Hello, today's lecture is going to

be about Biological Model Systems. So, what types of systems can

you choose to do experiments in? And if you remember from last lecture. There were
three key questions
that we needed to answer before we could define our experiment fully and,
and perform it. And the first, which we will be talking
about today is what biological system? so, what are the types
of biological systems? First, we need to understand a little bit,
about the fact, that we're actually using a model usually,
for what we actually want to study. A lot of the times we're interested
in human health and disease and it's very difficult to study that in,
in people for a variety of reasons, so we tried to study it in
things that are more simple. A model system, which captures
most of the properties that, that we hope to elucidate
by doing these experiments. and, and I've classified them into
a couple different categories. And just like with experimental
techniques there are lots of different model systems that we
can use to perform experiments in. I don't have time to go over all of them.
So,I've picked a couple of widely used
ones to just mention a little bit, about what they are. And what are the key
properties of,
of why people like to use them. So there's Single-cell organisms,
there's Multi-cellular organisms, there's Mammalian systems and of course,
one of the things that's starting to become more of a, a feasibility as
a model system are computational models. That's one of the primary goals of, or
maybe a promise of systems biology is to be able to use a computational model
as a models system with which you can, ask questions of it and
perform computational experiments. So first though, what is a model, exactly? So,
if you ask a biologist or a biochemist
this question, they might say, well, a Mouse is a model for
a particular disease state. You can have mice that
are particular genetic stains, which then capitulate a phenotype. Which is
consistent with human disease. A Cell line model, for example, if you're
studying a particular type of cancer, you might have a cell line model,
which was derived from a tumor, of that particular cancer
type you're interested in. You can grow these cells in culture and
do all sorts of experiments with them. but, obviously a cell line is, a bit far
removed from the tumor
that you actually want to study. and, so, you know,
you can kind of come to this idea or maybe as a simple definition that. A model is
just a to simplified or
convenient version of a complex or inconvenient entity. So, if we want to study a
human disease,
we can't do that very easily. So, let's study this in a mouse and
try to learn some things about it. And then, we can see if that
applies in the real situation. So, of course, the key characteristic for
that, is that the model has to capture the essence of the problem,
which you're interested in. so, why we use models? Of course,
we can't study what we want directly? And as I mention in the previous slide
one thing that's starting to be perhaps, feasible is instead of
using a Mouse model or a Cell line model, we might be able to
use a Computational model of a cell. Recently published effort by Jonathan Carr
in from the Covert Lab at, at Stanford. It was the first model of an entire
cell a microplasma probably, the simplest cell they could have modeled
but still, the complexity that's in this cell is, is quite remarkable even
though it's a simple unicellular organism. They were able to model all the basic
biochemical processes that occur in one of these cells over a cell cycle. So, with
that kind of a model,
then you can start to ask questions about. For example,
what happens if you knock out a gene? What's going to happen
globally in the cell? Okay, and so there, there's always
a bit of, of debate or, maybe, a bit of caution, when people say
they're going to study a disease but then not study it in humans or
in human tissue, or even in human cells. And there's, there's a nice commentary
on the topic that was published in Science a few years ago that I found,
that. Kind of sums up, some really good reasons,
why we want to use model organisms to learn things about things that might
be relevent for human disease. So first, just to quote from this paper,
model organisms will continue to provide insights into
replication, transcription, et cetera. And many other aspects of cell biology,
biochemistry, and physiology, because they offer
the keenest methods of analysis. And by that, they mean that, it's much
easier to look at things in model systems, than it is in the disease system. 2,
Model organisms will increasingly
be used for the direct investigation of medical problems that seemingly
have little to do with them. For example,
a lot of people are interested, interested in Alzheimer's Disease. It's a horrible
disease, and
it's increasing in prevalence. But it involves a basic
process of protein folding and aggregation, which can be studied. And a lot of much
more
simple model organisms. 3, Model organisms will
remain at the forefront for the forseeable future in efforts to
sort out biological complexity and achieve a more quantitative
understanding of life processes. So, this one is particularly relevant for
systems biology where, at its essence, we want to achieve a more
quantitative understanding of biology. And.
4, Model organisms offer the best hope for coming to grips with the breadth
of genetic diversity and the depth of its consequences. So, if we want to
understand, how
particular, polymorphisms that occur in a population, how does, how does that
effect the, the biochemical function of those proteins or the physiological
function of, of the tissue? It can't really be done
in human populations, so we need to study that in model organisms
where those things are modifiable. And then we can observe
the results in a finite time. And then, see if those results apply in,
in human trials. [COUGH] And, lastly, model organisms
will remain the proving ground for developing new technologies,
which typically spread quickly. So, if you want to figure out, how to
measure more things in a cheaper way. with, with more time points. We really need
to fine tune those
techniques with model organisms. And then scale them up. So, the first group of
model organisms that I'd like to
go over are Single-cell Organisms. And probably, one of the most widely
used ones is a bacteria called E.coli. So there's lots of information
about E.coli out there on the web. I've just listed a few good sources. Here on the
left,
which you can look up on your own time. Just a, a couple of key
characteristics about E.coli. So, there's lots and
lots of different strains of E.coli. So, when you're doing
experiments with them, you need to be very specific about
which strain that you're using. A common one is called K12,
and it's not pathogenic. And none of this lab strains of E.coli
that are commonly used are pathogenic, unlike the kind that you might,
hear about getting into the food supply. Those are the, the pathogenic, ones. Why
are they used? Well, they have a very fast doubling time,
so you can do experiments on them rapidly. They're simple to grow, and
they only have about 4,000 genes. And all of these genes can be
manipulated with relative ease. So it, it this system is very
amenable to rapid genetic studies, and very clean genetic studies. I, I've read in
many places that the, the E.coli is arguably the best
understood species on earth, because so many experiments have already been
done on it as a model organism. So, in addition to asking very specific
questions about your particular disease or research system. You can also use it to
ask very deep
questions about life in general and then stand on this prior mountain
of research, which has been done. So, know understanding very basic things
about, how molecular networks and circuits give rise to biological function. You
can ask those sort of questions. Understanding evolution. Understanding molecular
machines and
motors. Such as, flagellum or, or
ATPS protein pumps, for example. And it's also used as a,
as a biotechnology tool. It's used in most labs, nowadays,
just to produce DNA plasmids for use in other types of research or to produce
proteins of interest,
when you want to study that protein. And it's also used in
industrial applications so but there are some disadvantages. As with any model
system,
there are disadvantages, so you have to make sure that whatever
question you're trying to address aren't affected by these disadvantages. For
E.coli because it's a bacterium. You can't really ask a lot of questions,
about mammalian transcription or, translation because it doesn't
have a nucleus or chromatin. And it doesn't have all of
the protein production mechanisms, that are present in eukaryote
such as glycosylation, et cetera. So, you know, you have to think about
whether your model system will match the particular properties that you're
trying to capture in your experiments. Another commonly used, Single-cell
Organism is baker's yeast, S.cerevisiae. This is the yeast that is actually,
used to bake bread and make beer. But it is also used a lot in
biological research as a model system. I've listed a couple of
pictures of what Baker's yeast, may look like over here on the left. And a couple
of websites, which you
can go to, to learn more about them. A just that couple of key
characteristics as I mentioned. It's, it's very commonly used,
not only in research, but in, in almost all aspects of life. But as opposed to
E.coli,
these are eukaryotes. So, they have a nucleus, and you can study
many more basic cellular processes that are relevant to mammalian cells and
S.cerevisiae. For example, they have mitochondria,
they have cell cycle, which is remarkably similar
to the mammalian cells cycle. They have pretty conserved
trafficking processes, through golgi apparatus and
endoplasmic reticulum. They undergo meiosis,
which can be started in, in yeast. In fact, much of our understanding of
the cell cycle, comes from studies on, on yeast, which has been done to remarkably
applied very very well,
to mammalian systems. The Nobel prize in 2001
would which was shared by Hartwell is based on all this work. And it's also easy to
genetically manipulate. The you can use homologous
recombination to really do very targeted
genetic manipulations in and study the effect of genes on, on a variety
of things, which presently [NOISE] used. And just like [NOISE] any model
system they grow quickly and easily, which makes them amenable to
all sort of types of experiments. Okay. So, moving on to Multi-cellular Organisms,
the first one which I've chosen to highlight is
the nematode worm called C.elegans. And this is a very simple
Multi-cellular Organism. It's about a millimeter long, but
it really has, has many, physiological features, which can be studied, but,
you know, in a very simple way. so, for example, it's one of the simplest
organisms with a nervous system, so, and this nervous system is completely
mapped on the cellular level. So, it's, you know, a, a very convenient
way to study, neuronal signaling. eh, some very basic mechanisms
of neuronal signaling. It's also used to study,
reproduction and development. The developmental fate of every
single cell there's 1,031 cells in an adult male it's known. So, you know, you can
really start to
ask deep questions about, cell fate, and how that, you know,
a single cell differentiates into all of these different types of cells,
which make the adult organism. The 2002 Nobel Prize was
based on work in C.elegans. On organ development and apoptosis. And the 2006 Nobel
Prize was also
based on work in C.elegance with RNA interference a technique that we're
going to study more in the next lecture. So the next, Multi-cellular Organism
that we're going to go over is [INAUDIBLE] melanogaster
that's just the common fruit fly, slightly larger than the C.elegans
about 2.5 millimeters long. And this organism is used very
often to do genetic studies. It's very easy to do genetic manipulations
with this, with the fruit fly and they have very rapid generation times,
so it really, and sexual reproduction. So, it really facilitates genetic studies.
With regard to sexual reproduction so
and many human jidi, disease genes have homologues
in drosophila so, you know, that's a really convenient thing and why
it's studied very often in this context. Some things that it also has vision
can be studied to some extents. It also has some more complex
physiological and morphological features. And organs than C.elegans, so it can be
used to study,
some more complex physiology and, and tissue [INAUDIBLE] phenomena that can't
be studied in the, in the nematode worm. The next, Multi cellular Organism that,
that people commonly use is the Zebrafish Danio rerio and one of the
main reasons why people use the Zebrafish. In addition to the reasons
that seem to apply to all mo, model organisms is that they're easy
to grow, they, they grow rapidly, and they're amenable to genetic manipulation,
but these are also transparent. So during development they can be studied
by light in fluorescence microscopy. Which, enabled many, many,
questions to be addressed in this system. They're also commonly used as a model for
developmental toxicity. So, if you're interested in what's going
to, what effect a potential compound will have on development,
you can do screening with, with Zebrafish. And the results there
correlate quite well, with my, with what might happen
in higher organisms. [COUGH] okay,the last Multi-cellular
Organism that I'll go over is Arabidopsis thaliana which is a quickly growing
plant. That is robust and has a short life cycle. So, it's easy to grow,
quick to grow, and it's, it's, it's really suitable as a model system. It's used
for plant genetics. And it has a very small genome for
plants so that makes it somewhat suitable. It's used to study light sensing. Also,
it has a circadian clock, which is
remarkably similar to circadian clock, clocks found in many aspects of Biology. So
it's convenient to study for,
for those purposes, also for flowering, to understand that, better. So, now moving
on to Mammalian Systems and
one of the most widely used, systems to study,
mammalian cells is Cell Culture. Where you've isolated some cells from
a mammal, whether it Be mouse or rat or pig or dog or humans, many of these cells,
can be grown in a culture flask, or culture disk, dish,
with some appropriate modifications. So it's just a picture of
some cells in culture. Over there in a typical culture flask. so, one place you can
really look at
all the different cell lines that are available are, is a company called
ATCC, they have thousands of human cell lines, which you can buy, and then start
culturing in your own lab and grow them. That have information about where these
cells came from, how you grow them, et cetera. [NOISE] And of course, it's much
easier to study
cells in culture than whole organisms. So that, it's amenable to a lot more and
different types of perturbations and different measurements that you,
that you can make on these cells. It's obviously quicker, you can grow cells in
culture much quicker
than you can grow mice for example. And for those reasons,
it's also much cheaper, so you can do a lot more experiments for
the same amount of money. But, many cell lines are so
called transformed to meaning that they'll grow on top of each other and
grow indefinitely in culture and they've lost a lot of the properties which, which
they would have in an intact organism. So, obviously, there's, there's some
potential artifacts due to that. So you know, for example, a large majority
of human cell lines are derived from tumors, so they, they clearly already
have some, some major problems. With, with their genetics or, or other things,
which have caused
them to to be transformed. So, there's some caveats
to using cell lines. So, you have to understand, you know,
when they might be appropriate for answering your question, or,
or when they might not be. So, the next, Mammalian System, which I'll talk about
is the laboratory mouse, M.musculus. And one of the main advantages
of using a mouse is that now, you're in an intact memo, which is of
course much preferred to a cell line for a variety of reasons but
it's still not a human. So, even though many things
are considered between mouse and human there's of course this caveat. So, one has
to be careful in the,
in a interpreting results, of course. One of the main advantages of mice is
that, they're quickly reproducing. And they're amenable to genetic megi,
manipulation. You can knock out genes. You can knock-in genes. You can really have
some fun
control over their genome, which really makes them a preferred
genetic model for a Mammalian Systems. And to study the effect of
[NOISE] diseased genes in a physiological context and
that there's already a variety of mouse strains with the gene knock outs and
knock-ins. And also conditional expression,
meaning that, you know, a certain gene is only expressed in,
in a tissue of interest. For example, only expressed in the liver
or in a certain type of neuron in the brain, so you can really study
things in context like that. Strains also exist without
an immune system and this really facilitates studies in,
in cancer. So, if you have a human cancer cell line,
if you were to put that into a mouse, a normal mouse would just kill the, those
human cells because they're foreign that they'd be treated as, as,
as an invader and just destroy it. But these so-called nude mice without an immune
system will
tolerate the human cell line. And therefore, you can study cancer and
tumor growth and drug response in the context of a more physiological system
as opposed to in a tissue culture system. Another Mammalian System that's
commonly used is, the lab rat so, these aren't as genetically
manipulatable as mice. But they are re, they are very fast
reproducing, like most rodents, and most model systems. And they're also regarded
as
more intelligent than mice. So you'll, you'll see them being used
in a lot more behavioral experiments or in neuroscience, when people
are asking questions about you know, addiction or, or other sorts of
more neurological behaviors. they're, they're an excellent
model system for that. And lastly, I'd just like to talk about Computational
Models as a potential Model System. so, you know, one of the main reasons, why
we're doing system biology is to
build computational models that can be considered good enough
models of an entire system. You know, so that instead of studying
things in experiments, we can actually, study things within the context
of a computational model. We are a long way off from that
in my opinion, but there's been a very relevant effort recently, that I
mentioned at the beginning of the slide. That where a model has been built
that takes into account nearly, every bio-chemical process that
occurs in a single microplasma cell. So, you can then, use this model to
try to prevent what happens when you knock out a gene, or what happens when you
apply a certain compound to this cell. what, what's going to happen
to the cell cycle and all the other types of bio-chemical
processes that are going on. And this really provides a,
a hypothesis generator, and a ways of really increasing our knowledge,
about how things are regulated in a cell. And really, starting from a mountain of
prior knowledge that's represented in the form of this computational model. So, you
know, this is really the first
effort in this front but it will only, these models will only get better and
better as, as time goes on. So, what could one do with such a, Computational Model
besides,
answer experimental questions? Well I, I, I see many Potential
applications for such models. We can think of many on
the level of microorganisms that they're used very often
in waste water treatment. So, maybe you, we could use computational
models of the microorganisms to design better ones that, that do a better
job of remediation of waste water. that, that do it quicker and
more efficiently. And do it better. We could engineer microorganisms
that convert feedstock. So, for instance biomass feedstocks trying
to get everything towards more sustainable development that, that take biomass and
then convert it into precursors that we need to make various products like
plastics or, or pharmaceutical products. Instead, of taking that from petrochemical
feedstocks, use microbes to, to do that conversion for us. Better design based on
a computational model of them. One could use computational models of
cells and tissues to predict efficacy and toxicity of potential drugs. Prior to a
clinical trial. So, let's say we have a, a drug,
which has made it through a series of, of steps in the drug development
pipeline and now, you know, we want to have an idea of whether we should
go forward with a clinical trial or not. Well, we can run simulations if we have
a good enough computational model of the system that would predict maybe, you know,
this drug won't be effective
in a large percentage of the population. Or maybe this drug would be toxic in
a large percentage of the population. These are things, which could potentially
save a lot of
money in the drug development pipeline. We could identify patient
populations that are more or less likely to respond to a drug. So, if we have
models, which have,
single nucleotide polymorphisms or different, types of, genetic backgrounds
that are adjustable parameters. We can understand then,
what is the relationship between, those different genetic backgrounds and
the response of that patient to a drug. And this is really, I think, the goal of
what people are calling
personalized medicine for example in cancer every patient comes in
with a different panel of mutations if we can take this knowledge and
input it to such a computational model. We can really start to understand
the drug specificity of, of different patient population. And lastly, we can
predict new uses for already approved drugs
so-called repurposing. We can use computational models to very
rapidly look at drug combinations, something which quickly becomes infeasible
in the experimental realm due to a combinatorial explosion of possibility. But you
can do simulations to see,
what types of drug combinations might improve efficacy and find things you,
you might never have imagined. Or also to reduce toxic, toxicity. Maybe a drug is
really effective but
it also has high toxicity and you can apply a second drug,
which doesn't do anything to efficacy but would reduce toxicity, for example. So,
that's it for this lecture and next time, we're going to be talking
about Experimental perturbations.