesay
of harm
to the countrys
scientific
research.
You
cant
throw thembalk
on your
sample
Most
USjust
researchers
at the
idea and
of
restricting
number
entering
expect thethe
result
you getofispostdocs
100% reliable
without
putting
some critical
thinking into it,acell
says
the
system.
Jennifer
Lippincott-Schwartz,
James Trimmer,
of NeuroMab
Unibiologist
at the UShead
National
Instituteatofthe
Child
versityand
of California,
Davis, which
antiHealth
Human Development
inmakes
Bethesda,
bodies forsays
neuroscience.
Like many
suppliers,
Maryland,
that it is nearly
impossible
to
NeuroMabwho
explicitly
states
the types of experidetermine
has the
characteristics
of a
ment that
an antibody
should
be used
for, but
superstar
researcher
until
mid-way
through
a
scientists
do not
always
follow
the instructions.
postdoc
term.
I dont
think
its bad
when part
Ideally,
researchers
would
to buyinto
antiof that
workforce
has to
leaverefuse
and move
bodies
without extensive
validation
other
professions,
she says. They
carrydataor
with
would
perform
validation
them
skills
that are the
not wasted.
Theythemselves
still have
a (see
knowledge
base that isThis
valuable
to society.that
Bad antibodies).
is something
the process
time consuming
Rimm
IfBut
postdocs
are soisprized,
then one obvious
solution
is to reward
them. Boththat
the involve
2014
recommends
control experiments
engineering
cell lines
to both
and stop
National
Academies
report
andexpress
earlier reports
expressing
protein
of interest,
for example.
urged
US labthe
heads
to consider
creating
senior
Even
he acknowledges
that
few labs will
perstaff
scientist,
or superdoc
, positions.
These
form all
steps.
would
bethe
higher-paid,
permanent jobs for
Somepostdocs
scientists
buyhave
halfno
a dozen
talented
who
desire antibodto start
ies from
different vendors, and then run a few
their
own labs.
assays
see which
performs
But they
Some to
funding
agencies
and best.
institutions
may end
buying
the same
from
around
theup
world
already
offerantibody
this option.
Lippincott-Schwartz,
for example,
two
different places. The largest
vendorshas
compete
superdocs
in her
at
on catalogue
size,cell-biology
so they oftenlaboratory
buy antibodies
from
smaller
suppliers,
andOne
offer
the
National
Institutes
ofrelabel
Healththem
(NIH).
them as
forasale.
Bernard
says thatfor
thethe
2million
serves
software
developer
labs
super-resolution
of intracellular
antibodies on theimaging
market probably
represent
250,000500,000
unique
core antibodies.
structures.
The other
is a microscopy
specialist
many
researchers
rely on
andBy
lab necessity,
manager. They
both
mentor trainees,
word
mouth
or the published
literature
for
help
to of
write
publications
and keep
up with
advice.
But that creates
a self-perpetuating
the
latest technological
advances
in the field.
problem,
inscientists
which better-performing
antibodThese
staff
offer so much to
indiies that
become available
later
are can
rarely
vidual
laboratories,
she says.
They
doused,
the
says Fridtjof
Lund-Johansen,
proteomics
science
they love
without dealingawith
all the
THE SUPERDOC
2 1 M A Y 2 0 1 5 | V O L 5 2 1 | N A T U R E | 223
75
NEWS FEATURE
FEATURE NEWS
The number of researchers in US postdoctoral positions has more than tripled since 1979. The vast majority of postdocs are in the life sciences. Across fields,
median salaries for postdocs are outstripped by those for non-postdoc positions, when measured up to 5 years after receiving a PhD.
70
60
Postdoctoral appointees (thousands)
SOURCE: NATIONAL ACADEMIES
SEX
REDEFINED
THE POSTDOC PILE-UP

US$76,000
Median Non-postdoctoral
salaries
2010 Postdoctoral
Health
Engineering
Science
$43,000
Physical sciences 13%
50
40
Engineering 11%
30
Postdoc
disciplines
2012
20
Maths and computer

sciences 3%
Geosciences 3%
10
Psychology,
social sciences
and other 5%
Life sciences
65%
1979
2012
bureaucratic stuff associated with being the PI.

Some funding bodies do offer funds spe- positions and more staff scientiststo deflate
Each of her superdocs earns $20,00030,000 cifically for staff scientists, and others are the swollen postdoc population. That would
more than postdocs typically earna cost she introducing them. In March, the US National stop the postdoctoral fellowship from being
was able to cover by requesting more funds for Cancer Institute proposed a grant programme the default step after earning a doctorate. I
her labs annual budget from the NIH.
designed for superdocs that would cover a think the goal is to make the postdoc someBut other lab heads say that they struggle to salary in the range of $75,000100,000 for thing special, he says. It should be hard to
find the resources to pay for superdocs, and five years. It is planning to grant 5060 such get a postdoc harder than getting into
without an increase in funding, the inevita- research specialist awards throughout the graduate school.
ble trade-off is fewer workers. That reality is next 18 months.(see page 255).
The question is, can the scientific commuhard to stomach for lab heads who are trying
nity be convinced? No one interviewed for
this story whether lab heads or postdocs
to balance the pressure to produce results and
papersgenerally maximized by lots of staff
themselves wanted to give up these highly
B YonC Llow
A I Rsalarieswith
E A I N S W O R T H the desire to keep and The real solution to the
sexes
becomesproblem,
even blurrier.
Scientists
havepositions.
identified But
many
oflab
theleaders,
genes
postdoc
valued
research
few
involved in the
main forms
of DSD, and
have uncovered
variations
promote experienced employees. Its econom- Tilghman says, lies in dramatically
changing
institutions
or funders
seem willing
or ableinto
a clinical
geneticist,
Paul
is accustomed
to discussing
some
genes
thatsmaller,
have subtlespend
effectswhat
on a persons
or physiologiics, sand
we need
to face up
to James
that. There
may the
composition
of labsthese
to make
them
it takes anatomical
to reward them
approprimost people
delicateworking
issues with
his lab.
patients.
2010,
cal sex. Whats
more, new technologies
DNA
sequencing
and cell biolnot of
bethe
as many
in your
No But
withinaearly
higher
ratiohe
of permanent
staff scientists
ately. Petskoinsays
that
funding agencies
could
having
a particularly
awkward to
conversation
about
ogya are
that almost
everyone
is, to varying
degrees,
a patchwork
onefound
wantshimself
to talk about
that,
says Micoli.
trainees. This
was also
keyrevealing
recommendastep
in and enforce
change,
by demanding
that
sex.scientist struggling with this dilemma tion in the National Academies
of genetically
distinct
cells,universities
some with adirect
sex that
might not
matchoverhead
that of
One
report.
The
a portion
of their
46-year-old
pregnant
womancell
had
visited hismore
clinicI at
thethought
Royal about
the rest
their body.the
Somepaymentsmoney
studies even suggest that
thetosex
each cell
isALeslie
Leinwand,
a molecular
biologist
have
thisofquestion,
given
theofuniversity
Melbourne
HospitalofinColorado
Australia Boulders
to hear theBioresults more
of an amniocentesis
drives
through
a complicated
network of molecular
at the University
Im convinced that
at its
thebehaviour,
heart of the
rather
than the labtowards
creatingintermore
Frontiers
relies on two
test
to screenInstitute.
her babysShe
chromosomes
for postabnormalities.
Theisbaby
was actions.
I think
theres much
greater diversity
within male or female,
problem
the structure
of the lab,
says Tilghstaff-scientist
positions.
fine
but
follow-up
tests
had
revealed
something
astonishing
aboutup a and
is of
certainly
an areaDavy
of overlap
where
some
people
cantneeds
easilyto
docs,
Massimo
Buvoli
and
Steve
Langer,
who man,
who headed
2012there
study
the NIH
points
out that
the
solution
define themselves within the
binary or
structure,
says John
Achermann,
the
mother.
Her
body
wasnearly
built of
cells
from twoworkforce
individuals,
have
been in
her
lab for
two
decades.
(seeprobgo.nature.com/wsqzgj).
be global,
else postdocs
denied
jobs in one
ably
embryos
that had merged
infor
her ownThe
mothers
womb.
who
development
and endocrinology
at University
College
Butfrom
if shetwin
created
staff-scientist
positions
biggest
challenge,
shestudies
says, issex
persuadcountry
will simply slide
across country
borAnd
there wasthe
more.
One setAcademies
of cells carried
two Xing
chromosomes,
Londons
of Childders
Health.
themas
National
report
lab heads to the
embrace
such a Institute
model when
to find them elsewhere. In an ideal world,
recommendsthe
twomakes
increased
salaries
complement
that typically
a person
female;there
the other
had an X
These
do nothe
sitsays,
well in
a world in
whichbesex
is still
defined
is a tremendous
bias
in discoveries
favour of the
postdocs
would
able
to take
their
would
equal nearly
two-thirds
the annual
fundingallow
wherever
like. People
should
and
a Y. Halfway
through
her fifthofdecade
and pregnant
herthat
third
in binary
terms.
legal systems
for anythey
ambiguity
in biological
cheapwith
labour
graduate
students
andFew
postbe going
to the
bestcan
labs,
the best
places for
child,
thefor
woman
learned
thegrant,
first time
that a large
of her body
sex,
and
persons legal rights
and social
status
be heavily
influenced
budget
a typical
NIHfor
R01
on which
docspart
represent.
But that
bias
is ashort-sighted,
1
was
chromosomally
male
. Thats
ofto
science-fiction
material
by whether
birth
male
many
biomedical labs
rely.
Therekind
needs
be she argues,
whenfor
one staff
scientisttheir
can do
thecertificate
them tosays
work
andor
befemale.
trained, which are dotted
someone
who
justpeople
came inwho
for an
James.
The main
problem with
a strong
a place for
such
justamniocentesis,
want to stay says
work
of three less-experienced
researchers.
around
thedichotomy
world. is that there are interWeveAccording
got to persuade
facultycases
thatthat
thispush
is a the limits
be much
than itworat first seems.
to mediate
and
ask us to figure out exactly
where
atSex
thecan
bench,
butmore
I staycomplicated
awake at night
As for
Thuault-Restituito,
she does
not
rying
about
salaries
Massimo
and Steve.
regret
But if
she had
to walk
the
simple
scenario,
thefor
presence
or absence
of a Y chromosome
whata positive
the dividing
line
between
malesher
andpostdocs.
females, says
Arthur
Arnold
at
true trade-off,isand
trade-off
foristheir
Frankly,
I cant
afford
to payand
them
what they
counts:
with
it, you
are male,
without
it, you are
female.
But doc- the University of California,
Angeles,
who
studies
biological
sex
research
productivity.
thatLos
path
again, she
would
move
into another
deserve,
Leinwand
says.some
Anne
Carpenter,
a the boundary
tors
have long
known that
people
straddle
their
differences.
And
thats often
a very
difficult
because
sex PhDs
can
Labs stuffed
full of trainees
do not
always
career
much
earlier.problem,
She agrees
that fewer
sex
chromosomesbiologist
say one at
thing,
but their
gonads (ovaries
besays
defined
a number
of ways.
be flowing into postdocs, and is frank
computational
the Broad
Institute
translateortotestes)
better or
results,
Gregory
Petsko,
should
sexual
anatomy say
another. Parents
of children
theseofkinds
of con-National Academies com- with graduate students who ask her for advice:
in Cambridge,
Massachusetts,
requested
extrawithchair
last years
ditions
known
as intersex
conditions,
or differences
or and
disorders
of THE START
OF SEX
grant funds
to hire
more permanent
scientists
mittee
a neuroscientist
at Weill
Cornell If you are not 150% sure you want to do it
Medical
College
in New
City.
I dont
sex
development
(DSDs)
found
often face
about
whether
ThatYork
the two
sexes
are physically
is obvious,
but atthe
rather
than trainees,
but
thatdifficult
her pro-decisions
right different
now, dont
do a postdoc.
start of life,
think many
of us
needitthe
labsFive
to be
the into
size development, a human embryo has the potential
toposals
bring were
up their
child asbya grant
boy orreviewers,
a girl. Some
researchers
now say
that
is not.
weeks
criticized
who
asquestioned
many as 1 person
100using
has some
of DSD2we
why sheinwas
suchform
expensive
. have them. Petskotoproposes
form bothcombining
male and female
anatomy.
Next
the developing
kidneys,
Kendall
Powell
is atofreelance
writer based
in
staff
to do
the work.
When
genetics
is taken into consideration, the boundary
between the two
Lafayette,
Colorado.
bulges
known
as the gonadal
ridges
emerge alongside two pairs of
various strategiesterm
limits,
fewer
postdoc
THE REINVENTED LAB
224
NATURE
COLLECTIONS
9 A
V O L 5 2 0SUMMER
| N A T UREADS
RE | 147
VOICES OF
HUBBLE
BY ALEXANDRA WITZE
hen the Hubble Space Telescope blasted into space on 24 April

1990, it promised astronomers an unprecedented view of the
Universe, free from the blurring effects of Earths atmosphere.
But Hubbles quarter-century in orbit has never gone according to plan. The telescope a joint venture between NASA and
the European Space Agency (ESA) faced a crippling flaw after launch
that required astronauts to fly up and fix it. Later, problems with Hubble
and NASAs shuttle programme left the telescopes future in jeopardy.
Through it all, Hubble emerged as the worlds foremost astronomical
observatory. Conceived by astronomer Lyman Spitzer in the 1940s, the
telescope has led to fundamental discoveries, revealing for instance that
the furthest reaches of the Universe are full of galaxies and that dark
energy is pushing the cosmos apart at an ever faster rate. Its stunning
images have transformed scientific understanding of the Universe and
become wildly popular.
Here, Nature tells the story of Hubble through the words of some of
its key players, beginning in 1972. At that time, the space telescope was
little more than a set of engineering drawings.
SUMMER
2 8 2NATURE
| N A T COLLECTIONS
0 | 16 AP
R I L 2 0 READS
15
25
NASA
As the venerable
space telescope
turns 25 this month,
key scientists and
engineers recount the
highs and lows of its
stellar career.
NEWS FEATURE
FEATURE NEWS
NASA/CORBIS
SEX
REDEFINED

WIDER SPECTRUM THAN THAT.THE
MONTHS
IMMEDIATELY
AFTER
LAUNCH
WERE JUST A
NIGHTMARE.
Workers inspect
Hubbles 2.4-metre
main mirror in 1984.
BY CLAIRE AINSWORTH
sexes becomes even blurrier. Scientists have identified many of the genes
involved
in into
the main
ofaboard
DSD, and
uncovered variations in
ROBERT ODELL, FORMER HUBBLE PROJECT SCIENTIST: I was told it Hubble finally
soared
orbit forms
in 1990
thehave
space
s a clinical
James
accustomed
to discussing
some Discovery.
these genes
have
subtle
a persons
or physiologiwould
not takegeneticist,
very longPaul
to build
it.isBut
I went in with
my shuttle
Butthat
when
the
firsteffects
imageon
came
back,anatomical
it
the most
he cal
sex. to
Whats
more,
newastechnologies
in DNA sequencing and cell bioleyesofwide
open.delicate issues with his patients. But in early 2010,
was blurry
owing
a flaw
known
spherical aberration.
a particularly
awkward
conversation
about ogy are revealing that almost everyone is, to varying degrees, a patchwork
I found
could himself
see thathaving
building
Hubble was
going to
be the
future.
sex. It was a chance to lead and influence the devel- SANDRA FABER,
of ASTRONOMER,
genetically distinct
cells,
with SANTA
a sex that
UNIVERSITY
OF some
CALIFORNIA,
CRUZ:might not match that of
A 46-year-old
had visited
histhe
clinic
at theThe
Royal
rest
of their
Some studies
evenField
suggest
opment
of whatpregnant
I thought,woman
even then,
would be
most
picturethe
was
taken
withbody.
our camera
[the Wide
and that the sex of each cell
Melbourne
to hear the results of an amniocentesis
drives its behaviour,
through
a complicated
of molecular interimportantHospital
telescopeinofAustralia
my generation.
Planetary Camera],
and it looked
weird.
It was a star,network
but
test to screen her babys chromosomes for abnormalities. The baby
wasa bright
actions.
Iat
think
theres One
muchofgreater
diversity within male or female,
it had
point
the centre.
the astronomers
fine
OLIVIER,
but follow-up
hadCHIEF
revealed
something
and
there at
is certainly
area
of overlap
where some people cant easily
JEAN
FORMER tests
HUBBLE
ENGINEER:
Hubbleastonishing
was a onabout
our team
looked
the imagean
and
said,
This telescope
define
themselves
within
the binary
structure,
says John Achermann,
the
mother.
Her body
was technologies.
built of cells from
two
individuals,
probproving
ground
for many
Things
you
would has
spherical
aberration.
That
immediate
diagnosis
was
ably
from
twinbe
embryos
thatlike
haddesigning
merged inlatches,
her own
mothers extremely
womb. severe,
who studies
and endocrinology at University College
think
would
low-tech,
evolved
with sex
hugedevelopment
consequences.
And
wasproblem.
more. One
of cells
carriedmore
two Xand
chromosomes,
the Londons Institute of Child Health.
intothere
a major
Weset
kept
uncovering
more
complement
an X The months
These discoveries
do not
sitlaunch
well in awere
world
in awhich sex is still defined
challenges. that typically makes a person female; the other had
OLIVIER:
immediately
after
just
gotHalfway
to be such
a longher
programme
thatand
I began
to think
and Ita Y.
through
fifth decade
pregnant
with her
third in binary terms. Few legal systems allow for any ambiguity in biological
nightmare.
child,
thereal
woman
learned
forthe
first
time
a large
parttoof her body sex, and a persons legal rights and social status can be heavily influenced
its not
life, its
a game
and
one
daythat
theyre
going
was
male1.we
Thats
kind
material
forOurby
whether
their
sayswas
malereally
or female.
say:chromosomally
Were just kidding,
wanted
toof
seescience-fiction
how much you
FABER:
team
wanted
to birth
knowcertificate
whether that
someone
who
The
problem
withina and
strong
could take.
just came in for an amniocentesis, says James. true. We moved
themain
secondary
mirror
outdichotomy
of focus in is that there are interSex can be much more complicated than it at first seems. According
mediate
that push
the limits
and ask us
to figure out exactly where
orderto
to sample
thecases
spherical
aberration
at different
levels.
the
simple
scenario,
the presence
or absence
a Y chromosome
is what
dividing
line is between
males
females,
ODELL:
The
lowest period
was when
it was of
becoming
clear In
June, atthe
a project
meeting,
we showed
ourand
results
and says Arthur Arnold at
counts:
it, you
are male,
withoutthat
it, you
are female.
docCalifornia,
Los Angeles, who studies biological sex
that wewith
couldnt
afford
to do and
everything
we wanted
to. But
there
couldthe
beUniversity
no doubt. Itofwas
a catastrophe.
tors
have
people
straddle
the boundary
This
waslong
rightknown
in the that
earlysome
hardware
phase.
I proposed
that their differences. And thats often a very difficult problem, because sex can
sex
saylaunch
one thing,
but without
their gonads
(ovaries
or testes)
orI gotbeadefined
a number
ways.
headquarters.
wechromosomes
would initially
Hubble
all the
instruOLIVIER:
phone call
to comeofinto
NASA
ments
that were
developed.
proposed
that
out kinds
of We
sexual
anatomy
saybeing
another.
Parents ofI children
with
these
of conexplained what the problem was. The deputy adminisditions
known
as intersex
or differences
or disorders
START OFkept
SEX telling me, Olivier, youve got
desperation
because
peopleconditions,
were actually
saying we were
trator,ofJ. R.THE
Thompson,
sex
development
often face
difficult
about whether
That the
twoon
sexes
physically
going
to cancel(DSDs)
the programme
unless
youdecisions
significantly
to turn another
knob
theare
spacecraft
todifferent
fix this!isIobvious,
said, but at the start of life,
toreduce
bring up
child
a boyday
or afor
girl.
Some
researchers
now say
that
it ishave
not.aFive
weeks
into development,
a human
embryo has the potential
thetheir
costs.
Theas
lowest
me
was being
chewed
J. R.,
I dont
knob
to turn.
It took a few days
for the
2
asout
many
as 1 person
in 100 has
form of DSD
. the sci- top men toto
form both
female
anatomy.
Nexthad
to the developing kidneys,
in NASA
headquarters
forsome
not standing
up for
realize,
deepmale
downand
in their
hearts,
that they
When
is taken into consideration, the boundary between
two bulges known as the gonadal ridges emerge alongside two pairs of
ence
of genetics
the project.
a realthe
problem.
226
NATURE
1 6 ACOLLECTIONS
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| N A T U READS
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FEATURE NEWS
NEWS FEATURE
analysis1 showing that results

in 47
of 53 landtremendously.
A common
complaint
sciWe put
a telescope
in space
and it antibodies
could hardly
I felt As
they
the bandages
come off
you wontfrom
know
2million
forsee.
research.
of can,
2011,but until
felt likenot
a dog
take was
a bone
from
me.
mark cancer researchterrible.
papersIcould
be wouldnt
the market
worth
$1.6
billion, according
for sure. to entists is that companies do not provide the data
reproduced.
required to evaluate a given antibodys specificA few scientists whoThe
have
been burned
orHUBBLE
its lot-to-lot
variability.
might
problem
turnedby
out to originate from a spacing error ANTONELLA NOTA,ity
ESA
PROJECT
SCIENTIST,Companies
SPACE TELESCOPE
bad experiences with antibodies
haveused
begun
DEVASTATING
ship
a batch
of antibodies
with characterization
in the device
toto
shape
the primaryEFFECTS
mirror. The error SCIENCE INSTITUTE
(STSCI),
BALTIMORE,
MARYLAND:
When we saw
speak up. Rimms disappointment
set himbyonthe
a mirror
Therecontractor,
are signs that
problems with the
antibodies
information
derivedhad
from
a previous
batch.
had been made
Perkin-Elmer
first images,
it was like history
erased
those three
crusade to educate others
by writingand
reviews,
having
broad and
Corporation,
had beenare
missed
repeatedly
bypotentially
NASA. It devastating
years of pain. And the data are often derived under ideal conhosting web seminars and
raising
effects
the research
record.
affected
allthe
fiveproblem
of Hubbles
initialon
instruments,
and
could In 2009, one ditions that do not reflect typical experiments.
in countless conference
talks.
He and
others
journal devoted an entire issue to assessing
the were
Antibody
companies
for this
article
not
be fixed
from
the ground.
WEILER: We
all huddled
aroundcontacted
a little screen,
waiting
are calling for the creation of standards by antibodies that are used to study G-proteinsaidto
that
it isdown.
impossible
to testonly
theirtook
products
for the first image
come
It probably
five
which antibodies should
be made,
and
coupled
receptors
(GPCRs)
alllike
experimental
EDWARD
WEILER,used
FORMER
HUBBLE
CHIEF SCIENTIST:
I had
the uniquecell-signalling
seconds but itacross
seemed
six hours. conditions, but they do
described. And some half
a dozen
grass-roots
proteins
that
are targeted
by drugs
data
and work
honour
of being
the one to
explain
what
the impacts
on to treat
Firstvariwe sawprovide
a little reliable
dot in the
centre,
but itwith
was scientists
a really
efforts have sprung upthescientific
to provide better
ways ofous
disorders,
incontinence
to schizo- dot.
to improve
antibody
andstars.
performance.
programme
Hubble
wouldfrom
be. That
wasthe well-focused
And then
we sawquality
the faint
You just
use Google
find products,
day of infamy.
knew, right then,Many
that academics
we had nailed
it. Thattonight,
I slept
But it is too soon to call
the
causeabout
a moveavailable
antibodies
targeted 19like
signalling
sotrouble
optimizing
search results
can sometimes
But
luckily,
two hours
before
the press that
conference,
a baby. The
with Hubble
was over.
ment. There are all these
resources
out there,
receptors,
most
bound
to more
[Hubble
imaging
expert] John
Trauger
pulled
me aside
andthan one pro- matter more to a company than optimizing the
but nobody uses them and
tein,
meaningyou
that should
they could
not beWith
trusted
to actualvision,
reagents,
Tim Bernard,
headdoing
of the
said:many
Ed, people
I thinkarent
weve got
something
know
its corrected
the says
telescope
could start
even aware of them, says
Len We
Freedman,
who
distinguish
between
receptors.
biotechnology
Pivotal
about.
think we
can fix
this. We have
thesethe
four
relay the science astronomers
hadconsultancy
always hoped
for Scientific
includheads the Global Biological
Standards
Instiof epigenetics
relies heavily
anti- in Upper
Heyford,celestial
UK. Christi
Bird,such
a Frost
mirrors
that are flat,
but if weThe
putfield
a small
curve on them,
a ingon
responding
to fast-moving
events,
as&
tute, a non-profit group
in Washington
DC bodies
to identify
how
regulate
SullivanShoemakerLevy
analyst based in Washington
DC, says
curve
that is the opposite
of the bad
curve on
theproteins
mirror, that
the
death of comet
9, which plunged
committed to improving
biomedical
research.
gene expression have been modified. into
In 2011,
an just
that
researchers
arerepair
often more
interested
it will
cancel out.
Jupiter
months
after the
mission.
But thatin
4
Most vendors have no incentive
change
of 246 antibodies
used infirst
epigenetic
how
quickly
reagents
be delivered than in
I reportedtothis
to the evaluation
press conference.
I promised
big test for
Hubble
was
almostcan
a failure.
we even
had this
fix in
hand,
of course
believedfailed tests for searching for antibodies with appropriate valiwhats going on right now,
though
a lot
of and
studies
found nobody
that one-quarter
anything
we said. It was specificity,
not a friendly
situation.
I had
meaning
that they
oftenDAVID
bound
to dation
ItsPROJECT
the Amazon
effect:
they
want
LECKRONE,
FORMERdata.
SENIOR
SCIENTIST:
That
was
the it
more
onemuch
target.sympathy
Four antibodies
two or
three
withMany
free shipping.
neighbours come up to me
and than
say how
most were
excitinginweek
I had
ondays,
Hubble.
peopledont
BUYER BEWARE
perfectly
specific
but to the wrongrealize
target.that lessResearchers
who before
are aware
theimpact,
antibody
they had for me working on
a national
disaster.
than two weeks
theoffirst
went problem
into safe say
mode.
days before
a critical
Take the example of Ioannis Prassas, a proteoScientists often know, anecdotally,Hubble
that some
thatTwo
scientists
need to
be more
mics researcher at Mount
in was
antibodies
theirnot
field
problematic,
but avigilant.
are not magic
reagents.
FABER:Sinai
Our Hospital
big fear that
Hubble in
would
beare
fixed.
observation,
softwareAntibodies
engineer at Goddard
[Space
Flight
Toronto, Canada. He and
colleagues
had
it has been
difficult
to gauge
of the
You
cantand
justfixed
throw
them
your sample
and
Howhis
would
we keep
the publics
and NASAs
interest
alivethe size
Center]
figured
it out
it. It
was on
a brilliant
success,
problem
biology as a whole.
been chasing a proteinin
called
CUZD1,
expect
result
you
get is 100%
withHubble
while awhich
repair plan
could across
be invented?
to Perhaps
watch a comet
tearthe
apart
into
fragments
andreliable
crash into
they thought could be used to test whether the largest assessment comes from the
work
pub- a few
outmonths
putting after
someHubble
critical thinking
it, says
planet
had beeninto
repaired.
someone has pancreatic
cancer.
They
bought
by the
Human
Proteinhad
Atlas,Imagine
a Swedish
Trimmer, head
of NeuroMab
at the UniIt took
three
years
to makelished
that plan.
NASA
engineers
if thatJames
had happened
in 1993
instead of 1994.
a protein-detection kitto
and
wastedways
two years,
consortium
that
aims
develop
to fix each
instrument,
with
all to
thegenerate
work antibodies versity of California, Davis, which makes anti$500,000 and thousands
of by
patient
samples
bodies
for neuroscience.
Liketest.
many
suppliers,
done
astronauts
in bulky spacesuits working in zero ZOLTAN LEVAY, IMAGE
SCIENTIST,
STSCI: The first
That
was a
before they realized that
the antibody
in the1993, seven astronauts launched huge deal. NeuroMab explicitly states the types of experigravity.
In December
kit was recognizing a different
protein,
aboard cancer
the space
shuttle Endeavour to save Hubble.
WEILER: Its a classic
greatdo
American
comeback
scientists
not always
follow thestory.
instructions.
retrospect, Prassas says,WEILER:
a rushIftoyou
gethad
going
on me for the odds ahead of time, Id
Ideally, researchers would refuse to buy antiasked
a promising hypothesishave
meant
hesuccess.
and hisThis was the first time we ever tried One after another,
bodiesHubbles
without discoveries
extensive validation
dataor
saidthat
50%
began landing
wouldofperform
the validation
group had failed to dotoall
the right
tests.Five
If [spacewalks] all had to go perfectly. on the front pages
repair
a satellite.
newspapers
and in topthemselves
scientific
someone says, Here isBut
an assay
use,right.

thingsyou
keptcan
going
It was like a dream sequence. journals.
you are so eager to testYou
it you
can
forget
that
were
afraid
you
were going to wake up and there was
what has been promised
is not
flowchart
forscientific
effective success
validation
going
tothe
be acase.
problem.
WEILER: Hubblea multistep
has been the
greatest
in 6,
Withhejust
one with
picture
it could
how
Most scientists who We
purchase
antibodwhich
shares
anyone
whoshow
will listen.
went home
at the end of the mission like a surgeon NASAs history.
ies believe the label printed
on the
vial,
But the
process
is time consuming Rimm
goes home
after
ansays
eye operation: theyve done everything the Universe didnt
read
our textbooks.
Antibodies are produced by the immune for every protein in the human genome. It has Even he acknowledges that few labs will persystems of most vertebrates to target an invader looked at some 20,000 commercial antibodform all the steps.
Some scientists buy half a dozen antibodtists have exploited antibodies for research. If used effectively to look at protein distribution ies from different vendors, and then run a few
a researcher injects a protein of interest into in preserved slices of tissue5. This has led some assays to see which performs best. But they
a rabbit, white blood cells known as B cells scientists to claim that up to half of all com- may end up buying the same antibody from
will start producing antibodies against the mercially available antibodies are unreliable.
protein, which can be collected from the aniBut reliability can depend on the experiment. on catalogue size, so they often buy antibodies
mals blood. For a more consistent product, the Our experience with commercial antibodies from smaller suppliers, relabel them and offer
Bcells can be retrieved, fused with an immoris that they are usually okay in some applicathem for sale. Bernard says that the 2million
talized
cellGrunsfeld
and cultured to provide a theoretitions, but they might be terrible in others, says antibodies on the market probably represent
Left: John
(right)
refurbishes
cally
unlimited
supply.
Mathias Uhln at the Royal Institute of Tech- 250,000500,000 unique core antibodies.
Hubble
in 2009.
Three
decades
ago, scientists who needed nology in Stockholm, who coordinates the
Middle: thefor
impacts
word of mouth or the published literature for
antibodies
their experiments had to make Human Protein Atlas.
on Jupiter
of cometBut by the late 1990s, reathem
themselves.
Researchers ideally should check that an advice. But that creates a self-perpetuating
ShoemakerLevy
9. started to take over the
antibody has been tested for use in particular problem, in which better-performing antibodgent
companies had
Right:
the barred spiral
applications and tissue types, but the quality ies that become available later are rarely used,
chore.
galaxy more
NGC1300.
Today,
than 300 companies sell over of information supplied by vendors can vary says Fridtjof Lund-Johansen, a proteomics
NASA
ANTIBODIES
ARE NOT
MAGIC
REAGENTS.
2 8 4NATURE
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CLASSIC
GREAT
AMERICAN
COMEBACK
STORY.
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75
NEWS FEATURE
FEATURE NEWS
NOTA: Hubble can look in wavelength regimes that are not

accessible from the ground, like ultraviolet, because ultraviolet radiation gets absorbed by the atmosphere.
be a repulsive force rather than an attractive force. It works

against gravity.
SEX
REDEFINED
JENNIFER WISEMAN, SENIOR PROJECT SCIENTIST, GODDARD SPACE
FLIGHT CENTER, GREENBELT, MARYLAND: There was a burst of new
science from Hubble right after 1993. One of these iconic
images is the Eagle Nebula, where you see columns of gas
where stars have recently formed and are still forming.
The informal name is the Pillars of Creation, a grandiose
title. This gave us a visual clue as to the interaction of
young stars.
LECKRONE: Bob ODell got pictures of the Orion Nebula.
They showed these funny little cocoons all over the place.
As you looked more closely, you saw examples of stars surrounded by dark disks. My god, these are places where
planets must be forming!
ODELL: It was the only truly eureka moment Ive had as a
scientist.
WISEMAN: Hubble homed in on the core of the galaxy M87

to monitor the motion of gas there. The astronomers used
a spectrograph to find the gas was moving about a million
miles per hour in one direction on one side of the core, and a
million miles per hour in the other direction on the opposite
side. The only way something could be orbiting this fast
would be if there were something very massive in the core in
a very small volume. This was the first definitive observation
of a supermassive black hole in the core of another galaxy.
LECKRONE: Hubble continues to defy all expectations in creative new ways in which it can be used. Look at dark energy.
WISEMAN: The repaired Hubble had exquisite angular resolution that allowed us to look for individual stars, to separate
them in crowded regions. In this way you could actually
study populations of stars and map out their properties.

WE CALL
BIOLOGISTS NOW THINK THEREIT THE
IS A
WIDER SPECTRUM THAN THAT.PEOPLES
TELESCOPE.
WE HAVE
REALLY
BROUGHT
THE
UNIVERSE
TO PEOPLES
HOMES.
The public responded to the flood of gorgeous imagery.

Hubble became NASAs first Internet sensation.
LECKRONE: Weve developed a following of people who are

not astronomers but have learned to love astronomy.
LEVAY: Im honoured that people admire these results. It has

just kind of snowballed. People have done songs and stuff
inspired by Hubble. Theres poetry, artwork.
Weve been batting around ideas of why Hubble is so
much in the public consciousness. One is because we came
along right when the Internet was really starting to take
off. A lot of people had easy instant access to the results
from Hubble.
NOTA: We call it the peoples telescope. We have really

brought the Universe to peoples homes. Some 15 years ago
I was in this remote area of Papua New Guinea, living on
a ship that would dock in places where there wasnt even a
harbour. One time, we couldnt believe it, there was a kid
wearing a Hubble T-shirt. The child was delighted when
we gave him a set of Hubble cards to play with, to go with
his T-shirt.
WEILER: After I retired and moved to Florida, I negotiated
with my wife. Half the pictures in the house are Hubble,
and half are other things.
KENNETH SEMBACH, HEAD OF THE HUBBLE MISSION OFFICE, STSCI: We

know dark energy pervades the Universe because weve Astronauts continued to visit the telescope, upgrading
B Ybeen
C L A able
I R E Ato
I Nmeasure
S W O R T H the expansion rate of the Universe and replacing
sexesitsbecomes
even blurrier.
Scientists
have
many of the genes
instruments
regularly
to extend
itsidentified
life.
Hubbles
future
looked
In 1999,
astroat different times. The key to doing that has been look- Sometimes,
involved
in the
main
formsdim.
of DSD,
and have
uncovered variations in
nauts
an emergency
repaireffects
mission
three
clinicalsupernovae
geneticist, Paul
James
is accustomed
discussing
somelaunched
these genes
that have subtle
on aafter
persons
anatomical or physiologiing satadistant
[with
Hubble].
The moretodistant
of thehetelescopes
six gyroscopes
of the most
delicate than
issuesyou
with
his patients.
But inThe
early 2010,
cal sex. Whats
more, newfailed.
technologies in DNA sequencing and cell biolsupernovae
are dimmer
would
have expected.
found
particularly
awkward
about ogy are revealing that almost everyone is, to varying degrees, a patchwork
teams
thathimself
won thehaving
NobelaPrize
in Physics
in 2011conversation
realized
of genetically
distinct cells,
some with
a sex
thatsex.
the Universe was expanding at an accelerating rate.
JOHN GRUNSFELD,
NASA ASTRONOMER
AND ASTRONAUT
WHO
HASthat
PER-might not match that of
SPACEWALKS
TObody.
SERVICE
HUBBLE:
Hubble
had
gone that the sex of each cell
AThis
46-year-old
pregnant
had
visited
at theFORMED
RoyalEIGHT
the
rest of their
Some
studies
even
suggest
is the equivalent
ofwoman
throwing
a ball
up inhis
theclinic
air and
Melbourne
Hospital
in Australia
to hear
the results
of an
amniocentesis
behaviour,
a complicated
network of molecular interit just decides
to speed
up and keep
going
up. That
would
dark, and itdrives
was aitsreal
questionthrough
as to whether
the science
test to screen her babys chromosomes for abnormalities. The baby was actions. I think theres much greater diversity within male or female,
fine but follow-up tests had revealed something astonishing about and there is certainly an area of overlap where some people cant easily
the mother. Her body was built of cells from two individuals, prob- define themselves within the binary structure, says John Achermann,
ably from twin embryos that had merged in her own mothers womb. who studies sex development and endocrinology at University College
And there was more. One set of cells carried two X chromosomes, the Londons Institute of Child Health.
complement that typically makes a person female; the other had an X
These discoveries do not sit well in a world in which sex is still defined
and a Y. Halfway through her fifth decade and pregnant with her third in binary terms. Few legal systems allow for any ambiguity in biological
child, the woman learned for the first time that a large part of her body sex, and a persons legal rights and social status can be heavily influenced
was chromosomally male1. Thats kind of science-fiction material for by whether their birth certificate says male or female.
someone who just came in for an amniocentesis, says James.
The main problem with a strong dichotomy is that there are interSex can be much more complicated than it at first seems. According to mediate cases that push the limits and ask us to figure out exactly where
the simple scenario, the presence or absence of a Y chromosome is what the dividing line is between males and females, says Arthur Arnold at
counts: with it, you are male, and without it, you are female. But doc- the University of California, Los Angeles, who studies biological sex
tors have long known that some people straddle the boundary their differences. And thats often a very difficult problem, because sex can
sex chromosomes say one thing, but their gonads (ovaries or testes) or be defined a number of ways.
sexual anatomy say another. Parents of children with these kinds of conditions known as intersex conditions, or differences or disorders of THE START OF SEX
NATURE.COM
sex development (DSDs) often face difficult decisions about whether That the two sexes are physically different is obvious, but
at the select
start of life,
Scientists
to bring up their child as a boy or a girl. Some researchers now say that it is not. Five weeks into development, a human embryo
the potential
theirhas
favourite
as many as 1 person in 100 has some form of DSD2.
to form both male and female anatomy. Next to the developing
kidneys,
Hubble images:
When genetics is taken into consideration, the boundary between the two bulges known as the gonadal ridges emerge alongside
two pairs of
go.nature.com/onagtw
NASA/ESA/HUBBLE HERITAGE TEAM (STSCI/AURA)
228
NATURE
1 6 ACOLLECTIONS
V O L 5 2 0 SUMMER
| N A T U READS
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reproduced.
tremendously.
complaint
froman
sciservicing
in 2009], A
it common
was as if we
were seeing
2million antibodies for research. As
of 2011,mission,
the market was worth $1.6 billion, according
to Very
entists
that companies
do not
provide
old friend.
few is
people
have hugged
Hubble
thethe
waydata
I
global consultancy Frost & Sullivan.have. I knew all
required
to evaluate
a given antibodys
the handrails
practically
by name. specificWhen
ity or
variability.
might
we let it go, it was
in its
thelot-to-lot
best shape
of its life.Companies
We had accomDEVASTATING EFFECTS
ship
a batch
of antibodies
characterization
plished our job,
and
its science
heritagewith
would
continue.
And
the data are
often derived
ideal conThe telescope
remains
a premier
tool,under
particularly
effects on the research record. In for
2009,
one ditions that
do notsurveys
reflect typical
experiments.
time-consuming,
data-rich
that are
meant to
journal devoted an entire issue to assessing
Antibody companies
contacted
for to
thiscome.
article
benefitthe
the astronomical
community
for years
antibodies that are used to study G-proteinsaid
that it isfor
impossible
test to
their
products
Hubble set the
standard
uploadingtodata
a communal archive available
all astronomers.
coupled receptors (GPCRs) cell-signalling
across alltoexperimental
conditions, but they do
ous disorders, from incontinence JENNIFER
to schizoimprove antibody
quality
and performance.
LOTZ, to
ASTRONOMER,
STSCI: I feel
incredibly
lucky to
use Google
to find products,
have started my Many
careeracademics
in the golden
age of astronomy
and
available antibodies that targeted 19the
signalling
search
canallsometimes
golden agesoofoptimizing
Hubble. The
idea results
of saving
the data
receptors, most bound to more than
one
pro- itmatter
more
to a company
than optimizing
the
and
making
available
to people
after a certain
amount of
tein, meaning that they could not betime,
trusted
towasactual
of the
that
prettyreagents,
radical. says
NowTim
it is Bernard,
acceptedhead
practice.
distinguish between the receptors. You dont havebiotechnology
consultancy
to be the student
of the mostPivotal
famousScientific
profesThe field of epigenetics relies heavily
in to
Upper
UK.best
Christi
Frost &
soron
in antithe world
have Heyford,
access to the
dataBird,
in theaworld.
gene expression have been modified. JASON
In 2011,
an ASTRONOMER,
that researchers
are often
more
interested in
KALIRAI,
STSCI: People
have
the misconcepevaluation4 of 246 antibodies used intion
epigenetic
how
quickly
reagents
can be
delivered
than in
that its best
days
are behind
it. More
than
two research
studies found that one-quarter failed
testsevery
for day
searching
forofantibodies
with appropriate
valipapers
come out
Hubble. What
its doing today
specificity, meaning that they oftenisbound
to from
dation
data.
different
what
its Its
donethe
inAmazon
the past.effect: they want it
BUYER BEWARE
perfectly specific but to the wrongNOTA:
target.
arethat
aware
of the
antibody
Look at oneResearchers
example ofwho
a topic
didnt
even
exist
Take the example of Ioannis Prassas, a proteoScientists often know, anecdotally,when
that some
say thatexoplanets.
scientists need
toHubble
be more
Hubbleproblem
was launched:
When
mics researcher at Mount Sinai Hospital in antibodies in their field are problematic,
butwe didnt
vigilant.
not magicofreagents.
launched
evenAntibodies
know about are
the existence
planets
Toronto, Canada. He and his colleagues had it has been difficult to gauge the size
of the
You cant
justIn
throw
themthat
on your
and
outside
our Solar
System.
25 years
field sample
has comPerhaps
been chasing a protein called CUZD1, which problem across biology as a whole.
expect theHubble
result you
100% reliable
withpletely
revolutionized.
wasget
notis designed
to study
they thought could be used to test whether the largest assessment comes from exoplanets
work pub- but
out
putting
some critical their
thinking
into it, says
now
is characterizing
atmospheres.
someone
has pancreatic
cancer. They bought lished by the Human Protein Atlas,Hubble
a Swedish
Trimmer,
A pillar
of gas
alwaysJames
surprises
us. head of NeuroMab at the Uniand dust in the kit and wasted two years,
a protein-detection
consortium that aims to generate antibodies versity of California, Davis, which makes antiEagle
Nebula.
$500,000
and
thousands of patient samples
bodies
for neuroscience.
Like many
NASA is currently
testing
Hubbles successor,
thesuppliers,
James
NeuroMab which
explicitly
states the types
of experiWebb Space Telescope,
is scheduled
to launch
in
kit was recognizing a different
cancer
protein,
ment thatare
an still
antibody
should
be used for,
but
was over.
For an
astronomer and an astronaut, this was a 2018. But researchers
planning
for Hubbles
final
2
CA125, and did not bind
tograil
CUZD1
at allmissions.
. In
holy
of repair
Up we went, and soon enough years.
retrospect, Prassas says,we
a rush
to get
goingstar
on on the horizon. It was Hubble.
Ideally, researchers would refuse to buy antisaw this
bright
a promising hypothesis meant
he and
his was one moment when I was out WISEMAN: Hubble
bodies
extensive
validation
dataor
It wasthat
surreal.
There
rightwithout
now is as
scientifically
powerful
as
perform the
validation
group had failed to doatall
right
tests.
If arm, and the operator drove me ever, perhaps would
thethe
end
of the
robotic
more scientifically
powerful
thanthemselves
ever.
someone says, Here istowards
an assayHubble,
you can slowly
use, turning me over. I put out my
you are so eager to testindex
it youfinger
can forget
that
Rimm
passionate
he has
developed
and just
kind of tapped the telescope, to prove SEMBACH: In the
timeiswe
have left,about:
we want
to push
the
what has been promised
not the
real.
multistep
for effective
validation
toismyself
it case.
was all
envelope. Weawant
to doflowchart
different things
that we
havent 6,
Most scientists who We
purchase
antibodwhichput
he shares
withtoanyone
who will listen.
deployed
it on Christmas Day. I remember thinking, done before. Weve
out a call
the community
askies believe the label printed
on thepresent
vial, says
the Should
processwe
is time
consuming
Rimm
what better
could there be for planet Earth than a ing for creativeBut
ideas.
be devoting
more timeto
Rimm. As a pathologist,
I wasnt
trained
repaired
Hubble?
controlShould
experiments
involve
specific typesrecommends
of observations?
we bethat
devoted
engineering
cell lines
tothe
both
express and stop
to helping students
do research
with
observatory?
trained that you ordered
them.
later, in the wake of the Columbia shuttle
expressing
the protein
of interest,
example.
Four
years
We expect to
operate through
at least
2020. for
Right
now
Antibodies are produced
by NASA
the immune
for every
in the
humanagenome.
has pretty
Evengood.
he acknowledges
few labs
will perdisaster,
administrator
Seanprotein
OKeefe
cancelled
thingsIt look
That gives usthat
a chance
to overlap
a year or two
with
systems of most vertebrates
target anservicing
invader mission,
looked citing
at some
20,000
commercialfor
antibodform
all the James
steps. Webb Space Telescope.
finaltoplanned
safety
concerns.
Some scientists buy half a dozen antibodtists have exploited antibodies
for research.
used effectively
look at
ies fromASTROPHYSICS
different vendors,
andNASA:
thenWe
runwill
a few
MATT MOUNTAIN,
FORMERIfDIRECTOR,
STSCI: Whattomade
it protein
worse distribution
PAUL HERTZ, DIRECTOR,
DIVISION,
5
operate
Hubble
as long
as which
it staysperforms
scientifically
a researcher injects a protein
interest into
in preserved
of tissuepretty
. This has
led some
assays
to see
best.producBut they
was theof
instruments
started
failing. It slices
was actually
a rabbit, white blood cells
B cells
end
up buyinggoing
the same
antibody
from
scientists
todoing
claim that
up to
all My
combleak.known
It wasasclear
Hubble
was not
as well
as half
it of
tive.
guessmay
is that
somethings
to break
someday.
will start producing antibodies
shouldbe. against the mercially available antibodies are unreliable.
protein, which can be collected from the aniBut reliability can depend on the experiment.
onbecatalogue
so they
often With
buy antibodies
LECKRONE: It will
a gradual,size,
graceful
failure.
creative
mals blood. For a moreWEILER:
consistent
product,
the Ourchanged,
experience
with
from
smaller
suppliers,
them
Luckily
administrators
and
we commercial
got Mike antibodies
engineering you
can
keep doing
goodrelabel
science.
As and
longoffer
as
Bcells can be retrieved,Griffin
fused with
an immoris thatlooking
they are
okay in some
them
sale.
Bernard says
thatwe
thecan
2million
in there.
He supported
at usually
the alternatives,
weapplicahave at least
two for
good
instruments,
I think
keep
and
at the end
of the day we
got but
ourthey
servicing
talized cell and cultured
to provide
a theoretitions,
mightmission.
be terrible in others,
says when
antibodies
on theitself
market
represent
goingeven
the spacecraft
hasprobably
suffered multiple
cally unlimited supply.
Mathias Uhln at the Royal Institute
of Tech250,000500,000
unique
antibodies.
failures.
That might
take us to 2025.
Butcore
its not
going to be
Three decades ago, scientists
who needed
nology
in Stockholm,
coordinates
relyitson
MOUNTAIN: Griffin
announced
he would
allocate twowho
shuttles
with usthe
forever, By
andnecessity,
were reallymany
goingresearchers
to miss it when
wordP. of
antibodies for their experiments
hadan
toincredible
make Human
ProteinbyAtlas.
to this. Thats
commitment
a space agency gone. SEE COMMENT
287mouth or the published literature for
them themselves. But to
byathe
late 1990s,
rea-Suddenly
Researchers
ideally
should
science
mission.
the attitude
changed,
andcheck that an advice. But that creates a self-perpetuating
antibody
hasatbeen
tested for use inAlexandra
particular Witze
gent companies had started
to take
overfor
thethe whole
problem,
which
better-performing
there was
a future
team
Hubble.
writesinfor
Nature
from Boulder, antibodapplications and tissue types, but the
qualitySome
Colorado.
in this story
havelater
beenare
edited
forused,
chore.
iesquotes
that become
available
rarely
supplied
vendors
can vary says Fridtjof Lund-Johansen, a proteomics
brevity.
Today, more than 300
companies
sell over
GRUNSFELD:
When
we sawofitinformation
on approach
[on thebyfinal
IT WILL BE
A GRADUAL,
GRACEFUL
FAILURE.
ANTIBODIES
ARE NOT
MAGIC
REAGENTS.
2 8 6NATURE
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2 1 M A Y 2 0 1 5 | V O L 5 2 1 | N A T U R E | 229
75
HUBBLE HERITAGE TEAM (STSCI/AURA)/ESA/NASA
FEATURE NEWS
NEWS FEATURE
NEWS FEATURE
BLAME IT
ON THE
ANTIBODIES
Antibodies are the
workhorses of biological
experiments, but they are
littering the field with false
findings. A few evangelists
are pushing for change.
n 2006, things were looking pretty good for

David Rimm, a pathologist at Yale University
in New Haven, Connecticut. He had developed a test to guide effective treatment of the
skin cancer melanoma, and it promised to save
lives. It relied on antibodies large, Y-shaped
proteins that bind to specified biomolecules and
can be used to flag their presence in a sample.
Rimm had found a combination of antibodies that, when used to stain tumour biopsies,
produced a pattern that indicated whether
the patient would need to take certain harsh
drugs to prevent a relapse after surgery. He had
secured more than US$2million in funding to
move the test towards the clinic.
But in 2009, everything started to fall apart.
When Rimm ordered a fresh set of antibodies,
230
7 4 | N A T U R E | V O L 5 2 1 | 2 1 M A Y 2 0 1 5
his team could not reproduce the original

results. The antibodies were sold by the same
companies as the original batches, and were
supposed to be identical but they did not
yield the same staining patterns, even on the
same tumours. Rimm was forced to give up
his work on the melanoma antibody set. We
learned our lesson: we shouldnt have been
dependent on them, he says. That was a very
sad lab meeting.
Antibodies are among the most commonly
used tools in the biological sciences put
to work in many experiments to identify
and isolate other molecules. But it is now
clear that they are among the most common causes of problems, too. The batch-tobatch variability that Rimm experienced can
produce dramatically differing results. Even

more problematic is that antibodies often
recognize extra proteins in addition to the
ones they are sold to detect. This can cause
projects to be abandoned, and waste time,
money and samples.
Many think that antibodies are a major
driver of what has been deemed a reproducibility crisis, a growing realization that the
results of many biomedical experiments cannot be reproduced and that the conclusions
based on them may be unfounded. Poorly
characterized antibodies probably contribute
more to the problem than any other laboratory
tool, says Glenn Begley, chief scientific officer
at TetraLogic Pharmaceuticals in Malvern,
Pennsylvania, and author of a controversial

ILLUSTRATION BY NIK SPENCER/NATURE
B Y M O N YA B A K E R
FEATURE NEWS
reproduced.
BUYER BEWARE
Take the example of Ioannis Prassas, a proteomics researcher at Mount Sinai Hospital in
Toronto, Canada. He and his colleagues had
been chasing a protein called CUZD1, which
they thought could be used to test whether
someone has pancreatic cancer. They bought
a protein-detection kit and wasted two years,
kit was recognizing a different cancer protein,
Most scientists who purchase antibodies believe the label printed on the vial, says
Antibodies are produced by the immune
systems of most vertebrates to target an invader
such as a bacterium. Since the 1970s, scientists have exploited antibodies for research. If
a researcher injects a protein of interest into
a rabbit, white blood cells known as B cells
will start producing antibodies against the
protein, which can be collected from the animals blood. For a more consistent product, the
Bcells can be retrieved, fused with an immortalized cell and cultured to provide a theoretically unlimited supply.
Three decades ago, scientists who needed
antibodies for their experiments had to make
them themselves. But by the late 1990s, reagent companies had started to take over the
chore.
Today, more than 300 companies sell over

DEVASTATING EFFECTS
There are signs that problems with antibodies

ANTIBODIES
ARE NOT
MAGIC
REAGENTS.
for every protein in the human genome. It has
looked at some 20,000 commercial antibodies so far and found that less than 50% can be
used effectively to look at protein distribution
in preserved slices of tissue5. This has led some
scientists to claim that up to half of all commercially available antibodies are unreliable.
But reliability can depend on the experiment.
Our experience with commercial antibodies
is that they are usually okay in some applications, but they might be terrible in others, says
Mathias Uhln at the Royal Institute of Technology in Stockholm, who coordinates the
Human Protein Atlas.
Researchers ideally should check that an
antibody has been tested for use in particular
applications and tissue types, but the quality
of information supplied by vendors can vary

information derived from a previous batch.
And the data are often derived under ideal conditions that do not reflect typical experiments.
Antibody companies contacted for this article
said that it is impossible to test their products
across all experimental conditions, but they do
provide reliable data and work with scientists
to improve antibody quality and performance.
so optimizing search results can sometimes
matter more to a company than optimizing the
actual reagents, says Tim Bernard, head of the
in Upper Heyford, UK. Christi Bird, a Frost &
Sullivan analyst based in Washington DC, says
that researchers are often more interested in
how quickly reagents can be delivered than in
searching for antibodies with appropriate validation data. Its the Amazon effect: they want it
in two or three days, with free shipping.
problem say that scientists need to be more
You cant just throw them on your sample and
expect the result you get is 100% reliable without putting some critical thinking into it, says
James Trimmer, head of NeuroMab at the University of California, Davis, which makes antibodies for neuroscience. Like many suppliers,
NeuroMab explicitly states the types of experiment that an antibody should be used for, but
Ideally, researchers would refuse to buy antibodies without extensive validation dataor
Even he acknowledges that few labs will perform all the steps.
Some scientists buy half a dozen antibodies from different vendors, and then run a few
assays to see which performs best. But they
may end up buying the same antibody from
on catalogue size, so they often buy antibodies
from smaller suppliers, relabel them and offer
them for sale. Bernard says that the 2million
antibodies on the market probably represent
word of mouth or the published literature for
advice. But that creates a self-perpetuating
problem, in which better-performing antibodies that become available later are rarely used,
says Fridtjof Lund-Johansen, a proteomics
2 1 M A Y 2 0 1 5 | V O L 5 2 1 | N A T U R E | 231
75
NEWS FEATURE
BAD ANTIBODIES
The most common problems with

antibodies and how to avoid them.
Non-target
protein
Target
protein
Binding
site
Antibody
CROSS-REACTIVITY
VARIABILITY
WRONG APPLICATION
Problem: An antibody is supposed to recognize only

its target protein, but sometimes binds to others,
depending on the proteins present in a sample.
Problem: Separate batches of antibody can perform

differently. This happens most often when the
antibody is produced from a new set of animals.
Problem: Different experiments and experimental

conditions can change a protein's folding and
therefore its binding ability.
Solution: An antibody should be tested for off-target

binding using positive and negative controls.
Solution: Researchers should confirm lot numbers

and characterization data with vendors.
Solution: Scientists should check supplier's

recommended applications.
researcher at the University of Oslo. We have

very good antibodies on the market, he says,
but we dont know what they are. LundJohansen is trying to change that by developing
high-throughput assays that could compare
thousands of antibodies at once.
on the companys website. Abcams analysis of

purchasing behaviour shows that its customers
look at data pages on average nine times before
buying, suggesting that customers want more
information.
Abgent, an antibody company based in San
Diego, California, and a subsidiary of WuXi
AppTec in Shanghai, China, tested all of its
antibodies about a year ago. After reviewing
the results it discarded about one-third of its
catalogue. Whether that was a good decision
depends on whether customers will be willing to spend more for better reagents, says
John Mountzouris, site leader at the company.
Already, he says, customer complaints have
plummeted.
Some scientists are calling for much more
radical change. In a Comment in Nature in
February7, Andrew Bradbury of Los Alamos
National Laboratory in New Mexico and more
than 100 co-signatories proposed a massive
shift in the way antibodies are produced and
sold. They suggested using only antibodies that
have been defined down to the level of the DNA
sequence that produces them, and then manufactured in engineered recombinant cells.
This would circumvent much of the variability
introduced by production in animals. But the
proposal demands information about individual antibodies that many companies consider
to be trade secrets and the antibody marketplace and its millions of products would have
to be essentially demolished and reconstructed.
Uhln, a co-signatory on the Comment,
regards the plan as a distant hope. He estimates
that the recombinant antibodies that Bradbury
hopes for would each cost 10100 times more
to generate than the conventional sort, and
that they would not necessarily perform better. At the end of the day, how the binder works
TESTING TIMES
In the past decade, various projects have sprung

up to try to make information about antibodies easier to find. The online reagents portal
Antibodypedia (antibodypedia.com), which
is maintained by the Human Protein Atlas,
has catalogued more than 1.8million antibodies and rated the validation data available for
various experimental techniques. Antibodiesonline (antibodies-online.com), another portal,
set up a programme two years ago for independent labs to do validation studies, generally at
the vendors expense. But out of 275 studies,
less than half of the products tested have made
the cut and earned an independent validation
badge. The non-profit Antibody Registry (antibodyregistry.org) assigns unique identifiers to
antibodies and links them to other resources.
Another project, pAbmAbs (pabmabs.com/
wordpress), operates in a similar way to the
social-recommendation web service Yelp, by
encouraging people to review antibodies.
But none of these efforts has gained much of
a foothold in the scientific community. Many
of the scientists contacted for this article were
unaware that such resources existed.
The antibody market has grown so crowded
that a reputation for quality is becoming part
of some suppliers business plans. Now there
is so much competition that you have to differentiate yourself, says Bernard. Vendors such
as Abcam in Cambridge, UK, are encouraging
users to report their own data and rankings
232
7 6 | N A T U R E | V O L 5 2 1 | 2 1 M A Y 2 0 1 5
in the application is more important, he says.

Having a sequence for sure doesnt tell you if
it works. Other efforts are under way to find
cheap, fast, reliable ways of making antibodies without immunizing animals, for example
by expressing and optimizing them in viruses.
The pressure to characterize currently
available antibodies is surging. As part of
efforts to improve reproducibility, some
researchers have started to discuss enlisting
an independent body to establish a certification programme for commercial antibodies.
And several journals (including Nature) ask
authors to make clear that antibodies used in
their papers have been profiled for that particular application.
The quality will creep, rather than leap,
forward, says Trimmer, who hopes to see a
positive-feedback loop: as scientists become
aware of artefacts, they will be more likely to
challenge results and uncover more artefacts.
Already, he says, the widespread insouciance
about antibody validation has started to fade.
Its turning around a little bit, he says. We
need to keep talking about it.
Monya Baker writes and edits for Nature in
San Francisco, California.
1. Begley, C. G. & Ellis, L. M. Nature 483, 531533
(2012).
2. Prassas, I. & Diamandis, E. P. Clin. Chem. Lab. Med.
52, 765766 (2014).
3. Michel, M. C., Wieland, T. & Tsujimoto, G. NaunynSchmiedebergs Arch. Pharmacol. 379, 385388
(2009).
4. Egelhofer, T. A. et al. Nature Struct. Mol. Biol. 18,
9193 (2011).
5. Berglund, L. et al. Mol. Cell. Proteom. 7, 20192027
(2008).
6. Bordeaux, J. et al. BioTechniques 48, 197209
(2010).
7. Bradbury, A. & Plckthun, A. Nature 518, 2729
(2015).

W H AT I S
R E A L LY
R E A L?
A WAVE OF EXPERIMENTS
IS PROBING THE ROOT OF
QUANTUM WEIRDNESS.
wen Maroney worries that physicists

have spent the better part of a cen
tury engaging in fraud.
Ever since they invented quantum
theory in the early 1900s, explains Maroney,
who is himself a physicist at the University
of Oxford, UK, they have been talking about
how strange it ishow it allows particles and
atoms to move in many directions at once, for
example, or to spin clockwise and anticlock
wise simultaneously. But talk is not proof, says
Maroney. If we tell the public that quantum
theory is weird, we better go out and test thats
actually true, he says. Otherwise were not
doing science, were just explaining some funny
squiggles on a blackboard.
It is this sentiment that has led Maroney
and others to develop a new series of experi
ments to uncover the nature of the wavefunc
tionthe mysterious entity that lies at the
heart of quantum weirdness. On paper, the
wavefunction is simply a mathematical object
that physicists denote with the Greek letter psi
() one of Maroneys funny squiggles and
use to describe a particles quantum behaviour.
Depending on the experiment, the wavefunc
tion allows them to calculate the probability
of observing an electron at any particular

location, or the chances that its spin is oriented
up or down. But the mathematics shed no light
on what a wavefunction truly is. Is it a physical
thing? Or just a calculating tool for handling an
observers ignorance about the world?
The tests being used to work that out are
extremely subtle, and have yet to produce a
definitive answer. But researchers are optimistic
that a resolution is close. If so, they will finally be
able to answer questions that have lingered for
decades. Can a particle really be in many places
at the same time? Is the Universe continually
dividing itself into parallel worlds, each with an
alternative version of ourselves? Is there such a
thing as an objective reality at all?
These are the kinds of questions that every
body has asked at some point, says Alessandro
Fedrizzi, a physicist at the University of Queens
land in Brisbane, Australia. What is it that is
really real?
Debates over the nature of reality go back
to physicists realization in the early days of
quantum theory that particles and waves are
two sides of the same coin. A classic example
is the doubleslit experiment, in which indi
vidual electrons are fired at a barrier with two
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openings: the electron seems to pass through

both slits in exactly the same way that a light
wave does, creating a banded interference
pattern on the other side (see Waveparticle
weirdness). In 1926, the Austrian physicist
Erwin Schrdinger invented the wavefunc
tion to describe such behaviour, and devised
an equation that allowed physicists to calcu
late it in any given situation1. But neither he
nor anyone else could say anything about the
wavefunctions nature.
IGNORANCE IS BLISS
From a practical perspective, its nature does not

matter. The textbook Copenhagen interpreta
tion of quantum theory, developed in the 1920s
mainly by physicists Niels Bohr and Werner
Heisenberg, treats the wavefunction as noth
ing more than a tool for predicting the results
of observations, and cautions physicists not to
concern themselves with what reality looks like
underneath. You cant blame most physicists
for following this shut up and calculate ethos
because it has led to tremendous develop
ments in nuclear physics, atomic physics, solid
state physics and particle physics, says Jean
Bricmont, a statistical physicist at the Catholic
33
DAN HARRIS/MIT
BY ZEEYA MERALI
FEATURE NEWS
that view the wave
function as a real
entity psiontic
models.
To appreciate the
difference, consider
a thought experiment
that Schrdinger
described in a 1935
letter to Einstein.
Imagine that a cat is
enclosed in a steel box. And imagine that the
box also contains a sample of radioactive mate
rial that has a 50% probability of emitting a
decay product in one hour, along with an appa
ratus that will poison the cat if it detects such a
decay. Because radioactive decay is a quantum
event, wrote Schrdinger, the rules of quantum
theory state that, at the end of the hour, the
wavefunction for the boxs interior must be an
equal mixture of live cat and dead cat.
Crudely speaking, says Fedrizzi, in a psi
epistemic model the cat in the box is either alive
or its dead and we just dont know because the
box is closed. But most psiontic models agree
with the Copenhagen interpretation: until an
observer opens the box and looks, the cat is both
alive and dead.
But this is where the debate gets stuck. Which
of quantum theorys many interpretations if
any is correct? That is a tough question to
answer experimentally, because the differences
between the models are subtle: to be viable, they
An experiment showing
that oil droplets can
be propelled across a
fluid bath by the waves
they generate has
prompted physicists
to reconsider the idea
that something similar
allows particles to
behave like waves.
ace, he says, theres an overlap and you wont

be able to say where it came from. But if you
know how many of each type of card is in each
deck, you can at least calculate how often such
ambiguous situations will arise.
OUT ON A LIMB
A similar ambiguity occurs in quantum

systems. It is not always possible for a single
measurement in the lab to distinguish how
a photon is polarized, for example. In real
life, its pretty easy to tell west from slightly
south of west, but in quantum systems, its
not that simple, says White. According to the
standard Copenhagen interpretation, there
is no point in asking what the polarization is
because the question does not have an answer
or at least, not until another measurement
can determine that answer precisely. But
according to the wavefunctionasignorance
models, the question is perfectly meaning
ful; it is just that the experimenters like
the cardgame player do not have enough
information from that one measurement to
answer. As with the cards, it is possible to esti
mate how much ambiguity can be explained
by such ignorance, and compare it with the
larger amount of ambiguity allowed by stand
ard theory.
That is essentially what Fedrizzis team
tested. The group measured polarization and
other features in a beam of photons and found
a level of overlap that could not be explained by
WE WERE TOLD THAT SUCH EFFECTS CANNOT HAPPEN

C L A S S I C A L LY, A N D H E R E W E A R E , S H O W I N G T H AT T H E Y D O .
University of Louvain in Belgium. So people
say, lets not worry about the big questions.
But some physicists worried anyway. By the
1930s, Albert Einstein had rejected the Copen
hagen interpretation not least because it
allowed two particles to entangle their wave
functions, producing a situation in which
measurements on one could instantaneously
determine the state of the other even if the par
ticles were separated by vast distances. Rather
than accept such spooky action at a distance,
Einstein preferred to believe that the particles
wavefunctions were incomplete. Perhaps, he
suggested, the particles have some kind of hid
den variables that determine the outcome of
the measurement, but that quantum theories
do not capture.
Experiments since then have shown that this
spooky action at a distance is quite real, which
rules out the particular version of hidden vari
ables that Einstein advocated. But that has not
stopped other physicists from coming up with
interpretations of their own. These interpreta
tions fall into two broad camps. There are those
that agree with Einstein that the wavefunction
represents our ignorance what philosophers
call psiepistemic models. And there are those
34
have to predict essentially the same quantum

phenomena as the very successful Copenhagen
interpretation. Andrew White, a physicist at the
University of Queensland, says that for most of
his 20year career in quantum technologies the
problem was like a giant smooth mountain with
no footholds, no way to attack it.
That changed in 2011, with the publication
of a theorem about quantum measurements
that seemed to rule out the wavefunctionas
ignorance models2. On closer inspection, how
ever, the theorem turned out to leave enough
wiggle room for them to survive. Nonetheless,
it inspired physicists to think seriously about
ways to settle the debate by actually testing
the reality of the wavefunction. Maroney had
already devised an experiment that should
work in principle3, and he and others soon
found ways to make it work in practice46. The
experiment was carried out last year by Fed
rizzi, White and others7.
To illustrate the idea behind the test, imagine
two stacks of playing cards. One contains only
red cards; the other contains only aces. Youre
given a card and asked to identify which deck it
came from, says Martin Ringbauer, a physicist
also at the University of Queensland. If it is a red
the ignorance models. The results support the

alternative view that, if objective reality exists,
then the wavefunction is real. Its really impres
sive that the team was able to address a pro
found issue, with whats actually a very simple
experiment, says Andrea Alberti, a physicist at
the University of Bonn in Germany.
The conclusion is still not ironclad, how
ever: because the detectors picked up only
about onefifth of the photons used in the test,
the team had to assume that the lost photons
were behaving in the same way7. That is a big
assumption, and the group is currently work
ing on closing the sampling gap to produce a
definitive result. In the meantime, Maroneys
team at Oxford is collaborating with a group
at the University of New South Wales in Aus
tralia, to perform similar tests with ions, which
are easier to track than photons. Within the
next six months we could have a watertight
version of this experiment, says Maroney.
But even if their efforts succeed and the
wavefunctionasreality models are favoured,
those models come in a variety of flavours
and experimenters will still have to pick
them apart.
One of the earliest such interpretations
NATURE2 COLLECTIONS
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FEATURE NEWS
NEWS FEATURE
Wanalysis
A V E 1 showing
P A R T I that
C L results
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E SlandS
tremendously. A common complaint from scientists is that companies do notWave

provide the data
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previous batch.
Emerging
proteins that are targeted by drugs to treat variprovide reliable data and work with scientists
interference pattern
ous disorders, fromAccumulated
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electrons
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The
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Heyford,
UK. Christi
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propagate
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bodies
to this
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that regulate
Sullivan
analyst based
the
odds of
happening
are infinitesimal
for worlds,
Wiseman
says. in Washington DC, says
a single
particle, so
thatbeen
quantum
effects
domian that
Using
computerare
simulations
with
as manyin
gene expression
have
modified.
In 2011,
researchers
often more
interested
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evaluation
of 246 antibodies
in epigenetic ashow
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at the atomic
scale. But used
the probability
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they
shownthan
thatin
ofstudies
collapse
grows
astronomically
as particles
found
that
one-quarter failed
tests for this
searching
antibodies
with appropriate
model for
roughly
reproduces
a numbervaliof
specificity,
meaning
that they often
bound
dation data.
Its the
Amazon the
effect:
they want it
clump
together,
so that macroscopic
objects
loseto quantum
effects,
including
trajectories
more
than one
target.
Four
antibodies
were ofinparticles
in the
doubleslit
experiment
two or three
days,
with free shipping.
13.
their
quantum
features
and
behave
classically.
interferencewho
pattern
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to
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toisthe
are aware
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One wayspecific
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look fortarget.
quan TheResearchers
often
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tumScientists
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theory
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reagents.
the number
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isitno
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to gauge
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You
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them onresults
your sample
and
theory
predicts
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as a whole.
Perhaps ing
expect
thenumber
result you
is 100% reliable
withried
out doubleslit
interference
experiments
on the
ofget
universes,
says Wise
12
the large
largest
assessment
comes
from work
pub- man,
out putting
some
critical thinking
into
it, says
with
molecules
. But
if collapse
models
it should
be possible
to devise
ways
to
lished
by the
Human
Protein
Atlas,
a Swedish
Jameswhether
Trimmer,
of NeuroMab
Uniare
correct,
then
quantum
effects
will
not be check
hishead
multiverse
modelatisthe
right
consortium
aims to
generate
antibodies
of California,
Davis,
makes antiapparent
abovethat
a certain
mass.
Various
groups versity
meaning
that there
is nowhich
wavefunction,
bodies
forisneuroscience.
Like many suppliers,
are planning to search for such a cutoff using and
reality
entirely classical.
NeuroMab
explicitly states
thedoes
typesnot
of expericold atoms, molecules, metal clusters and
Because Wisemans
model
need
wavefunction,
it will remain
viable
if
that an antibody
should be
usedeven
for, but
nanoparticles. They hope to see results within a ment
experiments
rulefollow
out the
ignorance
scientists
do not always
the instructions.
a decade. Whats great about all these kinds of future
Also
surviving
would
betomodels,
Ideally,
researchers
would
refuse
buy antiexperiments is that well be subjecting quan models.
as the
Copenhagen
interpretation,
that
bodies
without
extensive
validation dataor
tum theory to highprecision tests, where its such
maintain
there is no
reality
just
would perform
theobjective
validation
themselves
never been tested before, says Maroney.
measurements.
Rimm
is passionate
about:
PARALLEL WORLDS
But then,
says White,
thathe
is has
the developed
ultimate
a multistep
flowchart
validation
One wavefunctionasreality model is already challenge.
Although
nofor
oneeffective
knows how
to do 6,
shares
anyone
whoexciting
will listen.
famous and beloved by sciencefiction writ it which
yet, he he
says,
whatwith
would
be really
is
the aprocess
time consuming
ers: the manyworlds interpretation developed toBut
devise
test foriswhether
there is in factRimm
any
recommends
experiments
in the 1950s by Hugh Everett, who was then a objective
realitycontrol
out there
at all. that involve
graduate student at Princeton University in New
expressing
of interest,
for example.
Jersey. In the manyworlds picture, the wave Zeeya
Meralithe
is protein
a freelance
writer based
in
function
evolution
of realityItso
for everygoverns
protein the
in the
human genome.
has London.
Even he acknowledges that few labs will perlooked at that
some
20,000 commercial
antibodform all the steps.
profoundly
whenever
a quantum measure
E. Phys. Rev.
1049
(1926).antibodies sois far
andthe
found
that less
than
50%
can be 1. Schrdinger,
Some scientists
buy28,
half
a dozen
ment
made,
Universe
splits
into
parallel
2. Pusey, M. F., Barrett, J. & Rudolph, T. Nature Phys. 8,
used effectively
to look
distribution
ies
from
different
vendors,
and
then run a few
copies.
Open the cats
box,atinprotein
other words,
and
475478 (2012).
in parallel
preserved
sliceswill
of tissue
This has led
some
toO.see
performs
best. But they
two
worlds
branch5. outone
with
a 3.assays
Maroney,
J. E.which
Preprint
at http://arxiv.org/
abs/1207.6906
(2012).the same antibody from
end up buying
scientists
toanother
claim that
up to half
of all com- may
living
cat and
containing
a corpse.
4. Barrett, J., Cavalcanti, E. G., Lal, R. & Maroney, O.
mercially
availableEveretts
antibodiesmanyworlds
are unreliable.
different
places.
Distinguishing
J. E. Phys. Rev. Lett. The
112, largest
250403 vendors
(2014). compete
But reliability
canstandard
depend on
the experiment.
catalogue
size,
soLett.
they
often
buy (2014).
antibodies
interpretation
from
quantum
theory 5.on
Leifer,
M. S. Phys.
Rev.
112,
160404
Branciard,
C. Phys.
Rev. Lett.relabel
113, 020409
withmake
commercial
antibodies
smaller
suppliers,
them (2014).
and offer
isOur
toughexperience
because both
exactly the
same 6.from
Ringbauer, M. et al. Nature Phys. 11, 249254
is that they But
are usually
in some
applica- 7.them
for sale. Bernard says that the 2million
predictions.
last year,okay
Howard
Wiseman
(2015).
butUniversity
they mightin
beBrisbane
terrible inand
others,
says 8.antibodies
the market
represent
attions,
Griffith
his col
de Broglie, L.on
J. Phys.
Radium 8,probably
225241 (1927).
13
Bohm, D. Phys. Rev. unique
85, 166179
(1952).
Mathias
Uhln aattestable
the Royal
Institutemodel
of Techcore
antibodies.
leagues
proposed
multiverse
. 9.250,000500,000
10. Bohm, D. Phys. Rev. 85, 180193 (1952).
nology
in Stockholm,
whocontain
coordinates
the 11.
Their
framework
does not
a wave
Couder, Y. & Fort, E. Phys. Rev. Lett. 97, 154101
word
of mouth or the published literature for
function:
particles
obey classical rules such
Human Protein
Atlas.
(2006).
Eibenberger,
Gerlich,
S., Arndt,
M., Mayor,
But S.,
that
creates
a self-perpetuating
Researchers
ideally
should
checkeffects
that an 12.advice.
as Newtons
laws of
motion.
The weird
M. & Txen,
J.which
Phys. Chem.
Chem. Phys. 15, antibodantibody
has been
tested for use
in particular
problem,
in
better-performing
seen
in quantum
experiments
arise
because
1469614700 (2013).
applications
and tissue
but the
quality 13.ies
there
is a repulsive
forcetypes,
between
particles
that
available
are rarely
Hall,
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2 8 0NATURE
| N A T COLLECTIONS
1 | 2 1 M SUMMER
A Y 2 0 1 5 READS
2 1 M A Y 2 0 1 5 | V O L 5 2 1 | N A T U R E | 235
75
CRISPR,
THE DISRUPTOR
BY HEIDI LEDFORD
hree years ago, Bruce Conklin came across a method that made
him change the course of his lab.
Conklin, a geneticist at the Gladstone Institutes in San Francisco,
California, had been trying to work out how variations in DNA affect various human diseases, but his tools were cumbersome. When he worked
with cells from patients, it was hard to know which sequences were important for disease and which were just background noise. And engineering a
mutation into cells was expensive and laborious work. It was a students
entire thesis to change one gene, he says.
Then, in 2012, he read about a newly published technique1 called
CRISPR that would allow researchers to quickly change the DNA of nearly
any organismincluding humans. Soon after, Conklin abandoned his
previous approach to modelling disease and adopted this new one. His lab
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is now feverishly altering genes associated with various heart conditions.

CRISPR is turning everything on its head, he says.
The sentiment is widely shared: CRISPR is causing a major upheaval
in biomedical research. Unlike other gene-editing methods, it is cheap,
quick and easy to use, and it has swept through labs around the world as
a result. Researchers hope to use it to adjust human genes to eliminate diseases, create hardier plants, wipe out pathogens and much more besides.
Ive seen two huge developments since Ive been in science: CRISPR and
PCR, says John Schimenti, a geneticist at Cornell University in Ithaca,
New York. Like PCR, the gene-amplification method that revolutionized
genetic engineering after its invention in 1985, CRISPR is impacting the
life sciences in so many ways, he says.
But although CRISPR has much to offer, some scientists are worried
ILLUSTRATIONS BY SBASTIEN THIBAULT
A powerful gene-editing technology is the biggest

game changer to hit biology since PCR. But with its
huge potential come pressing concerns.
FEATURE NEWS
that the fields breakneck pace leaves little time for addressing the ethical and safety concerns such experiments can raise. The problem was
thrust into the spotlight in April, when news broke that scientists had used
CRISPR to engineer human embryos (see Nature 520, 593595; 2015).
The embryos they used were unable to result in a live birth, but the report2
has generated heated debate over whether and how CRISPR should be
used to make heritable changes to the human genome. And there are other
concerns. Some scientists want to see more studies that probe whether
the technique generates stray and potentially risky genome edits; others
worry that edited organisms could disrupt entire ecosystems. This power
is so easily accessible by labsyou dont need a very expensive piece of
equipment and people dont need to get many years of training to do this,
says Stanley Qi, a systems biologist at Stanford University in California.
We should think carefully about how we are going to use that power.
RESEARCH REVOLUTION
Biologists have long been able to edit genomes with molecular tools.
About ten years ago, they became excited by enzymes called zinc finger
nucleases that promised to do this accurately and efficiently. But zinc
fingers, which cost US$5,000 or more to order, were not widely adopted
because they are difficult to engineer and expensive, says James Haber, a
molecular biologist at Brandeis University in Waltham, Massachusetts.
CRISPR works differently: it relies on an enzyme called Cas9 that uses a
guide RNA molecule to home in on its target DNA, then edits the DNA
to disrupt genes or insert desired sequences. Researchers often need to
order only the RNA fragment; the other components can be bought off
the shelf. Total cost: as little as $30. That effectively democratized the
technology so that everyone is using it, says Haber. Its a huge revolution.
CRISPR methodology is quickly eclipsing zinc finger nucleases and
other editing tools (see The rise of CRISPR). For some, that means
abandoning techniques they had taken years to perfect. Im depressed,
says Bill Skarnes, a geneticist at the Wellcome Trust Sanger Institute in
Hinxton, UK, but Im also excited. Skarnes had spent much of his career
using a technology introduced in the mid-1980s: inserting DNA into
embryonic stem cells and then using those cells to generate genetically
modified mice. The technique became a laboratory workhorse, but it was
also time-consuming and costly. CRISPR takes a fraction of the time, and
Skarnes adopted the technique two years ago.
Researchers have traditionally relied heavily on model organisms
such as mice and fruit flies, partly because they were the only species
that came with a good tool kit for genetic manipulation. Now CRISPR
is making it possible to edit genes in many more organisms. In April, for
example, researchers at the Whitehead Institute for Biomedical Research
in Cambridge, Massachusetts, reported using CRISPR to study Candida
albicans, a fungus that is particularly deadly in people with weakened
immune systems, but had been difficult to genetically manipulate in the
lab3. Jennifer Doudna, a CRISPR pioneer at the University of California,
Berkeley, is keeping a list of CRISPR-altered creatures. So far, she has three
dozen entries, including disease-causing parasites called trypanosomes
and yeasts used to make biofuels.
Yet the rapid progress has its drawbacks. People just dont have the
time to characterize some of the very basic parameters of the system,
says Bo Huang, a biophysicist at the University of California, San Francisco. There is a mentality that as long as it works, we dont have to
understand how or why it works. That means that researchers occasionally run up against glitches. Huang and his lab struggled for two months
to adapt CRISPR for use in imaging studies. He suspects that the delay
would have been shorter had more been known about how to optimize
the design of guide RNAs, a basic but important nuance.
By and large, researchers see these gaps as a minor price to pay for a
powerful technique. But Doudna has begun to have more serious concerns about safety.
Her worries began at a
meeting in 2014, when
A Nature collection
she saw a postdoc prenature.com/crispr
sent work in which a
CRISPR GENE EDITING
virus was engineered to carry the CRISPR components into mice. The
mice breathed in the virus, allowing the CRISPR system to engineer mutations and create a model for human lung cancer4. Doudna got a chill; a
minor mistake in the design of the guide RNA could result in a CRISPR
that worked in human lungs as well. It seemed incredibly scary that you
might have students who were working with such a thing, she says. Its
important for people to appreciate what this technology can do.
There is a
mentality that as
long as it works,
we dont have to
understand how
or why it works.
Andrea Ventura, a cancer researcher at Memorial Sloan Kettering
Cancer Center in New York and a lead author of the work, says that his
lab carefully considered the safety implications: the guide sequences were
designed to target genome regions that were unique to mice, and the virus
was disabled such that it could not replicate. He agrees that it is important
to anticipate even remote risks. The guides are not designed to cut the
human genome, but you never know, he says. Its not very likely, but it
still needs to be considered.
EDITING OUT DISEASE
Last year, bioengineer Daniel Anderson of the Massachusetts Institute of

Technology in Cambridge and his colleagues used CRISPR in mice to correct a mutation associated with a human metabolic disease called tyrosinaemia5. It was the first use of CRISPR to fix a disease-causing mutation
in an adult animal and an important step towards using the technology
for gene therapy in humans.
The idea that CRISPR could accelerate the gene-therapy field is a
major source of excitement in scientific and biotechnology circles. But as
well as highlighting the potential, Andersons study showed how far there
is to go. To deliver the Cas9 enzyme and its guide RNA into the target
organ, the liver, the team had to pump large volumes of liquid into blood
vesselssomething that is not generally considered feasible in people.
And the experiments corrected the disease-causing mutation in just 0.4%
of the cells, which is not enough to have an impact on many diseases.
Over the past two years, a handful of companies have sprung up to
develop CRISPR-based gene therapy, and Anderson and others say that
the first clinical trials of such a treatment could happen in the next one
or two years. Those first trials will probably be scenarios in which the
CRISPR components can be injected directly into tissues, such as those
in the eye, or in which cellscan be removed from the body, engineered in
the lab and then put back. For example, blood-forming stem cells might be
corrected to treat conditions such as sickle-cell disease or -thalassaemia.
It will be a bigger challenge to deliver the enzyme and guide RNA into
many other tissues, but researchers hope that the technique could one day
be used to tackle a wider range of genetic diseases.
Yet many scientists caution that there is much to do before CRISPR
can be deployed safely and efficiently. Scientists need to increase the
efficiency of editing, but at the same time make sure that they do not
introduce changes elsewhere in the genome that have consequences for
health. These enzymes will cut in places other than the places you have
designed them to cut, and that has lots of implications, says Haber. If

4 J U N E 2 0 1 5 | V O L 5 2 2 | N A T U R E | 37
21
NEWS FEATURE
It will be hard to
detect whether
something has
been mutated
conventionally
or genetically
engineered.
youre going to replace somebodys sickle-cell gene in a stem cell, youre
going to be asked, Well, what other damage might you have done at other
sites in the genome?
Keith Joung, who studies gene editing at Massachusetts General Hospital in Boston, has been developing methods to hunt down Cas9s off-target
cuts. He says that the frequency of such cuts varies widely from cell to
cell and from one sequence to another: his lab and others have seen offtarget sites with mutation frequencies ranging from 0.1% to more than
60%. Even low-frequency events could potentially be dangerous if they
accelerate a cells growth and lead to cancer, he says.
With so many unanswered questions, it is important to keep
expectations of CRISPR under control, says Katrine Bosley, chief executive of Editas, a company in Cambridge, Massachusetts, that is pursuing
CRISPR-mediated gene therapy. Bosley is a veteran of commercializing
new technologies, and says that usually the hard part is convincing others
that an approach will work. With CRISPR its almost the opposite, she
says. Theres so much excitement and support, but we have to be realistic
about what it takes to get there.
CRISPR ON THE FARM
While Anderson and others are aiming to modify DNA in human cells,
others are targeting crops and livestock. Before the arrival of geneediting techniques, this was generally done by inserting a gene into
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the genome at random positions, along with sequences from bacteria,

viruses or other species that drive expression of the gene. But the process is inefficient, and it has always been fodder for critics who dislike
the mixing of DNA from different species or worry that the insertion
could interrupt other genes. What is more, getting genetically modified crops approved for use is so complex and expensive that most of
those that have been modified are large commodity crops such as maize
(corn) and soya beans.
With CRISPR, the situation could change: the ease and low cost may
make genome editing a viable option for smaller, speciality crops, as
well as animals. In the past few years, researchers have used the method
to engineer petite pigs and to make disease-resistant wheat and rice.
They have also made progress towards engineering dehorned cattle,
disease-resistant goats and vitamin-enriched sweet oranges. Doudna
anticipates that her list of CRISPR-modified organisms will grow.
Theres an interesting opportunity to consider doing experiments or
engineering pathways in plants that are not as important commercially
but are very interesting from a research perspective or for home
vegetable gardens, she says.
CRISPRs ability to precisely edit existing DNA sequences makes
for more-accurate modifications, but it also makes it more difficult
for regulators and farmers to identify a modified organism once it
has been released. With gene editing, theres no longer the ability to
really track engineered products, says Jennifer Kuzma, who studies
science policy at North Carolina State University in Raleigh. It will
be hard to detect whether something has been mutated conventionally
or genetically engineered.
That rings alarm bells for opponents of genetically modified crops,
and it poses difficult questions for countries trying to work out how to
regulate gene-edited plants and animals. In the United States, the Food
and Drug Administration has yet to approve any genetically modified
animal for human consumption, and it has not yet announced how it
will handle gene-edited animals.
Under existing rules, not all crops made by genome editing would
require regulation by the US Department of Agriculture (see Nature
500, 389390; 2013). But in May, the agriculture department began
to seek input on how it can improve regulation of genetically modified cropsa move that many have taken as a sign that the agency is
re-evaluating its rules in light of technologies such as CRISPR. The
window has been cracked, says Kuzma. What goes through the window remains to be seen. But the fact that its even been cracked is
pretty exciting.
ENGINEERED ECOSYSTEMS
Beyond the farm, researchers are considering how CRISPR could or

should be deployed on organisms in the wild. Much of the attention
has focused on a method called gene drive, which can quickly sweep
an edited gene through a population. The work is at an early stage, but
such a technique could be used to wipe out disease-carrying mosquitoes
or ticks, eliminate invasive plants or eradicate herbicide resistance in
pigweed, which plagues some US farmers.
Usually, a genetic change in one organism takes a long time to spread
through a population. That is because a mutation carried on one of a
pair of chromosomes is inherited by only half the offspring. But a gene
drive allows a mutation made by CRISPR on one chromosome to copy
itself to its partner in every generation, so that nearly all offspring will
inherit the change. This means that it will speed through a population exponentially faster than normal (see Gene drive) a mutation
engineered into a mosquito could spread through a large population
within a season. If that mutation reduced the number of offspring a
mosquito produced, then the population could be wiped out, along with
any malaria parasites it is carrying.
But many researchers are deeply worried that altering an entire
population, or eliminating it altogether, could have drastic and unknown
consequences for an ecosystem: it might mean that other pests emerge,
for example, or it could affect predators higher up the food chain. And
THE RISE OF CRISPR
A BRIEF
HISTORY
OF CRISPR
DNA sequences called CRISPRs (clustered regularly interspaced short palindromic

repeats) are part of a bacterial defence system. After researchers showed in 2012
that CRISPRs could be used to edit genomes, use of the tools quickly spread, as
reflected by sharp rises in publications, patent applications and funding.
Key events in the

CRISPR story.
A cluster of biotech
companies has
sprung up to use
CRISPR technology.
Number of publications
1,600
Papers mentioning
induced pluripotent stem
(iPS) cells, another rapidly
adopted technique, are
shown for comparison.
1,200
iPS
cells
October 2011
CARIBOU BIOSCIENCES
Berkeley, California
800
Focus: Research, industry,

therapeutics, agriculture
CRISPR
Researchers find
CRISPR sequences
in Escherichia coli,
but do not characterize
their function8.
July 1995
CRISPR sequences are

found to be common in
other microbes9.
PUBLICATIONS
The number of papers about CRISPR has outstripped the numbers mentioning
the gene-editing technologies known as TALENs and zinc fingers.
December 1987
March 2007
Scientists at food
company Danisco
determine that the
repeats are part of a
bacterial defence
against viruses10.
Raised:
$11
MILLION
400
Zinc
fingers
TALENs
0
2006
2007
2008
2009
2010
2011
2012
2013
2014
June 2012
PATENTS
November 2013
EDITAS MEDICINE
In 2014, worldwide patent applications that mention

CRISPR leapt and a patent battle intensified.
Researchers report
that CRISPR can be
used to perform
genome editing1.
Cambridge, Massachusetts
Published patent applications
200
Focus: Therapeutics
Raised:
$43 MILLION
TOP 5 PATENT APPLICANTS:
Massachusetts Institute of Technology (MIT): 62

Broad Institute: 57
MIT bioengineer Feng Zhang: 34
Danisco: 29
Dow Agrosciences: 28
150
100
January 2013
CRISPR is used in
mouse and human cells,
fuelling rapid uptake of
the technique by
researchers1113.
November 2013
CRISPR THERAPEUTICS
50
Basel, Switzerland
Focus: Therapeutics
Raised:
0
2006
2007
2008
2009
2010
2011
2012
2013
2014
The University of
California and others
file for a patent on
the findings1.
$89 MILLION
FUNDING
April 2014
A sharp jump in US National Institutes of Health funding for

projects involving CRISPR is a harbinger of future advances.
80
Spending (US$ millions)
March 2013
November 2014
INTELLIA THERAPEUTICS
CRISPR funding in
2014 lagged behind
the nearly $160 million
for iPS-cell research.
60
MIT and the Broad

Institute are granted a
patent on CRISPR gene
editing, sparking a
fierce patent battle.
Cambridge, MA
Focus: Therapeutics
Raised:
$15
MILLION
40
March 2015
Report of the first

CRISPR gene drive,
which can spread an
edited gene rapidly
through a population6.
April 2015
20
0
2007
2008
2009
2010
2011
2012
2013
2014
DESIGN BY WES FERNANDES;

SOURCES: PUBLICATIONS:
SCOPUS; PATENTS: THE LENS;
FUNDING: NIH REPORTER.
Researchers report
that they have edited
human embryos with
CRISPR, triggering an
ethical debate2.
39
U P DAT E D O N 8 J U N E 2 0 1 5 | 4 J U N E 2 0 1 5 | VO L 5 2 2 | NAT U R E | 2 3
GENE DRIVE
CRISPR gene editing can be used to propagate a genetic

modification rapidly through generations. It might be used
to eradicate a population of disease-carrying mosquitoes.
STANDARD INHERITANCE
Mosquito with
modified gene
Wild-type
mosquito
Each parent passes on

one chromosome of a
pair to its offspring.
Offspring have a
50% chance of
inheriting the
modified gene.
Modified gene spreads slowly through population.
GENE-DRIVE INHERITANCE
The gene-drive system cuts the partner chromosome, then the
repair process copies the modification to this chromosome.
Mosquito with
modified gene +
gene drive.
Wild-type
mosquito
Cut
Repair
Nearly 100%
of offspring
inherit the
modified gene.
researchers are also mindful that a guide RNA could mutate over time
such that it targets a different part of the genome. This mutation could
then race through the population, with unpredictable effects.
It has to have a fairly high pay-off, because it has a risk of irreversibilityand unintended or hard-to-calculate consequences for
other species, says George Church, a bioengineer at Harvard Medical
School in Boston. In April 2014, Church and a team of scientists and
policy experts wrote a commentary in Science6 warning researchers
about the risks and proposing ways to guard against accidental release
of experimental gene drives.
At the time, gene drives seemed a distant prospect. But less than
a year later, developmental biologist Ethan Bier of the University of
California, San Diego, and his student Valentino Gantz reported that
they had designed just such a system in fruit flies7. Bier and Gantz had
used three layers of boxes to contain their flies and adopted lab safety
measures usually used for malaria-carrying mosquitoes. But they did
not follow all the guidelines urged by the authors of the commentary,
such as devising a method to reverse the engineered change. Bier says
that they were conducting their first proof-of-principle experiments,
and wanted to know whether the system worked at all before they
made it more complex.
For Church and others, this was a clear warning that the democratization of genome editing through CRISPR could have unexpected and
undesirable outcomes. It is essential that national regulatory authorities and international organizations get on top of thisreally get on
top of it, says Kenneth Oye, a political scientist at the Massachusetts
Institute of Technology and lead author of the Science commentary.
We need more action. The US National Research Council has formed
a panel to discuss gene drives, and other high-level discussions are
starting to take place. But Oye is concerned that the science is moving
at lightning speed, and that regulatory changes may happen only after
a high-profile gene-drive release.
The issue is not black and white. Micky Eubanks, an insect ecologist
at Texas A&M University in College Station, says that the idea of gene
drives shocked him at first. My initial gut reaction was Oh my god, this
is terrible. Its so scary, he says. But when you give it more thought and
weigh it against the environmental changes that we have already made
and continue to make, it would be a drop in the ocean.
Some researchers see lessons for CRISPR in the arc of other new technologies that prompted great excitement, concern and then disappointment when teething troubles hit. Medical geneticist James Wilson of the
University of Pennsylvania in Philadelphia was at the centre of booming
enthusiasm over gene therapy in the 1990sonly to witness its downfall when a clinical trial went wrong and killed a young man. The field
went into a tailspin and has only recently begun to recover. The CRISPR
field is still young, Wilson says, and it could be years before its potential
is realized. Its in the exploration stage. These ideas need to ferment.
Then again, Wilson has been bitten by the CRISPR bug. He says that
he was sceptical of all the promises being made about it until his own lab
began to play with the technique. Its ultimately going to have a role in
human therapeutics, he says. Its just really spectacular.
Heidi Ledford is a senior reporter for Nature in Cambridge,
Massachusetts.
Jinek, M. et al. Science 337, 816821 (2012).
Liang, P. et al. Protein Cell 6, 363372 (2015).
Vyas, V. K., Barrasa, M. I. & Fink, G. R. Sci. Adv. 1, e1500248 (2015).
Maddalo, D. et al. Nature 516, 423-427 (2014).
Yin, H. et al. Nature Biotechnol. 32, 551553 (2014).
Oye, K. A. et al. Science 345, 626628 (2014).
Gantz, V. M. & Bier, E. Science 348, 442444 (2015).
Ishino, Y., Shinagawa, H., Makino, K., Amemura, M. & Nakata, A. J. Bacteriol. 169,
54295433 (1987).
9. Mojica, F. J., Ferrer, C., Juez, G. & Rodrguez-Valera, F. Mol. Microbiol. 17, 8593
(1995).
10. Barrangou, R. et al. Science 315, 17091712 (2007).
11. Cong, L. et al. Science 339, 819823 (2013).
12. Mali, P. et al. Science 339, 823826 (2013).
13. Jinek, M. et al. eLife 2, e00471 (2013).
1.
2.
3.
4.
5.
6.
7.
8.
Modified gene sweeps rapidly through population.
240
4 | N A T U R E | V O L 5 2 2 | 4 J U N E 2 0 1 5

FEATURE NEWS
NEWS FEATURE
reproduced.
DEVASTATING EFFECTS
BUYER BEWARE
2
A wave
in the
CA125, and did not bind to CUZD1
at allof
. Ininnovative flat materials is following
scientists
do not always follow the instructions.
retrospect, Prassas says, a rush
to getof
going
on
Ideally, researchers would refuse to buy antiwake
graphene
but the most exciting applications
could
from stacking them into 3D devices.
group had failed to do all the right
tests.come
If
BY ELIZABETH GIBNEY
Most scientists who purchase antibodwhich he shares with anyone who will listen.
ies believe the label printed on the vial, says
Rimm.
As have
a pathologist,
I wasnt
trained they can think of to says Kis, but somehow they
recommends
controlasexperiments
that involve
hysicists
used almost
every superlative
got a reputation
not that interesting.
I
thatdescribe
you hadgraphene.
to validate
antibodies;
was just
engineering
cell
This
gossamer,I one-atom-thick
sheet of carbon thought they deserved a second
chance.
lines to both express and stop
He was right. Work by his
team andthe
a handful
soon
trained
that you
ordered them.
expressing
proteinof
ofothers
interest,
for showed
example.
is flexible,
transparent,
stronger
than steel, more conductive than
copper and are
so thin
that it isbyeffectively
two-dimensional
(2D). No
Antibodies
produced
the immune
for every protein
in thethat
human
genome.
It has Even
that few
labsproduce
will perdifferent
combinations
ofhe
theacknowledges
basic ingredients
could
systems
ofitmost
vertebrates
target
an invader
lookedfor
at some
20,000TMDCs
commercial
all the steps.
sooner
was
isolated
in 2004tothan
it became
an obsession
researchwith antiboda wide rangeform
of electronic
and optical properties. Unlike
such
as a the
bacterium.
less thanfor
50%
can bemany Some
scientists
buy half a dozen
antiboders
around
world. Since the 1970s, scien- ies so far and found that
graphene,
example,
TMDCs
are semiconductors,
meaning
that
tists
exploited
for research.
used effectively
to lookthey
at protein
distribution
frominto
different
vendors, and
then
run a few
But have
not for
Andrasantibodies
Kis. As miraculous
as If
graphene
was, says Kis,
have the
potential to beies
made
molecular-scale
digital
processors
researcher
a protein
interest
into
in preserved
slices
. This
has more
led some
to than
see which
performs
they
Iafelt
there hadinjects
to be more
thanofcarbon.
So
in 2008,
when he got
theof tissue
that5are
much
energyassays
efficient
anything
possiblebest.
with But
silicon.
a rabbit,
white
cells known
asinB nanoscale
cells scientists
may endaround
up buying
the same
antibody
to claim
to halfa of
com-laboratories
chance
to start
hisblood
own research
group
electronics
at thethat up
Within
fewallyears,
the world
had joined
thefrom
2D
will Federal
start producing
against
the (EPFL),
mercially
available
arefirst
unreliable.
Theand
largest
vendors
compete
Swiss
Institute ofantibodies
Technology
in Lausanne
Kis
focusedantibodies
quest. At
it was one,different
then twoplaces.
or three,
suddenly
it became
protein,
can of
besuper-flat
collected materials
from the aniBut reliability
can depend
onzoo
theof
experiment.
catalogue
size,
so they often
buy antibodies
his
effortswhich
on a class
that had been
languishing
whole
2D materials,on
says
Kis. From
a scattering
of publications
in
blood. shadow.
For a more consistent product, the Our experience with commercial
antibodies
from
smallersix
suppliers,
relabel
them
offer
inmals
graphenes
2008, 2D TMDCs
alone now
generate
publications
each
day.and
PhysiThesecan
materials
had anfused
ungainly
name
transition-metal
dichalBcells
be retrieved,
with an
immoris that they are
usuallycists
okaythink
in some
for sale.
says that
the 2million
thatapplicathere maythem
be around
500Bernard
2D materials,
including
not
cogenides
(TMDCs)
but
2D form
that was quite
simple.
A single
talized cell
and cultured
to aprovide
a theoretitions,
but they
might bejust
terrible
in others,
says antibodies
on thelayers
market
probably
represent
graphene
and TMDCs,
but also single
of metal
oxides,
and
callyofunlimited
supply. atoms such as molybdenum
Mathias
Uhln at
the Royal
Institute of
Tech- such
250,000500,000
core antibodies.
sheet
transition-metal
or tungsten
was
single-element
materials
as silicene andunique
phosphorene.
If you want
Three decades
ago,
scientists
who needed
nology
in Stockholm,
coordinates
researchers
rely on
sandwiched
between
equally
thin layers
of chalcogens:
elements,
such awho
2D material
with athe
given setBy
of necessity,
properties,many
says Jonathan
Coleman,
a
of mouth
or the
literature for
Dublin,
you will
findpublished
one.
their experiments
had to
make in Human
Protein
Atlas. physicist at Trinity Collegeword
asantibodies
sulfur andfor
selenium,
that lie below
oxygen
the periodic
table.
advice.
But that
creates in
a self-perpetuating
them themselves.
But
thetransparent
late 1990s, reaResearchers
ideally should
checkone
thatofan
TMDCs
were almost
asby
thin,
and flexible
as graphene,
Ironically,
the most
exciting
frontiers
2D materials is
gent companies had started to take over the antibody has been tested for use in particular problem, in which better-performing antibodapplications and tissue types, but the quality ies that become available later are rarely used,
chore.
Today, more than 300 companies sell over of information supplied by vendors can vary says Fridtjof Lund-Johansen, a proteomics
SOURCE: H. TERRONES ET AL. SCI. REP. 3, 1549 (2013)

OR
2D
2D NOT 2D
2D
ANTIBODIES
ARE NOT
MAGIC
REAGENTS.
2 7 4NATURE
| N A T COLLECTIONS
2 | 1 8 J USUMMER
N E 2 0 1 READS
5
2 1 M A Y 2 0 1 5 | V O L 5 2 1 | N A T U R E | 241
75
NEWS FEATURE
FEATURE NEWS
stacking them into structures that

are still very thin, but definitely 3D.
By taking advantage of the vastly different properties of various super-flat
materials, it should be possible to build entire digital circuits out of
atomically thick components, creating previously unimagined devices.
Applications are already being touted in fields from energy harvesting to
quantum communications even though physicists are just beginning
to learn the materials potential.
Each one is like a Lego brick, says Kis. If you put them together,
maybe you can build something completely new.
when they meet, they recombine and give up their energy as photons.
This ability to convert light to electricity and vice versa makes TMDCs
promising candidates for applications that involve transmitting information using light, as well as for use in tiny, low-power light sources and even
lasers. This year, four different teams demonstrated the ultimate control
over light emission, showing that the TMDC tungsten diselenide (WSe2)
could absorb and release individual photons69. Quantum cryptography
and communications, which encode information in one photon at a time,
need emitters like this, where you press a button and get a photon now,
says Urbaszek. Existing single-photon emitters are often made of bulk
semiconductors, but 2D materials could prove smaller and easier to integrate with other devices. Their emitters are necessarily on the surface,
which could also make them more efficient and easier to control.
Even as researchers were getting to grips with TMDCs, theorists were
seeking other materials that could be engineered in two dimensions.
One obvious candidate was silicon, which sits right below carbon in the
periodic table, forms chemical bonds in a similar way, has a natural band
gap and is already widely used in the electronics industry. Calculations
suggested that, unlike graphene, a sheet of atomically thick silicon would
have a ridged structure that could be squashed and stretched to create
a tunable band gap. But like graphene, this silicene would be a much
faster conductor of electrons than most TMDCs.
Unfortunately, theory also suggested that a 2D sheet of silicene would
be highly reactive and completely unstable in air. Nor could it be ripped
from a crystal like other 2D materials: natural silicon exists only in a
3D form analogous to a diamond crystal, with nothing resembling the
layered sheets of carbon found in graphite.
People said it was insane and would never work, says Guy Le Lay, a
physicist at Aix-Marseille University in France. But Le Lay, who had been
growing metals on silicon surfaces for years, saw a way to make silicene by
doing the reverse growing atomically thin sheets of silicon on metal.
And in 2012 he reported success10: he had grown layers of silicene on
silver, which has an atomic structure that matches the 2D material perfectly (see Nature 495, 152153; 2013).
Buoyed by that effort, Le Lay and others have
since moved down the carbon column of the
periodic table. Last year, he demonstrated a
similar
technique
to growmany
a 2D mesh
of gersexes becomes even blurrier.
Scientists
have identified
of the genes
involved in the main forms
of DSD,
and have
uncovered
in
manium
atoms
germanene
variations
on a substrate
these genes that have subtleofeffects
on. His
a persons
anatomical
or physiologigold11
next target
is stanene:
a 2D latcal sex. Whats more, new technologies
in DNA
sequencing
and
cellabioltice of tin atoms.
Stanene
should
have
band
ogy are revealing that almost
everyone
is, toeither
varying
degrees,
gap
larger than
silicene
anda patchwork
germanene,
of genetically distinct cells,which
some would
with a allow
sex that
not
of
itsmight
devices
tomatch
work atthat
higher
the rest of their body. Sometemperatures
studies even and
suggest
that the
sexitof
cell
voltages.
And
is each
predicted
drives its behaviour, through
a complicated
network
of molecular
inter-so
to carry
charges only
on its
outside edges,
actions.
I think
theres
diversity
within
malecompetition.
or female,
it should
conduct
withmuch
supergreater
efficiency.
But Le
Lay has
and
there isno
certainly
of overlap
where
somesuccessfully,
people cantresearch
easily
Although
one hasan
yetarea
reported
growing
stanene
define
themselves
within
the binary
groups
in China are
rumoured
to bestructure,
close. says John Achermann,
who studies sex development and endocrinology at University College
Londons
Institute
ELEMENTAL
SHIFTof Child Health.
These discoveries
dodifferent
not sit well
in aof
world
in whichtable.
sex is Zhangs
still defined
Others
are exploring
parts
the periodic
team
inand
binary
terms.
legal systems
allowUniversity
for any ambiguity
in biological
another
ledFew
by Peide
Ye at Purdue
in West Lafayette,
Indi12,13
sex,
and
persons
legal rights
and social
be heavily influenced
ana,
lasta year
described
stripping
2Dstatus
layers can
of phosphorene
from black
byphosphorus,
whether their
birthform
certificate
says male
orhas
female.
a bulk
of the element
that
been studied for a cenTheLike
main
problemphosphorene
with a strongconducts
dichotomy
is thatswiftly.
there are
tury.
graphene,
electrons
Butinterunlike
graphene,
it has
natural
ask
andusitto
is figure
more stable
than silicene.
mediate
cases
thatapush
theband
limitsgap
and
out exactly
where
Phosphorene
enjoyed
a meteoric
rise. At says
the 2013
meeting
of at
the
the dividing
line ishas
between
males
and females,
Arthur
Arnold
the
University
of California,
who
biological
sex
American
Physical
Society, itLos
wasAngeles,
the subject
of astudies
single talk
by members
differences.
And thats
often
difficult
problem,
can
of Zhangs group;
by 2015,
thea very
meeting
had three
entirebecause
sessionssex
devoted
betodefined
a number
of ways.
it. But like

its fellow
pure-element
2D materials, phosphorene reacts
very strongly with oxygen and water. If it is to last longer than a few hours,
THE
STARTtoOFbeSEX
it needs
sandwiched between layers of other materials. This natuThat
the two sexes
are physically
different
obvious,
but at difficult;
the start ofLelife,
ral instability
makes
fabricating
devicesiswith
the enes
Lay
it estimates
is not. Fivethat
weeks
into development,
a human
hasstill
thetheoretical.
potential
around
80% of the papers
aboutembryo
them are
to form
both maleboth
and female
anatomy.
Next to the
developing
kidneys,
Nonetheless,
Zhang and
Ye succeeded
in making
phosphorene
two
bulges known
the gonadal
emerge
alongside
pairs of14,
transistors.
Thisasyear,
the firstridges
transistor
from
silicenetwo
emerged
SEX
REDEFINED
Stacks of multiple kinds of flat
materials can exploit the best
properties of each.

ADVENTURES IN FLATLAND
A material that is just a few atoms thick can have very different fundamental properties from a material made of the same molecules in solid
form. Even if the bulk material is an old one, if you can get it into 2D
form it opens up new opportunities, says Yuanbo Zhang, an experimental condensed-matter physicist at Fudan University in Shanghai, China.
Carbon is the classic example, as physicists Andre Geim and
Konstantin Novoselov found in 2004 when they first reported isolating graphene1 in their laboratory at the University of Manchester, UK.
Their technique was almost absurdly simple. The basic step is to press
a strip of sticky tape onto a flake of graphite, then peel it off, bringing
with it a few of the atom-thick layers that make up the bulk material.
By repeating this process until they had single layers which many
theorists had said could not exist in isolation Geim and Novoselov
were able to start investigating graphenes remarkable properties. Their
work won them the 2010 Nobel Prize in Physics.
Physicists were soon hurrying to exploit those properties for applications ranging from flexible screens to energy storage (see page 268).
Unfortunately, graphene proved to be a poor fit for digital electronics.
The ideal material for that application is a semiconductor a material
that does not conduct electricity unless its electrons are boosted with a
certain amount of energy from heat, light or an
external voltage. The amount of energy needed
varies with the material, and is known as the
band gap. Turning the materials conductivity
B YonC Land
A I R off
E A Icreates
N S W O Rthe
T H 1s and 0s of the digital
world. But graphene in its pure form does not
geneticist,
Paul James
accustomed to discussing some
haves a clinical
band gap
it conducts
all theis time.
of theGeim
most delicate
issues withsuccess
his patients.
Still,
and Novoselovs
in But in early 2010, he
found
himself spurred
having athem,
particularly
making
graphene
Kis andawkward
many conversation about
sex.to start investigating alternative 2D
others
2
materials
that could
havewoman
a band gaps
A 46-year-old
pregnant
had visited
. They his clinic at the Royal
Melbourne
Hospital
in Australia
tobeen
hear the
results of an amniocentesis
began with
TMDCs,
which had
studied
test
screen
babys
forKiss
abnormalities.
Theits
baby
in to
bulk
formher
since
thechromosomes
1960s. By 2010,
team had built
firstwas
sinfine
but transistor
follow-up3tests
something astonishing
gle-layer
fromhad
therevealed
TMDC molybdenum
disulfide about
(MoS2;
the
Herassembly),
body was speculating
built of cellsthat
from
twodevices
individuals,
probseemother.
Flat-pack
such
could one
day
ably
from
twinelectronics
embryos that
hadsmall
merged
in her own
mothers
offer
flexible
whose
component
size
and lowwomb.
voltage
And
there was more.
setthat
of cells
two X
chromosomes,
requirements
wouldOne
mean
theycarried
consumed
much
less power the
than
complement
that
typically
makes aBeing
person
female; the other
X
conventional
silicon
transistors.
semiconducting
washad
notantheir
and
a Y.advantage.
Halfway through
fifthshowed
decade and
with
her absorb
third
only
Studies her
in 2010
thatpregnant
MoS2 could
both
child,
the woman
learned formaking
the firstittime
thatprobably
a large part
ofTMDCs
her body
and emit
light4,5 efficiently,
and
other
was
chromosomally
Thats
of science-fiction material for
attractive
for use inmale
solar1.cells
andkind
photodetectors.
someone
wholayer
just came
in for an
amniocentesis,
says
A single
of TMDCs
can
capture more
thanJames.
10% of incomSexphotons,
can be much
more complicated
it at firstthree
seems.
According
to
ing
an incredible
figure forthan
a material
atoms
thick, says
the
simple scenario,
thea presence
of aand
Y chromosome
is Nanowhat
Bernhard
Urbaszek,
physicistor
at absence
the Physics
Chemistry of
counts:
it, you are
male, andFrance.
withoutThis
it, you
female.
docObjectswith
Laboratory
in Toulouse,
alsoare
helps
themBut
in another
tors
have
long known
people
straddle
the boundary
hits
their
task:
converting
lightthat
intosome
electricity.
When
an incoming
photon
the
sex
chromosomes
sayitone
thing,
their gonads
or allowing
testes) or it
three-layer
crystal,
boosts
an but
electron
past the(ovaries
band gap,
sexual
anatomy
sayan
another.
Parents
of children
with
these kinds
conto move
through
external
circuit.
Each freed
electron
leavesofbehind
ditions
as intersex
differences
or disorders
of
a kind
of known
empty space
in theconditions,
crystal a or
positively
charged
hole where
sex
(DSDs)
oftenaface
difficult
about
andevelopment
electron ought
to be.
Apply
voltage,
anddecisions
these holes
andwhether
electrons
tocirculate
bring upintheir
childdirections
as a boy ortoaproduce
girl. Some
researchers
now say
that
opposite
a net
flow of electric
current.
as many
1 person
100
some form
of electricity
DSD2. into light. If elecThis as
process
canin
also
behas
reversed
to turn
Whenand
genetics
taken
into consideration,
thefrom
boundary
between
the
trons
holesisare
injected
into the TMDC
an outside
circuit;
PEOPLE SAID
IT WAS INSANE
AND WOULD
NEVER WORK.
242
NATURE
1 8 COLLECTIONS
J U N E 2 0 1 5 || NATURES
V O L 5 2 2SUMMER
| N A T U READS
RE | 275
FEATURE NEWS
NEWS FEATURE
analysis showing that results in 47 of 53 land- 2million antibodies forweak,

A means
common
complaint
scithe close
of their atoms
that
they canfrom
affect
research.
As ofproximity
2011, tremendously.
FLAT-PACK
each
others
properties
subtleisways,
says Wang
a physicist
at
mark cancer research papers ASSEMBLY
could not be the market was worth $1.6
billion,
according
to inentists
that companies
doYao,
not provide
the data
1
Transition-metal dichalcogenide (TMDC) crystals contain one transition-metal

reproduced.
global consultancy Frostthe
& University
Sullivan. of Hong Kong.
required
to evaluate
given antibodys
specificStacking
order, aspacing
and orientation
atom (green) for every two chalcogen atoms (orange). Some 40 such TMDCs
A those
few scientists
havehighlighted
been burned
bygreen in the periodic
ity or
its lot-to-lot
variability.
Companies
might
all control device behaviour.
Modelling
this
gives theorists
like me
a
mostly
made with who
the metals
in dark
table
can be split into
layers that are
flexible,
and excellent
badexperiences
with2Dantibodies
have
beguntransparent
to DEVASTATING
EFFECTS headache, but the new physical
ship aproperties
batch of antibodies
withthere,
characterization
are definitely
says Yao.
conductors of electricity. Some are also semiconductors.
speak up. Rimms disappointment set him on a There are signs that problems
antibodies
derived
a previous
batch.
Evenwith
graphene
can get ainformation
leg up from other
2Dfrom
materials,
says Marco
crusade to educate others by writing reviews, are having broad and potentially
devastating
And the
data are often
derived under
ideal
conPolini, a physicist
at the National
Enterprise
for Nanoscience
and
Nanohosting web seminars and raising the problem effects on the researchtechnology
record. In(NEST)
2009, one
thatteam
do not
typical experiments.
in Pisa,ditions
Italy. His
hasreflect
been working
on devices
in countless conference talks. He and others journal devoted an entire
tographene
assessing the
Antibodybetween
companies
forinsulator
this article
in issue
which
is sandwiched
2D contacted
layers of the
18
are calling for the creation of standards by antibodies that are used
to study
G-proteinsaid
thatis itfocused
is impossible
test their
products
boron
nitride
. When laser
light
on the to
device,
it gets
comTransition metal
which antibodies should be made, used and coupled receptors (GPCRs)
cell-signalling
acrossthe
all experimental
conditions,
butthan
theyindo
pressed and
channelled through
graphene layer,
much more
described. And some half a dozen grass-roots proteins that are targeted
by drugs
tosandwich
treat vari-graphene
providebetween
reliable bulk
data materials.
and work with
scientists
devices
that
In principle,
efforts have sprung up to provide better ways ous disorders, from incontinence
to schizoto improve
antibody
performance.
this could provide
a way for
information
to bequality
carriedand
between
chips
Chemical bonds link metal atoms and chalcogens
3
phrenia.
In
an
analysis
of
49
commercially
Many
academics
use
Google
to
find
products,
using
photons
rather
than
electricity.
That,
says
Polini,
could
mean
into a strong, flat sheet just one molecule thick.
A TMDC
But it is too soon to call the cause a moveavailable antibodies thatfaster
targeted
signalling
so optimizing search
can sometimes
and 19
more
efficient communications
withinresults
the chips.
to more than one pro- matter more to a company than optimizing the
Hment. There are all these resources out there, receptors, most bound
He
but nobody uses them and many people arent tein, meaning that theyPRACTICAL
could not be
trusted to actual reagents, says Tim Bernard, head of the
PREDICTIONS
Li Be
C N O F Ne
even aware of them, says Len Freedman, who B distinguish
between theThe
receptors.
biotechnology
consultancyofPivotal
Scientific
current buzz around 2D
materials is reminiscent
the excitement
reliesgraphene
heavily on
in Upper
Heyford,
UK. Christi
Bird, Univera Frost &
about
in anti2005, says
physicist
Jari Kinaret
of Chalmers
Naheads
Mg the Global Biological Standards Insti- Al SiTheP field
S ofClepigenetics
Ar
tute, a non-profit group in Washington DC bodies to identify howsity
proteins
that regulate
Sullivan analyst
based
Washington
DC, says
of Technology
in Gothenburg,
Sweden,
whoinheads
the European
Kcommitted
Ca Sc Tito improving
V Cr Mn biomedical
Fe Co Ni research.
Cu Zn Ga gene
Ge expression
As Se Br have
Kr been
modified.
In 2011,
an that
often
interested
Unions
Graphene
Flagship
aresearchers
programmeare
that
alsomore
studies
other 2Din
4
used in
how quickly
reagents
delivered
materials.
Butepigenetic
Kinaret cautions
that it could
takecan
twobedecades
to than
reallyin
RbMost
Sr vendors
Y Zr Nbhave
Mo no
Tc incentive
Ru Rh Pdto change
Ag Cd In evaluation
Sn Sb Te of I246Xeantibodies
whats going on right now, even though a lot of studies found that one-quarter
testsoffor
antibodies
with appropriate
valiassess thefailed
potential
thesesearching
materials.for
The
initial studies
on 2D materiLn Hf reagents
Ta W suck.
Re Os
CstheBa
Pb Bi Po meaning
At Rn that
often bound
totheirdation
antibody
Ir Pt Au Hg Tl specificity,
data.properties,
Its the Amazon
effect:
alsthey
are focusing
a lot on
electronic
because
thesethey
are want
close it
more than one target.to
Four
antibodies
were
in two orBut
threeI days,
shipping. if
physicists
hearts,
says Kinaret.
thinkwith
thatfree
the applications,
Fr Ra An Rf Db Sg Bh Hs Mt Ds Rg
BUYER BEWARE
perfectly specific butand
to the
wrong
Researchers
who are aware
of the antibody
when
theytarget.
come, are likely
to be in a completely
unpredicted
area.
Take the example of Ioannis Prassas, a proteoScientists often know, anecdotally,
thatlook
somegoodproblem
say
need
to make
be more
Materials that
in the lab
arethat
notscientists
always those
that
it
Ho Er Tm inYbtheir
Lu field
La Ce atPrMount
Nd PmSinai
Sm Hospital
Eu Gd Tbin Dy antibodies
mics researcher
areinto
problematic,
but One
vigilant.
Antibodies
are2D
not
magic reagents.
out
the real world.
major issue
facing all
materials
is how
Toronto, Canada.
his colleagues
theuniform,
size of the
You cant
justcheaply.
throw them
on your sample
and
produce
defect-free
layers
The sticky-tape
method
Ac Th He
Pa and
U Np
Pu Am Cm had
Bk Cf itEshasFmbeen
Md difficult
No Lr totogauge
as a well
whole.
Perhaps andexpect
been chasing a protein called CUZD1, which problem across biology
the resultbut
you
100% reliable withworks
for TMDCs
phosphorene,
is get
tooistime-consuming
to
they thought could be used to test whether the largest assessment comes
from
outtoputting
someblack
critical
thinking into
it, says
scale up.
It iswork
also pubexpensive
make bulk
phosphorus,
because
someoneit has
pancreatic
cancer.
bought
lished
the Human Protein
Atlas,
a Swedish
Jamesoccurring
Trimmer,white
headphosphorus
of NeuroMab
the Unialthough
survived
for only
a fewThey
minutes.
Still, Le
Layby
is optimistic
it involves
subjecting
naturally
toatextreme
a protein-detection
kitinsurmountable.
and wasted two years,
consortium
aims to
generate
versity of
which
makes
that
these issues are not
Just two years
ago, hethat
points
pressure.
Noantibodies
one has yet perfected
theCalifornia,
process ofDavis,
growing
single
sheetsantiof
$500,000
andother
thousands
of patient
samples
forthe
neuroscience.
Like many
suppliers,
out,
Geim and
physicists
were saying
that a silicene transistor 2D materials from scratch,bodies
let alone
layered structures
that physicists
before
realized
that
the antibody
in the
thestructures,
types of expericould
notthey
be made
with
current
technology.
So its always dangerous find so promising. It took aNeuroMab
long time toexplicitly
make ourstates
hetero
says
was recognizing
different
cancer protein,
that an antibody
shouldinbe
used How
for, but
tokit
predict
the future,alaughs
Le Lay.
Xiaodong Xu, a physicist at ment
the University
of Washington
Seattle.
scientists
do not always
thework
instructions.
can we speed that up or make
it automatic?
There isfollow
a lot of
to do.
retrospect,
Prassas says, a rush to get going on
Ideally,
researchers
would
refusefrom
to buy
antiTHE
NEXT DIMENSION
Such practical considerations
could
prevent 2D
materials
living
a promising
hypothesissearch
meantfor
that
he2D
andmaterials
his
bodies have
without
validation
dataor
Even
as some physicists
new
and try to under- up to their early promise. There
beenextensive
many rushes
like this,
and
perform
theI think
validation
themselves
group
hadproperties,
failed to do
all the
tests.
If
stand
their
others
areright
already
sandwiching
them together. some have turned out to bewould
fads, says
Kis. But
the sheer
number
someone
is an
assay
best, maybe the best of materials and different properties
(see Bad should
antibodies).
Thissomething
is something
that
Instead
of says,
tryingHere
to pick
one
andyou
say can
this use,
is the
make sure
comes
you are
so iseager
to test itthem
you can
forget
that that all their different out of this. Meanwhile, theRimm
passionatesays
about:
he hasArsenene,
developed
thing
to do
to combine
in such
a way
zoo isis
expanding,
Coleman.
what has been
promised
is not the
case.
a multistep
flowchart
for effectiveminds.
validation6,
advantages
are properly
utilized,
says
Kis.
a heavier cousin to phosphorene,
is already
on researchers
Most
scientists
who purchase
antibodwhich
he shares
with anyone
will listen.
This
could
mean stacking
components
made of different 2D materials
As people start to branch
out, they
are discovering
newwho
materials
that
believe
label
the vial,could
says also be layered inside have these wonderful properties,
But the
process
is time
consuming
Rimm
toies
make
tiny,the
dense
3Dprinted
circuits.onMaterials
says
Coleman.
The
most exciting
2D
Rimm. As
a pathologist,
I wasnt
trained already do when they material is probably one that
recommends
experiments
involve
components
something that
chip designers
hasnt beencontrol
made yet.
SEE BOOKSthat
& ARTS
P.284
thatlayers
you had
to validate
antibodies; I was
justof one another to make
grow
of different
semiconductors
on top
trained
thatasyou
them.
players. In standard devices, this is Elizabeth Gibney is a reporter
expressing
the protein
of interest, for example.
devices
such
theordered
lasers inside
DVD
for Nature
in London.
Antibodies
by the
immune
for every
protein
in the human genome. It has Even he acknowledges that few labs will pertricky:
each layerare
hasproduced
to chemically
bond
with the next,
and only
certain
Novoselov, K. S. et al. Science 306, 666669 (2004).
systems of most
to target
an invader
looked
at some
20,0001.
commercial
antibodform all the steps.
combinations
canvertebrates
be matched.
Otherwise,
the strain
between
the dif2. Novoselov, K. S. et al. Proc. Natl Acad. Sci. USA 102, 1045110453 (2005).
suchcrystal
as a bacterium.
Sincelayer
the 1970s,
scien- impossible.
ies so far and
found
than 50%
be A.,Some
scientists
buy
dozen antibodferent
lattices in each
makes bonding
With
2D that
3. less
Radisavljevic,
B.,can
Radenovic,
Brivio, J.,
Giacometti,
V. &half
Kis A.aNature
6, 147150 (2011).
tists havethat
exploited
antibodies
for the
research.
usedlayer
effectively
to look at Nanotechnol.
protein distribution
ies from different vendors, and then run a few
materials,
problem
goes away:
atomsIfin each
bond only
5
4. Mak,
K. F.,has
Lee,led
C., Hone,
J. & to
Heinz,
F. Phys. performs
Rev. Lett. 105,
136805
a researcher
a protein of
interest
intostrain
inispreserved
of tissue
. This
someJ., Shan,
assays
seeT.which
best.
But they
very
weakly to injects
the neighbouring
sheets,
so the
minimal.slices
Many
(2010).
a rabbit,
white blood cells
known as
B conductors
cells scientists
may
end up buying
claim that5.upSplendiani,
to half ofA. all
comlayers
of semiconductors,
insulators
and
can betostacked
et al.
Nano Lett.
10, 12711275
(2010).the same antibody from
start
producing
antibodies
against the
available
are unreliable.
different places.
The (2015).
largest vendors compete
towill
form
complex
devices
known generically
as vanmercially
der Waals
hetero-antibodies
6. Srivastava,
A. et al. Nature Nanotechnol.
10, 491496
7. He,on
Y.-M.
al. Nature Nanotechnol.
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protein, which
canweak
be collected
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on catalogue
size,(2015).
so they often buy antibodies
structures,
after the
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layers. But reliability can depend
8. Koperski, M. et al. Nature Nanotechnol. 10, 503506 (2015).
mals
blood.
a more graphene
consistenthas
product,
Our experience
with commercial
antibodies from smaller suppliers, relabel them and offer
Already,
forFor
example,
been the
used alongside
MoS2 and
9. Chakraborty, C., Kinnischtzke, L., Goodfellow, K. M., Beams, R. & Vamivakas, A. N.
Bcellstocan
be retrieved,
fused at
with
immorthat15they
usually okay
in some
applicathem(2015).
for sale. Bernard says that the 2million
WSe2
create
the junctions
theanheart
of solariscells
andare
photoNature
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et others,
al. Phys.Rev.
155501 (2012).
talized cell
and cultured
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might be10.
terrible
saysLett. 108,
antibodies
on the market probably represent
detectors
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the to
semiconductors
abilitiestions,
to absorb
photons
11. Dvila,
M. E., Xian,
L., Cahangirov,
S., Rubio, A. & Leunique
Lay, G. N.
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unlimited
supply.
Mathias
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Institute
of Tech250,000500,000
core
antibodies.
and
graphenes
swift
ability to carry the freed electrons
away.Uhln
In Febru(2014).
Three
decades
ago, and
scientists
who
neededthe solar-cell
nology inconcept
Stockholm,
who
coordinates
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By
necessity,
many
researchers
rely on
ary this
year,
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his team
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to 12.
Li, L. et al. Nature Nanotechnol. 9, 372377 (2014).
word of(2014).
mouth or the published literature for
antibodies
for their experiments
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Human
Protein
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make
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should
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an advice.
graphene
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Byby
selecting
TMDCs,Researchers
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15. Lee, C.-H. et al. Nature Nanotechnol. 9, 676681 (2014).
for
use
in
particular
gent companies
had started
to take over
the antibody has been tested
problem,
in
which
better-performing antibodchoose
the wavelength
of the photons
released.
16. Zhang, W. et al. Sci. Rep. 4, 3826 (2014).
applications
tissue17.
types,
butF. et
the
chore.
become
available later are rarely used,
Better still, sandwiching together different 2D layers
can allowand
physiWithers,
al. quality
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301306
(2015).
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can
vary Mater.
more their
than devices.
300 companies
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over
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Chalcogen
ANTIBODIES
ARE NOT
MAGIC
REAGENTS.
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