As I'm going to argue repeatedly today, biology has become a science
over the last 50 years. And, as a consequence, we can talk
about some basic principles. We can talk about some laws and
then begin to apply them to very interesting biological problems.
And so our general strategy this semester, as it has been in the past,
is to spend roughly the first half of the semester talking about the
basic laws and rules that govern all forms of biological life
on this planet. And you can see some of the specific
kinds of problems, including the problem of cancer,
how cancer cells begin to grow abnormally, how viruses proliferate,
how the immune system functions, how the nervous system functions,
stem cells and how they work and their impact on modern biology,
molecular medicine, and finally perhaps the future of biology and
even certain aspects of evolution. The fact of the matter is that we
now understand lots of these things in ways that were inconceivable 50
years ago. And now we could begin to talk about things that 50 years
ago people could not have dreamt of. When I took this course, and I did
take it in 1961, we didn't know about 80% of what we
now know. You cannot say that about mechanics
in physics, you cannot say that about circuit theory in electronics,
and you cannot say that, obviously, about chemistry.
And I'm mentioning that to you simply because this field has
changed enormously over the ensuing four decades. I won't tell you what
grade I got in 7. 1 because if I would,
and you might pry it out of me later in the semester,
you probably would never show up again in lecture.
But in any case, please know that this has been an
area of enormous ferment. And the reason it's been in such
enormous ferment is of the discovery in 1953 by Watson and Crick of the
structure of the DNA double helix. Last year I said that we were so
close to this discovery that both Watson and Crick are alive and with
us and metabolically active, and more than 50 years, well,
exactly 50 years after the discovery. Sadly, several months ago one of the
two characters, Francis Crick died well into his
eighties, and so he is no longer with us. But I want to impress on
you the notion that 200 years from now, we will talk about Watson and
Crick the same way that people talk about Isaac Newton in terms of
physics. And that will be so because we are only beginning to
perceive the ramifications of this enormous revolution that was
triggered by their discovery. That is the field of molecular
biology and genetics and biochemistry which has totally
changed our perceptions of how life on Earth is actually organized.
Much of the biology to which you may have been exposed until now has
been a highly descriptive science. That is you may have had courses in
high school where you had to memorize the names of different
organisms, where you had to understand how evolutionary
phylogenies were organized, where you had to learn the names of
different organelles, and that biology was, for you,
a field of memorization. And one point we would like,
hopefully successfully, to drive home this semester is the notion
that biology has now achieved a logical and rational coherence that
allows us to articulate a whole set of rules that explain how all life
forms on this planet are organized. It's no longer just a collection of
jumbled facts. Indeed, if one masters these
molecular and genetic principles, one can understand in principle a
large number of processes that exist in the biosphere and begin to apply
one's molecular biology to solving new problems in this arena.
One of the important ideas that we'll refer to repeatedly this
semester is the fact that many of the biological attributes that we
posses now were already developed a very long time ago early in the
inception of life on this planet. So if we look at the history of
Earth, here the history of Earth is given as 5 billion years,
this is in thousands obviously. The Earth is probably not that old.
It's probably 4.5 or 4 or 3 billion years but, anyhow,
that's when the planet first aggregated, as far as we know.
One believes that no life existed for perhaps the first half billion
years, but after half a billion years, which is a lot of time to be
sure, there already begins to be traces of life forms on the surface
of this planet. And that, itself,
is an extraordinary testimonial, a testimonial to how evolutionary
processes occur. We don't know how many planets
there are in the universe where similar things happened.
And we don't know whether the solution that were arrived at by
other life systems in other places in the universe,
which we may or may not ever discover, were the similar solutions
to the ones that have been arrived at here.
It's clear, for example, that to the extent that Darwinian
Evolution governs the development of life forms on this planet that is
not an artifact of the Earth. Darwinian Evolution is a logic
which is applicable to all life forms and all biosystems that may
exist in the universe, even the ones we have not discovered.
However, there are specific solutions that were arrived at
during the development of life on Earth which may be peculiar to Earth.
The structure of the DNA double helix.
The use of ribose in deoxyribose. The choice of amino acids to make
proteins. And those specific solutions may not be universal.
Whether they're universal in the sense of existing in all life forms
across the planet, the fact is that many of the
biochemical and molecular solutions that are represented in our own
cells today, these solutions, these problems were solved already 2
and 3 billion years ago. And once they were solved they were
kept and conserved almost unchanged for the intervening 2 or 3 billion
years. And that strong degree of conservation means that we can begin
to figure out what these principles were early on in evolution of life
on this planet and begin to apply them to all modern life forms.
From the point of view of evolution, almost all animals are identical in
terms of their biochemistry and in terms of their physiology.
The molecular biology of all eukaryotic cells,
that is all cells that have nuclei in them, is almost the same.
And, therefore, we're not going to focus much in this course this
semester on specific species but rather focus on general principles
that would allow us to understand the cells and the tissues and the
physiological processes that are applicable to all species on the
surface of the planet. Let's just look here and get us
some perspective on this because, the fact of the matter is, is that
multicellular life forms, like ourselves, we have, the average
human being has roughly three or four or five times ten to the
thirteenth cells in the body. That's an interesting figure.
The average human being goes through roughly ten to the sixteenth
cell divisions in a lifetime, i.e. ten to the sixteenth times in
your body there will be cells that divide, grow and divide.
Every day in your body there are roughly ten to the eleventh cells
that grow and divide. Think of that, ten to the eleventh.
And you can divide that by the number of minutes in a day and come
up with an astounding degree of cellular replication going on.
All of these processes can be traceable back to solutions that
were arrived at very early in the evolution of life on this planet,
perhaps 550, 600 million years ago when the first multicellular life
forms began to evolve. Before that time, that is to say
before 500 to 600 million years ago, there were single-cell organisms.
For example, many of them survive to this day. There were yeast-like
organisms. And there were bacteria. And we make one large and major
distinction between the two major life forms on the planet in terms of
cells. One are the prokaryotic cells. And these are the cells of
bacteria, I'll show you an image of them shortly, which lack nuclei.
And the eukaryotic cells which poses nuclei and indeed have a highly
complex cytoplasm and overall cellular architecture.
We think that the prokaryotic life forms on this planet evolved first
probably on the order of 3 billion years ago, maybe 3.
billion years ago, and that about 1. billion years ago cells evolved
that contained nuclei. Again, I'll show them to you
shortly. And these nucleated cells,
the eukaryotes then existed in single-cell form for perhaps the
next 700 or 800 million years until multi-cellular aggregates of
eukaryotic cells first assembled to become the ancestors of the
multi-cellular plants and the multi-cellular animals that exist on
the surface of the Earth today. To put that in perspective, our
species has only been on the planet for about 150,
00 years. So we've all been here for that period of time.
And a 150,000 sounds like a long time, in one sense,
but it's just a blink in the eye of the Lord as one says in terms of
the history of life on this planet, and obviously the history of the
universe which is somewhere between 13 and 15 billion years old.
You can begin to see that the appearance of humans represents a
very small segment of the entire history of life on this planet.
And here you can roughly see the way that life has developed during this
period of time from the fossil record. You see that many plants
actually go back a reasonable length of time, but not more than maybe 300
or 400 million years. Here are the Metazoa.
And this represents --
Well, can you hear me? Wow, 614 came in handy.
OK. So if we talk about another major division,
we talk about protozoa and metazoa. The suffix zoa refers to animals,
as in a zoo. And the protozoa represents single-cell organisms.
The metazoa represent multi-cellular organisms. And we're going to be
focusing largely on the biology of metazoan cells this semester,
and we're going to be spending almost no time on plants.
It's not that plants aren't important. It's just that we don't
have time to cover everything. And, indeed, the molecular biology
that you learn this semester will ultimately enable you to understand
much about the physiology of multi-cellular plants which happen
to be called metaphyta, a term you may never hear again in
your entire life after today. That reminds me,
by the way, that both Dr. Lander and I sometimes use big words.
And people come up to me afterwards each semester each year and say
Professor Weinberg, why don't you talk simple,
why don't you talk the way we heard things in high school?
And please understand that if I use big words sometimes it's to broaden
your vocabulary so you can learn big words.
One of the things you should be able, one of the big take-home lessons of
this course should be that your vocabulary is expanded.
Not just your scientific vocabulary but your general working English
vocabulary. Perhaps the biggest goal of this course,
by the way, is not that you learn the names of all the organelles and
cells but that you learn how to think in a scientific and rational
way. Not just because of this course but that this course
helps you to do so. And as such, we don't place that
much emphasis on memorization but to be able to think logically about
scientific problems. Here we can begin to see the
different kinds of metazoa, the animals. Here are the metaphyta
and here are the protozoa, different words for all of these.
And here we see our own phylum, the chordates. And,
again, keep in mind that this line right down here is about 550 to 600
million years ago, just to give you a time scale for
what's been going on, on this planet.
One point we'll return to repeatedly throughout the semester is that all
life forms on this planet are related to one another.
It's not as if life was invented multiple times on this planet and
that there are multiple independent inventions to the extent that life
arose more than once on this planet, and it may have. The other
alternative or competing life forms were soon wiped out by our ancestors,
our single-cellular ancestors 3 billion years ago.
And, therefore, everything that exists today on this
planet represents the descendents of that successful group of cells that
existed a very long time ago. Here we have all this family tree
of the different metazoan forms that have been created by the florid hand
of evolution. And we're not going to study those phylogenies simply
because we want to understand principles that explain all of them.
Not just how this or that particular organism is able to digest its food
or is able to reproduce. Here's another thing we're not
going to talk about. We're not going to talk about
complicated life forms. We're not going to talk very much,
in fact hardly at all, about ecology. This is just one such thing,
the way that a parasite is able to, a tapeworm is able to infect people.
This is, again, I'm showing you this not to say this is what we're
going to talk about, we're not going to talk about that.
We're not going to talk about that. There's a wealth of detail that's
known about the way life exists in the biosphere that we're simply
going to turn our backs on by focusing on some basic principles.
We're also not going to talk about anatomy. Here in quick order are
some of the anatomies you may have learned about in high school,
and I'm giving them to you each with a three-second minute,
a three-second showing to say we're not going to do all this.
And rather just to reinforce our focus, we're going to limit
ourselves to a very finite part of the biosphere.
And here is one way of depicting the biosphere. It's obviously an
arbitrary way of doing so but it's quite illustrative.
Here we start from molecules. And, in fact, we will occasionally
go down to submolecular atoms. And here's the next dimension of
complexity, organelles. That is these specialized little
organs within cells. We're going to focus on them as
well. We're going to focus on cells. And when we start getting to
tissues, we're going to start not talking so much about them.
And we're not going to talk about organisms and organs or entire
organisms or higher complex ecological communities.
And the reason we're doing that is that for 40 years in this department,
and increasingly in the rest of the world there is the acceptance of the
notion that if we understand what goes on down here in these first
three steps, we can understand almost everything else in principle.
Of course, in practice we may not be able to apply those principles to
how an organism works or to how the human brain works yet.
Maybe we never will. But, in general, if one begins to
understand these principles down here, one can understand much about
how organismic embryologic develop occurs, one can understand a lot
about a whole variety of disease processes, one can understand how
one inherits disease susceptibilities,
and one can understand why many organisms look the way they do,
i.e. the process of developmental biology.
And so, keep in mind that if you came to hear about all of these
things, we're going to let you down. That's not what this is going to be
about. This also dictates the dimensions of the universe that
we're going to talk about because we're going to limit ourselves to
the very, very small and not to the microscopic. On some occasions
we'll limit ourselves to items that are so small you cannot see them in
the light microscope. On other occasions we may widen our
gaze to look at things that are as large as a millimeter,
but basically we're staying very, very small. Again, because we view,
correctly or not, the fact that the big processes can be understood by
delving into the molecular details of what happens invisibly and cannot
be seen by most ways of visualizing things, including the light and
often even the electron microscope. Keep in mind that 50 years ago we
didn't know any of this, for all practical purposes,
or very little of this. And keep in mind that we're so close to this
revolution that we don't really understand its ramifications.
I imagine it will be another 50 years before we really begin to
appreciate the fallout, the long-term consequences of this
revolution in biology which began 51 years ago. And so you're part of
that and you're going to experience it much more than my generation did.
And indeed one of the reasons why MIT decided about 10 or 12 years ago
that every MIT undergraduate needed to have at least one semester of
biology is that biology, in the same way as physics and
chemistry and math, has become an integral part of every
educated person's knowledge-base in terms of their ability to deal with
the world in a rational way. In terms of public policy,
in terms of all kinds of ethical issues, they need to understand
what's really going on. Many of the issues that one talks
about today about bioethics are articulated by people who haven't
the vaguest idea about what we're talking about this semester.
You will know much more than they will, and hopefully some time down
the road, when you become more and more influential voices in society,
you'll be able to contribute what you understood here,
what you learned here to that discussion.
Right now much of bioethical discussion is fueled by people who
haven't the vaguest idea what a ribosome or mitochondrion or even a
gene is, and therefore is often a discussion of mutually shared
ignorance which you can diffuse by learning some basics,
by learning some of the essentials. Here is the complexity of the cell
we're going to focus on largely this semester, which is to say the
eukaryotic rather than the prokaryotic cell.
And this is just to give you a feeling for the overall dimensions
of the cell and refer to many of the landmarks that will repeatedly be
brought up during the course of this semester.
Here is the nucleus. The term karion comes from the
Greek meaning a seed or a kernel. And the nucleus is what gives the
eukaryotic cell its name. Within the nucleus, although not
shown here, are the chromosomes which carry DNA.
You may have learned that a long time ago. Outside of the nucleus is
this entire vast array of organelles that goes from the nuclear membrane,
and I'm point to it right here, all the way out to the outside
of the cell. The outside limiting membrane,
the outer membrane of the cell is called the plasma membrane.
And between the nucleus and the plasma membrane there is an enormous
amount of biological and biochemical activity taking place.
Here are, for example, the mitochondria. And the
mitochondria, as one has learned, are the sources of energy production
in the cell. And, therefore, we'll touch on them very
briefly. This is an artist's conception of
what a mitochondrion looks like. Almost always artists' conceptions
of these things have only vague resemblance to the reality.
But, in any case, you can begin to get a feeling for what one thinks
about their appearance. Here are mitochondria sliced open
by the hand of the artist. And, interestingly, mitochondria
have their own DNA in them. One now accepts the fact that
mitochondria are the descendents of bacteria which insinuated themselves
into the cytoplasms of larger cells, roughly 1.5 billion years ago, and
began to do a specialized job which increasingly became the job of
energy production within cells. To this day, mitochondria retain
some vestigial attributes of the bacterial ancestors which initially
colonized or parasitized the cytoplasm of the cell.
When I say parasitized, you might imagine that the
mitochondria are taking advantage of the cell.
But, in fact, the mitochondria represent the essential sources of
energy production in the cell. Without our mitochondria, as you
might learn by taking cyanide, for example, you don't live for very
many minutes. And the vestiges of bacterial origins of mitochondria
are still apparent in the fact that mitochondria still have their own
DNA molecule, their own chromosome. They still have their own ribosomes
and protein synthetic apparatus, even though the vast majority of the
proteins inside mitochondria are imported from the cytoplasm,
i.e., these vestigial bacteria now rely on proteins made by the cell at
large that are imported into the mitochondrion to supplement the
small number of vestigial bacterial proteins which are still made here
inside the mitochondrion and used for essential function
in energy production. Here is the Golgi apparatus.
And the Golgi apparatus up here is used for the production of membranes.
As one will learn throughout the semester, the membranes of a cell
are in constant flux and are being pulled in and remodeled and
regenerated. The Golgi apparatus is very important for that.
Here's the rough endoplasmic reticulum. That's important for the
synthesis of proteins which are going to be displayed on the surface
of cells, you don't see them depicted here,
or are going to be secreted into the extracellular space.
Here are the ribosomes, which I might have mentioned briefly
before. And these ribosomes are the factories where proteins are made.
Again, we're going to talk a lot about them. And,
finally, several other aspects, the cytoskeleton. The physical
integrity, the architecture of the cell is maintained by a complex
network of proteins which together are considered to be the
cytoskeleton. And they enable the cell to have some rigidity,
to resist tensile forces, and actually to move.
Cells can actually move from one place to the other.
They have motile properties. They're able to move from one
location to another. The process of cell motility,
if that's a word you'd like to learn.
Here is what a prokaryotic cell looks like by contrast.
And I just want to give you a feeling. First of all,
it looks roughly like a mitochondrion that I
discussed before. But you see that there is the
absence of a nuclear membrane. There's the absence of the highly
complex cytoarchitecture. Cyto always refers to cells.
There's the absence of the complex cytoarchitecture that one associates
with eukaryotic cells. In fact, all that a bacterium has
is this area in the middle. It's called the nucleoid, a term
which you also will probably never hear in your lifetime.
And it represents simply an aggregate of the DNA of the
chromosomes of the bacterium. And, in most bacteria, the DNA
consists of only a single molecule of DNA which is responsible for
carrying the genetic information of the bacteria. There's no membrane
around this nucleoid. And outside of this area where the
DNA is kept are largely ribosomes which are important for protein
synthesis. There's a membrane on the outside of this called the
plasma membrane, very similar to the plasma membrane
of eukaryotic cells. And outside of that is a meshwork
that's called the outer membrane, it's sometimes called the cell wall
of the bacterium, which is simply there to impart
structural rigidity to the bacterium making sure that it doesn't explode
and holding it together. And then there are other versions
of eukaryotic cells. Here's what a plant cell looks like.
And it's almost identical to the cells in our body, except
for two major features. For one thing,
it has chloroplasts in it which are also, one believes now,
the vestiges of parasitic bacteria that invade into the cytoplasm of
eukaryotic cells. So, in addition to mitochondria
which are responsible for energy production in all eukaryotic cells,
we have here the chloroplasts which are responsible for harvesting light
and converting it into energy in plant cells. The rest of the
cytoplasm of a plant cell looks pretty much the same.
One feature that I didn't really mention when I talked about an
animal cell is in the middle of the nucleus, here you can see,
is a structure called a nucleolus. And a nucleolus, or the nucleolus
in the eukaryotic cell is responsible for making the large
number of ribosomes which are exported from the nucleus into the
cytoplasm. And, as I mentioned just before,
the ribosomes are responsible for protein synthesis.
It turns out this is a major synthetic effort on the part of most
cells. Cells, like our own, have between 5 and 10
million ribosomes in the cytoplasm. So it's an enormous amount of
biomass in the cytoplasm whose sole function is to synthesize proteins.
As we will learn also, proteins that are synthesized by the
ribosomes don't sit around forever. Some proteins have long lives.
Some proteins have lifetimes of 15 minutes before they're degraded,
before they're turned over. One other distinction between our
cells, that is the cells of metazoa and metaphyta,
are the cell walls, analogous to the cell walls of
bacteria, this green thing on the outside. As I said before,
we do not have cell walls around our cells. And we will,
as the semester goes on, go into more and more details about
different aspects of this cytoarchitecture during the first
half of the semester. Here, for example,
is an artist's depiction of the endoplasmic reticulum.
Why it has such a complex name, I cannot tell you, but it does.
It's called the ER in the patois of the street. The ER.
And the endoplasmic reticulum is a series of membranes.
Keep in mind, not the only membrane in the cell is the plasma membrane.
Within the cytoplasm there are literally hundreds of membranes
which are folded up in different ways.
Here you see them depicted. And one set of these membranes,
often they're organized much like tubes, represents the membranes of
the endoplasmic reticulum which either lacks ribosomes attached to
it or has these ribosomes attached to it which cause this to be called
the rough endoplasmic reticulum to refer to its rough structure which
is created by the studding of ribosomes on the surface.
As we will learn, just trying to give you a feeling
for the geography of what we're going to talk about this semester,
these ribosomes on the surface of the endoplasmic reticulum are
dedicated to the task of making highly specialized proteins which
are either going to be dispatched to the surface of the cell where they
will be displayed on the cell's surface or actually secreted into
the extracellular space. Many of the proteins that are
destined for our body are not kept within cells but are released into
the extracellular space where they serve important functions,
and so we're going to focus very much on them.
Here's actually what some of these things look like in the electron
microscope to see whether we can either believe or fully discredit
the imaginations of the artists. Here's the rough endoplasmic
reticulum I showed you in schematic form before. And you can see why
it's called rough. All these black dots are ribosomes
attached on the outside. Here's the Golgi apparatus.
You see these vesicles indicated here. And a vesicle,
just to use a new word, is simply a membranous bag.
And keep in mind, by the way, that we're not going to
spend the semester with these highly descriptive discussions.
Our intent today is to get a lot of these descriptive discussions out of
the way so that we can begin to talk in a common parlance about many of
the parts, the molecular parts of cells and organisms.
Here is the mitochondrion which we saw depicted before.
It looks similar to, but not identical to the artist's
description of that. And keep in mind that the
mitochondrion in our cells, as I said before, are the
descendents of parasitic bacteria. Here's the endoplasmic reticulum,
and the way it would look, as it does in certain parts of the
cell when it doesn't have all of these ribosomes studded on the
surface. The endoplasmic reticulum here is involved in making membranes.
The endoplasmic reticulum here is involved in the synthesis and export
of proteins to the cell's surface and for secretion, as
I mentioned before. Much of what we're going to talk
about over the next days is going to be focused on the nucleus of the
cell, that is on the chromosomes on the cell and on the material which
is called chromatin which carries the genetic material.
So the term chromatin is used in biology to refer simply to the
mixture of DNA and proteins, which together constitutes the
chromosomes. So chromatin has within it DNA,
it has protein, and it has a little bit of RNA in it.
And we're going to focus mostly on the DNA in the chromatin,
because if we can begin to understand the way the DNA works and
functions many other aspects will flow from that.
I mentioned the cell's surface, and I just want to impress on you
the fact that the plasma membrane of a cell is much more complicated than
was depicted in these drawings that I showed you just before.
If we had a way of visualizing the plasma membrane of a cell,
we would discover that it's formed from lipids. We see such lipids
there, phospholipids, many of them. We'll talk about them
shortly. That the outside of the cell, there are many proteins,
you see them here, which thread their way through the plasma
membrane, have an extracellular and intracellular part.
And these transmembrane proteins, which reach from outside to inside,
represent a very important way by which the cell senses
its environment. This plasma membrane,
as we'll return to, represents a very effective barrier to segregate
what's inside the cell from what's outside of the cell to increase
concentrations of certain biochemical entities.
But at the same time it creates a barrier to communication.
And one of the things that cells have had to solve over the last 700
to 800 million years is ways by which the exterior of the cell is
able to send certain signals and transmit that information to the
interior of the cell. At the same time,
cells have had to use a number of different, invent a number of
different proteins, some of them indicated here,
which are able to transport materials from the outside of the
cell into the cell, or visa versa. So the existence of
the plasma membrane represents a boon to the cell in the sense that
it's able to segregate what's on the inside from what's on the outside.
But it represents an impediment to communication which had to be solved,
as well as an impediment to transport. And many of these
transmembrane proteins are dedicated to solving those particular problems.
Here you see, once again an artist's depiction
form, aspects of the cytoskeleton of the cell. And when we talk about
the cytoskeleton we talk about this network of proteins which,
as I said before, gives the cell rigidity.
Keep in mind that the prefix cyto or the suffix cyt refers always to
cells. Allows the cell to have shape. And here you can see this
network as depicted in one way, but here it's depicted actually much
more dramatically. And here you begin to see the
complexity of what exists inside the cell. Here are these proteins.
These are polymers of proteins called vimentin which are present in
very many mesenchymal cells. Here are microtubules made from
another kind of protein. Here are microfilaments,
in this case made of the molecule actin. And if we looked at
individual molecules of actin they would be invisible.
This is end-to-end polymerization of many actin molecules.
And we're looking here under the microscope from one end of the cell
to the other end of the cell. And you can see how these molecules,
they create stiffness, and they also enable the cell to
contract and to move. Some people might think that the
interior of the cell is just water with some molecules floating around
them. But if you actually look at what's present in the cell,
more than 50% of the volume is taken up by proteins.
It's not simply an aqueous solvent where everything moves around freely.
It's a very viscous slush, a mush. And it's quite difficult
there for many cells to move around from one part of the
cell to the other. Here you begin to get a feeling now
for how the connection, which we'll reinforce shortly in
great detail, between individual molecules and the cytoskeleton.
And here you see these actin fibers. I showed them to you just moments
ago stretching from one end of the cell to the other.
And each of these little globules is a single actin monomer which
polymerize end-to-end and then form multi-strand aggregates to create
the actin cytoskeleton. Here's an intermediate filament and
here's the microtubules that are formed, once again giving us this
impression that the cell is actually highly organized and that that high
degree of organization is able to give it some physical structure and
shape and form. I think we're going to end today
two minutes early. You probably won't object.