- [Announcer] This
program is a presentation of UCTV for educational
and noncommercial use only. (electronic synthesizer music) - Well, good afternoon. I'm William Lester, professor of chemistry and chair of the Hitchcock
Professorship Committee. We're pleased along with
the Graduate Council to present Professor Sidney
Altman, this year's speaker at the Charles M. and Martha
Hitchcock Lecture Series. As a condition of this bequest, we're obligated and happy to tell you how the endowment
came to UC Berkeley. It's a story that
exemplifies the many ways this campus is linked to
the history of California and the Bay Area. Dr. Charles Hitchcock, a
physician for the Army, came to San Francisco
during the Gold Rush, where he opened a
thriving private practice. In 1885, Charles
established a professorship here at Berkeley as an expression
of his long-held interest in education. His daughter, Lillie Hitchcock Coit, still treasured in San Francisco. For a colorful personality as
well as her large generosity, greatly expanded her
father's original gift to establish a professorship
at UC Berkeley, making it possible for us to
present a series of lectures. The Hitchcock Fund has become
one of the most cherished endowments at the
University of California, recognizing the highest distinction of scholarly thought and achievement. Thank you Lillie and Charles, and now a few words
about Professor Altman. Sidney Altman is internationally renowned for his important contributions to the fields of biochemistry
and molecular biology. He and Thomas Cech share the
1989 Nobel Prize in chemistry for their independent studies demonstrating the
catalytic ability of RNA. Altman discovered RNase P
and the enzymatic properties of the RNA subunit of that enzyme. He found that RNA, which
was previously believed to be simply a passive
carrier of genetic codes between different parts of the cell, could also initiate
and catalyze reactions. This discovery refuted the
formerly unquestioned principle that molecules could either
carry information like RNA or catalyze chemical
reactions like proteins, but they could not do both. I apologize for the music. Altman's breakthrough opened
up many new fields of research and biotechnology, especially
focused on RNA structure and function. Professor Altman has been a faculty member at Yale University since 1971, teaching both undergraduate
and graduate courses. Also at Yale, he has served as a chair of the department of biology, 1983 to '85, and dean of Yale College, 1985 to '89, and is currently the Sterling Professor of Molecular, Cellular,
and Developmental Biology. Since his Nobel Prize in 1989, he has been awarded honorary degrees from the University of
Montreal, New York University, Connecticut College, McGill University, University of Colorado,
University of British Columbia, Dartmouth College, Lake Forest College, Concordia University, and
the University of Toronto. In recognition of his
illuminating research, Altman has been named a fellow by the University of Colorado, the Damon Runyon Fund,
the Anna Fuller Fund, the California Institute of Technology, and Dartmouth College. Altman currently serves on
the Committee on Human Rights of the National Academy of Sciences. He has been on the board of trustees of the Dime Institute for the History of Science and Technology. He has received a Rosentee Award for basic biomedical research,
and that was in 1989. Innovators of Science Award, 1992, the Novartis Drew Award in
biomedical research in 1999, and is an Einstein professor of the Chinese Academy of Sciences as well as a visiting professor at the University of Glasgow. Please join me in welcoming
Professor Sidney Altman. (applauding) - Thank you, Professor Lester, for that very generous introduction. I'm of course happy to
be here back in Berkeley, especially on such a
beautiful day as this one. I apologize for those of you
that have taken a few days, a few hours out of the brilliant sunshine to come and listen to me
in this dark and gloom. But maybe we can make it
interesting in some way. I'm going to talk today
about entering the RNA world, and before I talk today and tomorrow, I want to start off by doing something that people usually do at
the end of their lectures these days. It's not infrequent these days to see a final slide at somebody's lecture which has six or seven
different awards of money awarded to a different person and 30 or 40 people who participated in the research that's been talked about. I simply want to say that
my work over the years has been supported by your taxes. The money comes from NIH
and at one point from NSF, and it's very easy to
calculate with round numbers, that each of you have
given a few pennies a year in terms of your income
tax to my research, so I thank all of you for
that, and I'm grateful for it, and that's why I mention it now, and I will mention it again tomorrow. Now, really I should start this lecture with some discussion
of the origin of life. And I'm not talking about human life, I'm talking about life, per say. One can ask some questions that may have or you might construe as
being of a philosophical bend and you may ask for philosophical answers, but if I'm asked or pressed
hard in that regard, I will simply answer with a grunt or more articulately with a yes or a no because I'm really not
interested in the philosophy of what I'm going to talk about. So one of the questions we can ask is, why is there life? And after we consider that briefly, we can ask, where, when, and how? And then another question we can ask is, why do we do experiments on something that we can never really
answer in any unique way? We might get a general
answer of what happened four billion years ago, but it's unlikely that we'll get an answer that will exactly
duplicate what did happen. And the question then is,
should we do experiments? And what do we learn
from doing experiments? And my answer to that is, we do experiments in any case
because that is what we do. In our own nature, we are problem solvers. And if there are questions around, no matter what they are
or what field they're in, we'll try and solve that problem. We'll try and answer the questions. Okay, so I don't think I can answer about the question about why there is life. It happened. And my preference is to think it happened as a consequence of
initially inorganic events that took place in our world,
and we went from there. But then the question is, did
it take place in our world? Now there is a theory which
several people have advanced on this question partly
because they were stumped in terms of trying to think
of what happened in our world. That theory, as some
of you might recognize, is called panspermia, and the idea is that life or some very extremely
primitive example of life was brought to Earth by
meteors or meteorites as they fell to Earth that passed through the
atmosphere of another planet on which life already existed, or they resulted from
impacts on another planet where life already existed, and a rock or several rocks
appeared on this planet. There isn't much point in
talking more than that. If it did happen on another planet, whatever did happen perhaps duplicates what we might think about
what happened on our planet. Now, the first slide you see is an illustration taken
from an article from Science about maybe 15 years ago that was discussing the origin of life. And it's really rather straightforward, if you can understand it. Here we have the formation of Earth. It's a red ball, red because supposedly there
was a lot of volcanic activity about four and half billion years ago. And we must remember, that the universe started
about 11 billion years ago. So this a relative newcomer. And then we have a stable hydrosphere, which we'll get to again in a few minutes. That is to say, stable composition, chemical composition of
the sky and the oceans, both of which are extremely important. 4.2 billion years ago. And about that time, we
have prebiotic chemistry. And what does that mean? That simply means from
very basic hydrocarbons, some chemicals were formed
that could participate in the origin of life as we know it today. Let me just define life,
for an instance, as saying that you have to information
stored in some way in a molecule, and it has to be transmitted accurately from that molecule to daughter molecules. The accurate transmission
is what is most important. Now these particular little
molecules indicated there are actually are molecules that are currently important in life, and we don't know whether
they were important say 4 billion years ago, and again, I'll get to that shortly. Then we have the pre-RNA world, and I'm not sure what this represents, but it seems to be a parent molecule giving rise to daughters,
et cetera, et cetera. But I'm not clear exactly
what's going on here. And then we have an RNA world, and we'll talk about the
origin of that particular term, and it's not clear that there was indeed an RNA world initially, but probably at some point,
there was an RNA world. And then we have the
first DNA, protein life, and then diversification of life. And here we have a
diagram which is typical of people dealing with
evolutionary diagrams indicating various branches occurring from a stem organism back here. Okay, so there are some
very simple questions. Extremely simple, you will say, or maybe much too simple from
what I'm going to tell you that one has to ask about
these particular times, let's say 4 billion years ago or so. And they are the nature
of the ocean and water, that is to say what is the
chemical nature of the oceans? How much water was there? The nature of the sky, how much oxygen or methane or
carbon dioxide was in the sky? The temperature of the sky and the oceans. Electrical discharge in the sky. And the time it took for events
we're going to talk about. Now, this is important
because I think in 1951, Miller and Yuri published a
paper in which they put some very simple hydrocarbons-- A hydrocarbon is something made up of carbon, hydrogen,
and oxygen into a flask, and they irradiated that with UV light. UV light being the
equivalent of lightning, and that went on for a few hours, and the experiment was over. They looked at what they saw, and they found a lot of brown gunk in the bottom of the tube. When that was analyzed, they
found many simple amino acids, and amino acids are the
basic elements of proteins. And so that experiment was regarded as a landmark in terms of indicating that that was all you needed to form life, because you could make
essentially amino acids and then proteins from that point. That was at a stage when
it was still thought that proteins were essential
for the evolution of life. We know, I think probably
definitely at this point, that that certainly was not true, that is to say that
proteins were necessary. And of course, initially the
sky was probably much more of a percentage of the
chemicals in the sky, it contained much more
methane and carbon dioxide rather than oxygen as it does now, because you had all the emissions from volcanic eruptions over the years, and the ocean, too, was
let's say contaminated by such chemicals. Now if you read various periodicals as most of us do or most of
us who are scientists do, like Science and Nature, every few weeks or every few months, you will see another paper calculating what the percentage of
oxygen of the oceans were or what percentage of various chemicals that were in the oceans and how much oxygen there was in the sky. Now these are not mindless calculations. They're based on the chemical nature of various rocks on the Earth and reasonable assumptions
about how they formed. So as you watch these
publications from year to year, you will find that these
experiments change somewhat. Perhaps that was one of the reasons why I was never extremely interested let's say in the quote, origin of life, because to me it seemed like something that we could only speculate about, and in fact, it struck
me that this is something that you could fruitfully
think about in the bathtub but perhaps nowhere else. Now this is another graph that illustrates some of the things that
I just talked about. This was taken from a paper
in Nature a few weeks ago from Donahue and Ancliff about the origins of certain fossils. But here on this axis, we have the time, billions of years ago. 4 billions right here, and
we have the oceans here. They're anoxic up to this point, which means very little or no
oxygen at all in the oceans, and then they're sulphidic, which means they have
a lot of sulfate ions and other sulfur compounds in them. And then they're oxic at this point here. Now there seems to be
transition points here and here, but I will indicate
that that's conjecture. If there were changes, and
there probably were changes, they probably occurred over
a few hundred million years. And the same thing is true when we look at the atmosphere per say. There's supposedly a
great oxidation event here at about 2.5 billion years ago, and the percentage of oxygen went up, stayed constant for
awhile, then went up again. Now on top of the graph, there
are various things indicated. Here we have expanse stromatolites. Now these are, we're
talking about fossils here. Stromatolites, if you see a
picture of them in a rock, they look like spaghetti. It's not absolutely clear
that they were fossils, although many people think that they were. And in fact, they seem to
be given the indication that they were the first living
fossils that we could find. So that's about 3 and a
half billion years ago, but they already show
considerably existence of complex life. So life must have started perhaps 500 million years before that. This paper that I used this figure from is about the Gabon fossils, which are supposedly
fossils which indicate the beginning of eukaryotic life, that is organisms with a nucleus. And here we have the oldest
certain bacteria fossils around this so that's about 2
and a half million years ago. And then we go up to
much more recent times. And of course humans or pre-human fossils would be just at the limit down here. Now there is one theory
that clays, mineral clays have something to do
with the origin of life. And the idea is that you can have clays which are of a particular
chemical composition in layers so that for example you
have a particular layer where the clay is laid down and all the direction of the clays are pointed in one particular axis here, and this might be another kind of clay also laid down in this direction, and these are others here. And the idea was that,
this is Graham Cairns-Smith is one of the principal authors here. The idea was near the
surface of these clays, it's quite probable that
the chemical composition of the medium was uniform and distinct from the rest of the surrounding medium, however you want to define that, and in fact, it is
suggested that if there were some molecules that were viable in terms of their utility for life, they could be laid down on these strata in a particular direction, and in fact, for example if you have
the D and L amino acids, for example is one idea,
where you have stereo-isomers of the amino acids, one of these layers you
might only have the L acids, on the other, the D acids. The same thing could be true with sugars. So this is a way of separating essential molecules that
were essential for life. There's no evidence that this is real. Although a lot of people,
especially some geologists, put some weight to this kind of theory. Now, 1967, Crick and Orgel and Woese wrote separate articles. Woese wrote a book, and J.D. Bernal, who was
towards the end of his life, wrote something in England, saying that it seemed possible that RNA could be involved
at the beginning of life, but it was unclear to say that. And Crick, Orgel, and Woese said specifically in their papers that no enzymatic activity or
no any kind of activity could be associated with RNA, other than its informational content. So it's unlikely that
we have to consider RNA for this event at all. There was an idea, and I think Bernal was one of
the people that put it forward that RNA mostly live as a
single-stranded molecule, I'll get to that in a second. That is there's a long
polymer by itself in solution, and it could fold up in
various ways in solution, and in fact, in the cell
what was known at that time, it was relatively easy to find it in various parts of a cell. However, DNA was a
double-stranded molecule which two strands are helically
intertwined about each other and it was fairly inert
in terms of chemistry. It lived only in cell
nuclei, nowhere else. This is in eukaryotes. So DNA was unlikely to be
used if you needed something that could be an interesting molecule. That is, those are weak arguments for RNA possibly being
there at the origin of life, and Crick, Orgel, and Woese said no activity has been shown for RNA so we'll dispose of it for awhile. This is in '67. So let's talk about RNA for a second, and I'm sorry for you
professional molecular biologists in the audience. I'm not sorry for you personally. I feel very proud of you in these days when molecular biology
seems to be faltering along, but because you know all this, let me talk about this anyway. So we have here the
phosphate backbone of RNA. Phosphate connected to a sugar connected to another phosphate sugar. This the backbone of one strand of RNA. And connected to each sugar at this end, there is what is called a base, adenine, cytosine, guanine, and uracil in these particular cases. And the information value of RNA is found in the sequence of the bases because the bases themselves
can form complexes or hydrogen bonds with other bases and transmit information
in that particular way. So this is an important
basic lesson about RNA and what it's nature is at the moment. The next slide simply shows another detailed picture of RNA, of two particular subunits here, phosphate sugar, phosphate sugar and a couple of bases. And here we have various alternatives to the bases that you can make. Diaminopurine, hypoxanthine,
et cetera, et cetera. Various other bases here, which will all have the appropriate hydrogen bonding characteristics. You can have different sugars, different phosphate linkages. In fact, people who do experiments, supposedly on the origin of life, I know have made molecules where hexoses replaced the riboses in
this particular position, and they did perfectly well. They had the bases on the hexose, but in fact, they did not have the right physical/chemical properties
as we understand them today, to be ribonucleic acids. However, we do have to
admit that there could be a series of molecules that
did not have quite the same chemical composition as today's RNA does. So we can admit that, but
we're not going to discuss it any further at the moment. Now, here is the
classical, iconic equation about information transfer today. That is to say we have DNA, can be copied into RNA, which
can be copied back into DNA, and then RNA can go to
what are called ribosomes, and the information RNA
will be made into proteins. And you notice here I
put genetic information. Genetic information because
they all have sequences of bases and here we have structure
and biochemical catalysis. You can designate
certain parts of proteins as having certain kinds of information, but we have no way of
knowing how that information can be replicated and transmitted exactly to another molecule or protein. We just don't know how
it's going to happen, and because we don't know, that effects entirely our
notions about the origin of life. This is another drawing
which is abbreviated from the one I talked about a minute ago. We have the same position here, but in this particular case, we're going to eliminate protein, because in the original central
dogma which I indicated, all those transformations of
DNA making RNA back to DNA, DNA replicating itself,
RNA replicating itself, they're all carried out by
proteins or protein enzymes. And we'll talk about
enzymes in a few minutes. But if we say that proteins didn't exist at the beginning of life because there's no way you could copy the information of proteins
and make more proteins from it, then we're left with this situation here. As it happens, it was then
found that RNA could carry out some very simple biochemical reactions. This was done by Cech, in which he showed that
RNA could cleave itself, under certain conditions, and our lab work where we showed
the RNA associating with a protein subunit could
cleave other pieces of RNA. Now, as scientists always do, and in fact, this is a
classic example of that and the example really
was given by Wally Gilbert in a short paper he wrote. It wasn't a paper, it was a
comment he wrote for Nature, and he was a physicist really, but he became a molecular biologist. You take one or two examples and you generalize that
completely into a new theory encompassing very many problems and events in one particular, smaller,
two or three small sentences. He said, "Now you have information in RNA "with biochemical catalysis." Okay, information RNA. And before Wally got onto the scene, we could say, "This
has a possible future." Then Wally said, with one or two events of the kind we're talking about, that means that RNA could
have any kind of catalysis, and therefore, it could carry
out metabolism inside cells. So life is possible now with only RNA containing the information
and biochemical catalysis. And then he said we don't need DNA at all across the cellular. It's just not necessary. We have RNA, presumably it could make
itself under some conditions, it could carry out metabolic reactions. This is all we know, and
that was the beginning, and he called it the RNA world. So most of the thinking
about these events now are directed to the RNA world, and really that's what
we have to wonder about. Now, this is a very old slide that Hugh Robertson made many years ago, and it just illustrates
what kind of structures RNA can be involved in. First of all, when you have
something that looks like this, which you can call a
double-stranded piece of RNA, there are actually these bases here are joined together by very
weak bonds called hydrogen bonds and the hydrogen bond was
suggested by Linus Pauling back around 1940, and I thought it was much more important than the structure of proteins. So here's another place where
you have another particular double-stranded region held
together by hydrogen bonds. And here are particular bases,
A, U, C, G, U, A, et cetera, where we know where
the hydrogen bonds are. They're stuck together here. Here's another one here. The point is that we have
many sequences in RNA where you have the supposed hairpins here, and in fact, if you look
at any stretch of RNA, you will find hairpins. There's no question about it that the bases occur
of sufficient frequency so that you will find
regions like this in RNA. In fact, this is another diagram taken from something
that was written about 10 years ago or so. If you have a region of RNA
with a number of hairpins in it, and then you have something
like the RNA subunit of RNase P, which could many years ago
be called something else. We call it M1 for various reasons. We know how this cleaves RNA. It actually cuts the region between the beginning of the double
strand here in a single strand. So this is left by itself. Here's another cut here. You're left with this hairpin by itself. Here's another cut here. So you're left with a
bunch of different hairpins with sizes down here of different lengths. And then you could well imagine
that you might, for example, attach a pre-nucleotide
sequence here, C-C-A, and that in fact can happen inorganically, we know that happens. And ultimately from this, you
might wind up with something that looks like a piece of transfer RNA, and transfer RNA is very important today. It's involved in protein synthesis. So this is a speculative by simple idea of how very simple chemical reactions can occur in RNA a very long time ago. Now, there was some notion after Gilbert suggested the RNA world that we really ought to look
for other enzymatic reactions carried out by RNA. We do know of some other
reactions at the moment, but there aren't very many of them. And they fall into a very specific class. They're no more than five or so. Larry Gold, who is at the
University of Colorado, devised a technique, and
it's illustrate here, but I'm not gonna go
through it all in detail. In fact, I would suggest for those of you who don't understand anything
I say, just forget it. Just think about the more important, well what I think are the
more important things. Larry said the following, if you make a randomized piece of RNA-- By randomized, I mean the following. That is to say, you can chemically
make a piece of RNA now, and you can put in a specific
base at every position. But Larry said, we'll
put in all four bases at every position so that
you could make one sequence, you've put in four bases at one position. That means you now have four
different sequences, et cetera. So he made a piece of RNA that had maybe 75 or so random
RNA nucleotides in it and did a reaction to-- Well, he made this, it was in a test tube, he maybe had a mil, one
milliliter of the reaction, which might have had a trillion trillion different sequences in it. He said now, if you have a
very special way of selecting for a particular function
from this series, and I won't go into the details yet. Here's the RNA population. We have a means of selecting
one particular function for it. That means that out of the
trillion trillion pieces of RNA, we have one RNA that has
the function we want. Then using the tricks of
molecular biology at that time, which is cDNA synthesis, which is to make DNA from
this selected piece of RNA and then amplify it with PCR amplification which even high school students know how to do that right now, but I would surmise that they
know nothing about the details then you can in fact amplify
that one piece of RNA into a million and a million pieces of RNA and then you can characterize it. So that was a very clever
and important reaction that Gold hypothesized. And let's just talk
about what an enzyme is. An enzyme is a catalyst. If you put many years ago
lead in your gasoline, it accelerated the combustion of gasoline. So lead was a catalyst. In biochemistry, an enzyme's a catalyst that works in a chemical
sense over and over again on another class
of molecules, substrates, substrates here, and is
unchanged by the reaction. So one of the enzymes we can talk about is Ribonuclease P or its RNA subunit, and it's substrate is other RNA molecules, it just cuts them. So that's an enzyme, that's a substrate. Now, about 10 years ago, I
made this particular list of enzymes using Gold's technique which people had already
isolated and characterized. And you can see many of
the particular enzymes that are involved in effective
replication and metabolism in DNA inside cells today. And if you did this again today, it would have maybe three
times as many enzymes involved. So there doesn't seem to be any inhibition in RNA having any particular
enzyme you could imagine, and the idea is that in
each one of these cases, the RNA that we're talking
about would be folded in a different way to
encompass its substrate and then perform a
chemical reaction with it. And we also have RNA with
small molecules attached. We've recently shown that a
perimeting synthesis can occur. That's one class of bases. This has nothing to do
with Gold's technique, but it's been shown that this can be done. And we have RNA self replication, which I'll talk about briefly. This is another success in terms of RNA and in showing that the RNA
world existed at some level. The question is why doesn't it exist now? We haven't found any of these
reactions in nature today. We can make them in a test tube, but we haven't found them at all. The question is one, were there
random pieces of RNA around so that you had the ability
to choose one specific one from everything you did at one time? And secondly, was there enough time around for you to do everything? It's not clear that that is the case. This is just a diagram of an
RNA self replication scheme that Jerry Joyce at the Salk Institute published about a year or so ago. Let me just say that he
showed it could work. Now with two pieces of RNA in a reaction, he showed that they could
replicate themselves entirely. So there's no protein involved here. It's just the RNA which replicates itself, and I'll just very briefly go over it. Here you have one piece of RNA, and another piece of RNA here. Okay, here they are here and here. Then you have an enzymatic reaction which joins this piece to this piece. Now we know that RNA can do that. Okay? So now we have these two
pieces completely joined. This is the other reaction going on here. And now this is an enzyme
of one kind presumably. Here it is here. Here again is A and B, but
the complexes look different because they're the complements
of the original strand here and we can go on and on
and on in this cycle, and I'm not gonna talk about
that anymore at this point. It's just showing
replication can take place if you're clever enough
in thinking about it. Now let me talk a little bit about what we know about RNA today. This is just a very small
summary of catalytic RNAs today. In fact, the summary if
I drew a complete list would not be very much bigger than this. So this is important because this we think are
reactions of catalysis by RNA which are probably very ancient reactions, and I'm not gonna go into the arguments about why they're very ancient, but they exist in today's world. There's the RNA subunit of RNase P with its cleavage of other RNA. Group I introns, which was
discovered by Tom Cech. He showed that in a piece of RNA, which is let's say this long, there is one piece here that
functioned inside the cell and another piece here that
functioned inside the cell, and in between, there was another region that did not function inside the cell. And he showed that that region
in between could be cut out and the two end regions
could be joined together in what is called a splicing reaction. So that was a very
important reaction to show. Group II introns are similar. They were discovered later. These particular reactions
are very important reactions. Plant viroid RNAs are
about 350 nucleotides long so they're pretty small. They don't code for any proteins at all, and they're circular, and
they're single-stranded. So in fact, you could have
a little bit of plant viroid on your fingertips and rub it into the leaf of the plant that is the host for this viral RNA, and that plant will become
sick entirely and die within 30 days, let's say,
if it's a tomato plant or something like that. So plant viroid RNAs are
very important pathogens for plants. Many of the commercially important plants have plant viroids, and we have to prevent the
viroids from infecting them. Hepatitis delta RNA is a little bit, not much different but
a little bit different. It's 1600 nucleotides long,
it codes for one protein. It's single-stranded. It can be found in the human bloodstream, but if you have hepatitis
B virus in your bloodstream and you also have the hepatitis delta RNA, you're dead within three weeks. So the hepatitis delta
RNA makes hepatitis B a serious and lethal disease. Normally, not normally but yeah normally, you can live for several years
with a hepatitis B infection. You might get sick one way or the other, and in some people, it
develops into a cancer, but it is nothing that will
destroy you in three weeks. And in certain parts of the
world, normally southeast Asia, the blood banks constantly
screen their supplies for hepatitis delta RNA. That's just an aside. There's a fungal virus that
has an RNA that cleaves itself, and recently, we have
evidence that RNA in ribosomes at the peptide elongation
site also is an RNA enzyme. That is to say the RNAs by themselves will join one amino acid to another. Now this is extrapolating a little bit from what we know about
the crystals of ribosomes, which have been just described in the last 7 or 8 years or so. It appears if you draw a
sphere around the point where two amino acids get joined together, there is no protein in
that sphere but simply RNA. And that's the reason for saying that the ribosomal RNA is a RNA enzyme. There are some people, in fact some rather
prominent ribosomologists, who disagree with that
statement, but that's okay. We'll accept that for the moment. And splicing RNAs, there are
various complexes inside cells which aid in splicing pieces of RNA, can perform an artificial
splicing reaction by themselves in vitro,
but it's not important. That one, remember this. One simply has to remember that there are several different reactions where we know this happens. Now, I'm gonna talk very, very briefly about RNase P and a
couple of other reactions. What I've shown here is a tRNA. This structure here in two
dimensions is a transfer RNA. The dots indicate hydrogen bonds joining these pieces together. And this sequence up here
is actually made from DNA. When you're making this piece of RNA, but we don't need it inside the cell. And the enzyme I'm talking
about, the RNA subunit of RNase P cuts it right here, and it cuts all tRNA
precursors in all organisms at this particular point. So that's one thing we know about. This is the Cech reaction
which I discussed. Here are the two pieces
which are important, and this piece and the
intermediate here get spliced out. There are two parts of the reaction. There's a G that's at the prime
site here, one side of it, and that gets cut out. And then there's a hydroxyl group here, and that moves over here,
and then we cut that out, and we're left with this
particular reaction here which are the two pieces joined together. And we're left with this piece here, which is called an intron,
as a separate molecule here. So this is a reaction, and we don't have to worry
about this circle here. Actually, it's just a linear piece here. This reaction is a cell splicing reaction, which from the definition of enzymes means it's not a real enzyme. But this product of the reaction here can with various minor modifications be turned into an enzyme,
but it doesn't work that way normally in nature. This is another view of the central dogma as I drew it before, but
this is today's view. And this appeared in
another paper recently, and it simply indicates
to you that the world is much more complicated
than we had thought. Here's DNA or chromatin
being made into RNA. And we have messenger RNA
here being made into proteins, but there are telomeres involved in making sure the DNA's the
right size and chromosomes. There's primer RNA involved
in replication of DNA. This RNA can be transcribed,
various pieces of RNA can be transcribed into
RNase P, a small nuclear RNA, these here, and oRNAs also. These work on tRNAs,
tmRNAs which we can talk, ribosomal RNA, 7SL RNA. These are all substrates
for these reactions. And these particular reactions here, pieces of RNA, micro RNA, siRNA,
other NC or noncoding RNAs are involved in regulating hundreds of developmental reactions. What I want to show here is
simply that these new RNAs here, which have been discovered
over the last 10 to 15 years, are where the action is
today in molecular biology. You might consider that
statement a bit of propaganda, but in fact, I think it's true. Those RNAs are essential in
controlling developmental events in higher organisms and
in fact lower organisms but not extremely primitive eukaryotes. And the future of biology
for the next 10 years or so depends upon our understanding of those particular reactions. These are just lists
of what we have to do, and I don't think it's
important to talk about those. One of the things that is
the hallmark of evolution as life went on, is that whatever systems
we're talking about became more complex. I'm not talking just about
bacteria becoming man ultimately. That's certainly complexity, but this is complexity
at the molecular level. So we have new genes and new mutations to aid in providing basic information. This is very important in terms of what we have learned
about molecular biology or about genetics in the
last five years or so. At the molecular level, we
utilize everything in the genome. There's no more junk DNA. All parts of DNA are utilized
in one way or another, in terms as we understand it now, to make noncoding RNA or micro RNA that control developmental events. We're just beginning to
understand noncoding RNAs which are RNAs of several
thousand nucleotides long, and we don't really know what they do. We do know what one of
them does certainly. That's the exist RNA, which
is important in inactivating an X chromosome in human females. Human females have two Xs,
and one of them is inactivated in all cells. And the exist RNA which is a
few thousand nucleotides long is critical for that particular function. And I won't talk about that
anymore at that moment. It's getting late, and I
wanted to end this lecture with a statement about
some of the people who have I won't say mentors because
they weren't really mentors. They're people I admired enormously as I was growing up in science, and they had a huge effect
on me of one kind or another. Leonard Vermin and Matt
Messelsen and Sidney Brenner, but there was one people who
I never actually worked for. He was one of the people at the lab where I was for two years in England, and he ultimately went on
to win two Nobel Prizes. His name was Fred Sanger. And I'm going to end this
lecture by reading very briefly something about Fred Sanger
that I wrote a few years ago. I was doing an experiment which
I was using radioactivity, radioactive phosphorous
in much higher quantities than we use them now, and I had spilled something on my desk, and it was a sufficiently large accident that I felt I had to tell
the people responsible. And the person I wound
up with was Fred Sanger from his lab upstairs from mine. And so this is what I'm going to read. Fred listened to me and came
downstairs to the second floor. Without a word, he put on some
rubber dishwashing gloves, grabbed a can of Ajax and some sponges and knelt down to try to
see how much radioactivity he could get off the floor. Not much. I objected to what he was doing, because I thought I
should be doing that job. And quite soon, he said
that I had done enough and decided to clear the area. I stripped my clothing
off, donned a labcoat, and drove home where I left
the clothes in the coal shed to cool off. Hugh Robertson called the
contaminated space Yucka Flats, which I thought was pretty good. Sometime later, that
whole floor and bench area were removed. I cannot imagine a person
of Fred's reputation taking on such a modest and thankless task and refusing any help. The image of him on his knees on the floor trying to wash away the
radioactivity I had spilled is still fresh in mind. There are many ways, I suppose, of exhibiting humility and greatness, and this was one of them. Thank you. (audience applauding) Well the question is could I speculate about the possibility
of an actual organism that had no protein at
all and it was just RNA. I doubt whether that existed
at any particular time but anything I say now can be
used against me in court at any time. One of the kinds of experiments some people are doing at the moment, is to make lipid spheres in which case you then try and have
RNA enclosed by the lipid or you have RNA going
through a hole in the lipid. The idea is that lipids or fatty molecules make up most of our cell
membranes and walls, so that is important. Now, we are learning something
about making the lipids, but it strikes me as being
very remotely possible that there might be RNA with
a metabolism at the moment. You have to have all those
RNAs I mentioned before carry out catabolic reactions. I doubt that that's possible. We might be able to talk
about very small lipid spheres with one or two things going on it that ultimately evolved to something else, but that's about all I'll say to that. - [Audience Member] So
considering our estimates of the age and size of the universe and considering your own personal guess at the unlikelihood of
unique origins of life, would you say that our universe
is old enough and big enough to allow for two unique origins of life? And although I'll accept a grunt, I would prefer something more concrete. - You're saying that there
could be two different origins? Yeah, sure, no problem. There are reasonable
estimates now that there are possibly hundreds of
Earth-like planets in the universe which we're just waiting to discover. And the idea that one of them might have conditions like those on
Earth, it's quite possible. So without any hesitation, I'll
say that it's quite possible there's another source of life
somewhere in the universe. It may not be life as we recognize it, but that's okay. - [Audience Member] So I'm
one of those geochemists that actually tries to disentangle what the early Earth was like, and a lot of my friends are geobiologists who study things like
hopanoids and other molecules that may be biomarkers of early,
I'd say, unicellular life. But we don't talk to you guys that often, and so I want to know from a molecular biologist's perspective, what sort of signatures
could we be looking for? Again, I work on the inorganic stuff, but I'm curious because it
felt a little disparaging. - [Altman] Signatures of
the existence of life? - Sure. Or you know the-- Once you go back far
enough in the rock record, things are very much degraded. There's not much that we
actually have from early when things may have started. - Well, if we're looking
for life as we know it, then one has to look for
the existence of a polymer that has information, okay? That could be something like RNA or DNA. But what people have looked
for in the past for example on the probes of Mars is metabolism and the production of
certain kinds of gasses. So what else can I say? That's what people do. I mean it's simple to look for metabolites of one kind or another
that we know do not exist in the inorganic world. - [Audience Member] Okay, just curious. - [Male Audience Member]
Why do you think the bases are restricted to the
five bases in DNA and RNA when I understand that
there are many other bases that could possibly fit in? - Yeah, well people actually
have synthesized other bases which have the ability to hydrogen bond, and they can use these other bases, which are not like the ones,
the five that we talked about or four that I talked about, and they work in terms of
reactions in test tube. So that's why I say with
some degree of certainty that it's likely that we
might have had something else other than recognizable RNA at one time. - [Lester] And again, let
us think Professor Altman for a very splendid,
interesting presentation. (audience applauding) (electronic synthesizer music)
