So, in this section, what we are going to cover

is an introduction to simulation neuroscience.

First we are going to look at the approaches to study the brain
and then we are going to go through the rationale, the principles,
data strategy, informatics strategies, reconstruction strategies,
and simulation strategies.
So, after this course, this lecture, the first lecture,
you should have an understanding of what simulation neuroscience is,
you should have a general idea
on how we treat data and our approach to informatics,
what we mean by reconstruction
and what kind of strategies we use to do reconstruction,
tissue reconstruction,
and what strategies we use for simulation.
These are very general concepts.
We are going to go in the next lectures much deeper
and you should also have an understanding of what the caveats are
for simulation neuroscience.
So, we are going to look at the approaches to study the brain,
because I think we should take a step back and say:
how do we advance scientific knowledge?
With our three branches of exploratory science if you wish
to discover new knowledge.
One of them is, of course experimental.
That is the ground truth approach,
you observe, you hypothesize, you test,
and you make more measurements.
For the brain of course, we can look at normal brains.
Everything from genes, protein, cell, circuits,
cognition, psychophysics, all the way up to behavior,
and then of course you have nature's experiments which are the disease brain.
You can look at the effect of toxins, effect of drugs,
lesions on the brain,
mutations that are occurring
and degeneration with aging,
and all of these provides you sort of
a repertoire of conditions
where you can actually try to understand
what the brain is doing.
The second is theoretical neuroscience or theory
where you essentially hypothesize
about the data or about the observations
and one can look at them in at least four different categories.
They are sort of informatics
which really tries to look at the trends
or correlations and patterns in the data.
Theoretical neuroscience
is trying to explain the data.
You see the data, you want to predict outcomes of an experiment,
and you have a theory about the data
and your observation.
Computational neuroscience is more about building
a model to replicate the experimental data
and generally, it is to build a minimal model
and the idea is that if you can explain a phenomenon
in the simplest possible way,
then you have the deepest understanding.
It is debatable, but that is the idea of computational neuroscience.
Then you have applied neuroscience,
where basically you can say that if I really do understand
how neurons work, then I can build a device that will listen to them
and I can develop a treatment that will cure them
and that is applied neuroscience.
Then there is simulation neuroscience
and in neuroscience, this is relatively new.
We're sort of driving this
or trying to pioneer this.
And the way to think of simulation neuroscience is that
it unifies both experimental and theoretical approaches.
The difference in simulation neuroscience is that you consider
every detail of the brain.
Nothing is left out.
So for example, if you had a theory of how language works
and you had a couple of equations that could build a machine
that would be able to speak.
That would be wonderful.
It would indicate that you have a deep understanding of language,
but it won't help you understand how a genetic mutation
impacts language
and how that affects the next neuron and the next circuit
and the brain activity and how you should treat it.
So simulation neuroscience is about taking all the data into account.
All the knowledge into account and integrating it.
It is also about filling the gaps of knowledge
with hypotheses, because we may not be able to measure everything.
Okay. So, another way to look at,
to get a perspective on the way we approach the brain
is that there are individual researchers
and in the world there are probably about 200,000 individual neuroscientists
that are exploring the brain.
So they are looking at a genetic level, at the protein level,
at the behavioral level and there is a huge repertoire
of different techniques that can be used
to be able to probe the brain
and to assess what is going on.
And this is producing a massive range of data
and today there are about a 100,000 scientific papers
produced by these individual research from all around the world.
So there is an enormous amount of data being produced
to understand the brain
and we actually do know lots and lots of little pieces.
In individual research, every lab has its own method,
its own conditions, its own instruments, its own biases
and of course, that means that
it is not always easy to compare data
and findings across laboratories.
And it is quite a significant problem that in neuroscience,
a significant amount of the research that has been done in individual
and individual laboratories...
...are difficult to reproduce or impossible to reproduce,
but nevertheless, they provide a massive source
of data and knowledge.
The second approach to the brain is to go large-scale,
to go industrial scale.
For example, the way that the Allen Institute
approaches brain mapping
or the Human Connectome Project
or some parts of the Human Brain Project,
the European Human Brain Project
and the idea there is to standardize.
In the case of the Allen Institute, for example, they would
standardize all the methods
and they will produce 20,000 atlases where each atlas
is telling you where one gene is in the whole brain
and so you have 20,000 genes, 20,000 atlases
and they do that very systematically.
So, you have very solid, large block of data.
So this is large-scale brain mapping
and it is really sort of industrial scale neuroscience.
It is extremely valuable data for simulation neuroscience,
because it is highly standardized
and it is much easier to use.
But the individual research is very valuable
to actually validate the model,
the reconstructed tissues that are built afterwards.
So all data is valuable, all approaches are valuable.
Then of course, you have to database the brain
and this has a very long history. There is a lot of efforts that have gone
into databasing the brain.
It was started in 1990 by Bill Clinton actually.
He started the US Human Brain Project,
which was an effort to database the brain.
It has been a very difficult, very long journey,
because there are so many different types of data
and different conditions and different questions.
It is very difficult to decide how to database the brain,
but there are now international efforts
and it is also an effort in the European Human Brain Project
to database the brain in a systematic way.
It is not a self problem. There are a lot of challenges
and you are going to have a lecture about it in this MOOC series later on.
And how do we approach the data.
And then we have of course:
why do we do all of this?
In the end, we want to put all the pieces together
and that is reconstruction simulation or simulation neuroscience.
Another aspect is, which simulation neuroscience
and large-scale industry mapping of the brain introduce
is really what is called "team science".
It is very different, it is where you have a lot of people with different expertise
sitting around the table and solving one problem.
Very different from the individual...
..that is sitting in the lab and addressing a specific question.
It is not whether one is better or worse than another,
they are all part of the whole approach
that the world today is using to study the brain
and they are all playing a specific role and they have their benefits
in their own particular way.
In many cases team neuroscience is indispensable.
It has to be done that way
and in many cases, you have to have individual research.
Let's look now at the rationale.
Why do we need to do simulation neuroscience?
What is the goal of doing simulation neuroscience?
We have experiments, we have theory.
Many people say you only need theory,
you only need experiments,
you don't need to simulate the brain.
There is a lot of debate and discussions and all kinds of ideas out there
about simulation neuroscience.
Why do you need it?
Well, first of all, what we have to bear in mind
is that actually simulation science
is at the pinnacle of almost all the hard sciences.
So you have got a material science in the beginning,
you were tinkering around with chemistry and materials
and you were building things,
you were experimenting how materials work and how strong they are
and how flexible they are and so on and so forth.
Today, you simulate them.
You simulate materials almost
and you can actually simulate a huge repertoire of materials
before you actually produce them.
In engineering, there is almost nothing that is not simulated today.
Toilet paper.
Do you realize that you cannot actually produce toilet paper without simulation?
These are very fine, very soft tissue that you have to cut
in very specific ways and you have to roll them out
at lightning speed in perfect...
this cannot be done by experimentation.
It cannot even be done by theory.
You actually have to simulate the physics of the tissue
in order to be able to wrap it.
Diapers, the space shuttles.
They have to be simulated in detail, all the electronics.
Aircrafts, they are being built through simulations
and then they are sent out to fly
without even a test run.
They just design them, simulate
and they are ready to go.
So simulation science is the pinnacle of most of the sciences.
It hasn't arrived yet at neuroscience, but...
..well, it has arrived now at neuroscience.
So, I want to give you the rationale, why do we need
simulation neuroscience to understand the brain?
The first and actually, the main reason
is that understanding the brain is a big data problem.
If you look at the numbers, you realize that
there is no way that you are going to be able to understand
all these pieces
and how they interact together.
You have 20,000 genes.
About half of them are expressed in every cell in the brain.
There is about 1,500 that are very sort of over expressed
in the brain, but most cells express about 30% to 50% of their genes.
Then they produce around 200,000 proteins,
different types of proteins, but each protein has a variant.
So you have about a million protein variants per cell.
Then you have, probably, we predict
about a billion molecules in a cell.
There are thousands of molecular pathways.
There are millions of molecular interactions per second in a cell.
There at least 2,000 cell types.
So we have about 900 brain regions.
In each brain region, there can be...
..at a minimum of two types of cells, but in many cases
10, 20, 50 types of cells.
So there is well over 2,000 different cell types.
In the mouse brain, you have about a thousand kilometers of fibers.
In the human brain about a million kilometers of fibers.
In the mouse brain, about a trillion synapses,
in the human brain about a thousand trillion synapses.
Mouse brain about a hundred million neurons,
in the human brain, about a hundred billion neurons.
So just for one instance,
one age, one species, one strain,
individual variations and one disease,
this is everything you have to map
and understand how they all interact together
to give rise to the emergent behavior,
to give rise to psychophysical properties,
to give rise to cognition, to give rise to a behavioral repertoire
and so on and so forth.
Imagine if you have to do it for all the ages,
all the species,
all individual variations,
and for the more or less 600 different brain diseases.
This is not a problem that we can solve only with experimental neuroscience.
Experiments of neuroscience is key to ground truth.
You have to go back and test. Always go back and test and experiment,
but there is no way that you can understand the brain
if you do not have a strategy where you can look at
how all of these elements are interacting with each other.
And be able to predict and look, explore
how they could be changing the interactions
in different states of age species and diseases.
So it is a big data problem
and there is no theory that is going to solve this whole problem for you
in terms of understanding all the details of what is going on in the brain
and there is not one experiment that is going to solve all of this.
So for simulation neuroscience, the claim is:
it is essential for an ultimate understanding
of all the components of the brain
and how they give rise to us,
our personalities and behavior.