Hello, my name is Ravi Iyengar, and

welcome to this course introduction to

systems biology.
In this course, I will describe to you how
a combination of
experimental approaches and competition
can provide us with a deeper
understanding of how components within a
cell come together
to interact and give rise to behaviors at
a cellular level.
This course is, can be a test stand alone
course or be taken as part of a five
course series that can lead to a
certificate in systems biology.
If you take the CDs, this course is
followed by a course that
describes, and provides you with an
overview
of experimental approaches used in systems
biology.
A course on duo organization or
bioinformatics,
net and network analysis and graph theory.
A course on dynamical modeling, and then a
course
on bringing all the experimental and
computational approaches
together by eh, and this will be done
using detailed
analysis of research papers in the field,
followed by a ca, capstone course.
Okay, let us get started.
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So what is systems biology?
Bi, biology itself is a very broad term in
the context in the, of this
course biology is sort of encompasses from
molecular to cellular
to tissue and org, tissue/organ and
physiological functions.
So mainly in this course it will, we will
focus
on mammalian cell biology as the basis for
understanding systems biology.
Systems Biology is the study of how study
of how molecules
interact and come together to give rise to
sub-cellular machines that
form functional units that are capable of
the operations that are needed for
physiological functions at the cell
tissue/organ levels and so on.
So, so the term Systems Biology started to
be widely used in the early 2000s.
Prior to this the field was often called
Complex Systems.
And Complex Systems is an even vaguer
term, and it encompasses studies,
not only in biology, but also in physics,

and chemistry,
and social sciences, like sociology, and
even economics.
And it's really hard to sort of wrap one
around what, what the field of complex
systems really is.
There are some methodologies, especially
network analyses that are common between
all these fields but nevertheless, complex
systems is sort
of being a field that sort of not being
used
or it's too broad a term to be really
meaningful.
One way to think about how systems biology
has come about
is to sort of think of identify a few key
papers.
And I just selected few that are many more
one could sort of use to
use to sort of serve as examples of how
systems biology got started in the past
decade or so.
In terms of experiments, the development
of microarrays to
measure the levels of thousands of mRNAs
simultaneously, allowed
us to see how many components in a cell
change in response to stimulus.
The paper that I have cited was among the
first papers that showed
how the transcriptional program in human
fibroblasts could, would respond to a
stimulus.
So the, this sort of set the stage for
large scale data gathering.
In terms of computation, there were
several key papers also published in 1999.
One paper that Upti Bhalla and I published
showed how properties could emerge from
interaction between
biological signaling pathways and how
these properties such
as switching could ri, give rise to
biological function.
Another important mm, sort of property
that
is, that emerges in systems is robustness.
And a paper by Uri Alon and Naama Barkai
and others
in Stan Leibler's lab studied robustness
in
bacterial chemotaxis and a combination of
experiments and modeling.
They were able to show how the system
exhibit robust behavior inter- in response
to many perturbations.
So one can ask the question and people
often do.
Isn't systems biology, especially in the

context of
mammalian systems, just physiology with a
new name?
And the answer is yes, up to a point.
Physiology has always provided us with
quantitative description of functions
at the tissue and at the tissue and organ
level.
Most often from a phenomenological
perspective.
These descriptions are very precise often,
and very useful and are an
essential starting point actually, for
modern systems biology.
[SOUND] So, take for instance the
filtration of urine
in the kidney or the electromechanical
activities of the heart.
These have been described in pr-, with
great
precision and in detail, but nevertheless,
these descriptions
do not encompass the molecular and the
genomic
details that give rise to these observed
physiological functions.
So in classical physiology, molecular
biology, and biochemistry
were not often fully considered in
physiological descriptions.
Systems biology starts to use, use this
microbiology and biochemistry of cellular
components to understand how physiological
functions
at cell and tissue organ levels arise.
Systems biology, as I told you, is a very
sort of broad area of
inquiry, and there are many branches to
it, and it's worthwhile to sort of
get some of these definitions and branches
identified, so that as we go through the
course, one can put these different areas
of sort of research in perspective.
And one of these most important ones is
genomics.
Genomics the term genome, which was sort
of first utilized, used in the 1920s,
refers
to a set of chromosomes, and genomics
considers genes in the context of whole
genome.
A little different from genetics I guess
where one can say in genetics many
times one can consider a gene by itself,
what the characteristics of
the gene are and how its function is
affected by its intrinsic characteristics
rather than considering it in context of a
chromosome or a whole genome.
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The difference is sort of oh, sort of

overlapping and [UNKNOWN].
So anyway, genomics explores understanding
how genes are
organized within the chromosome and the
whole genome.
and, and characteristics of genes, such as
single nucleotide
polymorphisms, copy number variations,
mutations, etcetera.
There's also the field of epigenomics,
that deals with methlation
of the DNA and how this regulates
expressions of genes.
There is of course, like I said
with [INAUDIBLE] transcriptional
profiling, and since changes in
gene expression is a major way in which
[UNKNOWN] cells would maintain
homeostasis, and change state.
[UNKNOWN] Patterns of MRNA expression is,
is critical for our understanding of
regulation.
So one can consider genomics, as one
bookend of systems biology.
Because, after all, all of the cellular
components, the proteins, the lipids,
everything arrives from the, cha, from the
characteristics specified by the genome.
Lipids and other smaller molecules from
the proteins that
are made from that, in turn, synthesize or
degrade them.
And, and so, genomics is a, one critical
book end of systems biology.
The other end of systems biology would be
the physiological functions.
And one can think of that systems biology
enables us to
understand how the genomic characteristics
when they're expressed in terms of
proteins and how these proteins can then
be further modified by environmental
signals and other perturbations to give
light to dynamic physiological functions.
So this can, physiology and genomics can
be considered two bookends of systems
biology.
Another term that we need to be cognizant
of is the term multiscaled.
.
The context of this course multiscale
refers to the scales of organizations.
Molecular components for instance,
molecular components to sub cellular
machines, transcriptional machinery, cells
motility machinery and so on.
These sub cellular machines in turn go to
form cells.
Cells to tissues and organs, and

were interacting all against the whole

organisms.
So the increasing levels of organization,
give rise
to new, give rise to new properties and
capabilities.
And of course, systems biology involves
the study
of how these new properties and
capabilities arise.
And so, understanding this multi-scale
organization is sort of
an intrinsic part of the study of systems
biology.
Sometimes multi-scale in the context in
which we work of,
also refers to different timescales such
as milliseconds to seconds, to
minutes, to days, and this reflects sort
of, say, the activity
of channels that open and close at the
level of milliseconds.
But the activities of the channels may
give rise to
changes in gene expression, or the
epigenomic status of the
D of the chromosomes give rise to changes
that are
expressed at the level of days or even
weeks and months.
A good way to think on a very broad
classification of how systems biology
approaches can be bend is to think of top
down and bottom up approaches.
Top down approaches start from
descriptions of the
system as a whole, understanding systems
characteristics and capabilities.
Typically, top down models provide a big
and sometimes comprehensive picture of the
system.
However relationships in top down models
often are defined by correlations and
causal
inferences is not possible in the scale at
which these large models are described.
So this is sort of a, a limitation of
these top down models currently.
In contrast, bottom up models start with
cellular components
such as genes, proteins, or protein
products such as lipids
and sugars and develop and understanding
how functional systems
such as sub cellular machines are
assembled, controlled, and operated.
Bottom-up approaches have been what has
been most common in
molecular biology, biochemistry, cell
biology over the last 50 years.

This approach is sometimes called

reductionist, starting reducing the system
to one key component and then starting
from that component of interest and seeing
how the rest of the system develops so the
bottom of approaches
are good in that they provide mechanistic
understanding, tell us how things work.
So this is sort of a very important
aspect.
Positive aspect of bottom-up approaches.
But, as the systems gets larger, one can
often get
lost in the details, and one cannot really
decipher how
a small detail with rela-, in relationship
to one or
a few components relates to systems
behavior as a whole.
It's sort of a case of one can't see the
forest by just looking
at the leaves, and although this sounds
like a cliche, this really is true.
So in reality, one needs a combination of
both bottom up and top down models to give
a useful perspective in systems biology.
And as we do our course, as we go
through the course, you will see how this
becomes apparent.
This is, this sort of concludes this first
half of this course.
In the next part, I will discuss some more
of these terms
and how large data sets are organized and
where we want to go.
Thank you.
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