The Story of Deciphering the Ribosome – with Venki Ramakrishnan

[MUSIC PLAYING] [APPLAUSE] Well, hello. What a top crowd. How nice to see you all. My name is Vivian Perry and
you’ll know who this is. Thank you, Ramakrishnan. And tonight we’re going to be
talking about the Gene Machine, Venki’s wonderful book. And if you haven’t read it
yet, I urge you to read it. It’s a great read. And this is going to be a
story of a career in science that could, at any moment,
have not ended as it has done. It’s a story I think
that illustrates the march of science perfectly. It’s the way that
intractable problems suddenly become solvable because
of advances in technology. It’s a story of intense
competition and prizes. And finally, it’s a story
about science and how it works, and this man,
Venki Ramakrishnan. And what I wanted to start with,
Venki, was a bit about you. Before we get to the
star of the show, which is of course the ribosome,
I wanted to take us back to where you started. So you were born
in Northwest India, your parents were scientists– In South India. South India, sorry. Your parents were scientists,
but you didn’t get into any top science schools. So if somebody had
come and seen you then, you would not be somebody
that they would have said, this is somebody who
is going to go far. Yeah, it’s hard to say because
most bright students in India wanted to do
engineering or medicine. And they would go take
this big national exam. And there were all
these coaching classes that they would have to go to in
order to prepare for the exam. And my parents were
quite intellectual. They thought this
was all nonsense and, you know, they weren’t
going to pay for any of that. And so I didn’t do very
well on any of these exams and I didn’t get into any
of these Indian institutes of technology, the IITs or one
of the top medical schools. But my mother wanted me to take
this other sort of exam, which was designed to identify
students who were good in science, basic science. And it was modelled after the
Science Talent Scholarship in the US, which for a long
time was called Westinghouse and then became Intel, and
now it’s something else. I forget who’s sponsoring it. But I took that, and I
got that scholarship. And one of the
conditions was that you had to do basic
science you couldn’t do engineering or medicine. And so that’s– Which must of have been a bit
of a disappointment to your dad, because he– Yes, he wanted me
to be a doctor. But I made a deal with him
that if I got the scholarship, I would do an undergraduate
degree in physics. And if I didn’t get it, I
would go into medical school, our local medical school. And he said, fine. And somewhat to
his mixed feelings, I got the scholarship. So there you are, age 19. You disappear off to the US. But again, it’s
not a great school. It’s not a top school– No. –that you go to. Yeah. So that was also a
weird thing, which was, you know, first of all,
I graduated from university when I was 19. And I wanted to go off to the
US because my parents were spending a summer there
on a short sabbatical. My dad was on a
short sabbatical. And I hadn’t taken the GRE. So most of the top schools
wouldn’t accept me. But this one place,
Ohio University said, you know, sure, we’ll
give you a fellowship. And of course I
hadn’t heard of it. And my father said, you know– I think quite erroneously,
he said, well, you know, you can go anywhere. And if you work
hard, you’ll be fine. You. Know and that was his attitude. And he still thinks– you
know, he’s 92-years-old and he thinks he was a prophet. [LAUGHING] But actually I THINK it’s
completely the wrong thing. Because when you
go to the school– a graduate school at any place,
it’s all in your peer group that sort of drive you on
and motivate you and so on. So it’s very important
to go to the best place you can get into. And it has to be said
that you didn’t probably work quite as hard as you
could have done at that stage. NO. I think part of the
problem is the first two years in physics graduate
school are coursework and then you take these exams. And I took these exams and
that’s when I realised I wasn’t really cut out to be
a physicist, because they, as you know, they asked me,
so what are you interested in? And I could really tell them. And then they said,
well, have you read anything interesting
at all, you know, in the last few months? And I just sort of really
think hard and then come up with this lame
topic that I’d seen on the cover of a magazine. And so I realised, you know,
I realised actually maybe I wasn’t so interested in physics. And I often say– so I have all these
other interests. I became a chess player and
hopped freight trains, which is illegal, but there you are. See, all these things
you’re learning about this splendid gentlemen
who hopped freight trains. Just remember that. [LAUGHING] Anyway. Essential prerequisite
to the Nobel Prize is hop a freight train. So I often say, you know, if I
had graduate students like me, I would just fire them. [LAUGHING] And you also got married. I mean– Yes. –you were a very young man. And you married and you and
Vera had a child already then. So there you were– 23-years-old, I was married
with a six-year-old stepdaughter and, you know, a baby. It was about six weeks old. And I was off to start
my second career. And why did you choose biology? So when I was in physics
and I was disillusioned with a mixture of my
problem and possibly my own aptitude for it, I used
to read Scientific American. And I would see all these
fascinating articles on biology. And it seemed as though
biology was at the stage that physics had been in the
early 20th century with quantum mechanics and relativity and
atomic structure and so on. So I thought, you know, this
would be really fascinating. And then I also knew
that lots of physicists like Francis Crick
or Max Delbruck or Max Perutz, who founded
the LMB where I work. All of these people had made
that sort of transition. And so I decided maybe
this would be worth doing. And luckily Vera, you know,
was game to sort of humour me in going back to graduate school
and living on a very modest graduate student stipend
with two children in Southern California without a car. So I think having a
supportive spouse was really quite important for it. And we’re going to
hear quite a lot more about various support for you
over the years and how crucial that was. So there you were. You’d come out of physics. You’d only done two
years in biology, and you decide that you’re
going to work on ribosomes. And tell us then what was
known about the ribosome at that particular time. Yeah. So when I went to graduate
school in biology again– first of all, most
places wouldn’t accept me because I already had a PhD. But a few places did. And the University of California
at San Diego I thought had the best
combination of quality and a place where I could
have two young children. And so I went there and I
started learning about DNA and genes and realised
that actually DNA coded for proteins. All of these things
that we call genes are actually bits
of information that allow you to make proteins. But the way that it’s
made is that if you think of DNA as this
archive of our genes, just as if you go to
the British Library, they’re not going to take
out their valuable books. They’re going to make you make a
photocopy or a microfilm of it, and then you work with the copy. And so the cell
does the same thing. It has this archive tucked
away in the nucleus, which contains all its genes. And then as it needs particular
genes, it makes a copy of it called messenger RNA. And that’s exported
from the nucleus out into the cytoplasm,
the rest of the cell, and then this very
large molecule. And large and
small are relative, so it’s tiny by human standards. You know, if you take the
width of a human hair, you could line up 20,000
of these molecules along the width of a human hair. So it’s very small
by our standards. But by molecular
standards it’s enormous. It has a million atoms. And so, you know, it’s
called a ribosome. And it’s this very
ancient machine. And what it does is it reads
the messenger RNA, which is essentially like a sentence
in a four-letter alphabet, which is the four types of
bases that DNA and RNA have. And using that,
reading that sentence and reading three
letters at a time, it stitches together
a different kind of chain, which is
the protein chain. So the protein chain is this
long chain of amino acids, and there are 20 types of them. And each gene has a different
order of these 20 amino acids. So you can think of hundreds
and hundreds, thousand of individual beads
with different beads in different orders. And the miracle is– you take this long chain– and
in this very theatre in 1968, David Phillips showed the
structure of a lysozyme, which was the third protein to
be solved, which is right here. Now– We just happened to have
one we made earlier. –when he showed what this
chain would look like, if it was extended, it came down
from the ceiling to the floor. OK. And how does it know how
to fold up into this shape? Well, it’s the order of the
amino acids in the chain that miraculously contains the
information to allow the chain to fold up into its shape. And it’s that folded shape
that gives each protein its special function. Because it’s the
shape of the protein, the structure of it
that allows it to work. And so we have all
sorts of proteins. You have a protein in your
eye that allows you to see, called rhodopsin. You have another protein
called haemoglobin, which allows you to carry
oxygen from your lungs in through your blood. You have a long
filamentous protein called collagen, which makes
up your skin and connective tissues. Greg Winter got the Nobel
Prize this year for work on antibodies. Well antibodies
are also proteins, and they help fight
off infections. So we can hear because
of proteins in our ears. We can sense touch because
of proteins in our nerves and so on. So proteins carry out
thousands of functions. Every one of them is made by the
ribosome reading instructions in the gene for that protein. So you’ve got this factory, the
ribosome, and information comes in, and product goes out. Exactly. And something goes on in it. And in the 1970s that
was pretty much it. That was what you
knew at the time. Yes. I would say a bit was known
in the sense, the players that came into the ribosome and
brought in the amino acids were these small adaptor molecules. That was known. It was known that it read them
in blocks of three at a time, and it was known that
other proteins would have to come into the
ribosome at different points and help it do something
and go on to the next step. But the problem was, they
couldn’t see any of this. They didn’t know
anything about what these molecules looked like. And so it was a
bit of a black box. And I say in the book, you know,
imagine if you’re a Martian and you hovered over
the Earth and you saw these little objects move
around in straight lines. And then if you
look closely you’d see there were even
smaller objects that would enter these objects. And the object
would only move when there are these small objects
inside the bigger object. And when the little objects
got out, the object would stop. And you wouldn’t know
anything about it. And then you’d get
closer and you’d say, oh, it emits carbon dioxide and
water, and it uses up gasoline. So you’d get a little bit
of an idea of this thing. But unless you actually
looked at the thing and saw it had an engine and a
steering wheel and, you know, crankshaft and so on, you would
have no idea how it worked. And it was the same
with the ribosome. It was just this
sort of black box that seemed to
miraculously do this thing. And you knew that structure
was essential to function. Yeah. So it’s, unless you
knew its structure, you wouldn’t be able to
work out its function. Yeah. And that’s been a
theme– you know, the idea that you have to see
something to understand it, that’s been a theme
for hundreds of years. So, you know, when Galileo
could see moons of Jupiter and so on and planets,
that gave a huge impetus to understanding
the solar system, the Heliocentric theory. And later on when Robert
Hooke was able to see– or van Leeuwenhoek were
able to actually see microbes and cells,
we got the idea that all life consists of
units formed from cells. So in every case, seeing
the next level of detail has transformed the field. And in a classic example
of molecular structures, the double-helix of DNA,
before that we had no idea how heredity could be transmitted
and how information could– molecules could even
carry information. So when you saw the double-helix
structure, suddenly you had, for the first time
in centuries– I mean, people have been
wondering for centuries, how come your children
are like their parents and how come we don’t give birth
to sheep or things like that? And so, you know, I
think for the first time those sorts of
things became clear. And it was the same
with other molecules. So let’s park the
ribosome for a moment. It’s this black box,
and go back to Venki. And the thing that
really changed your life was reading an article in
the Scientific American about neutron scattering. Yeah. I’m afraid not at all
a useful technique in biology, although
some people who use it and do it for a living
will probably be outraged. But anyway. But it was on the ribosome. And there were two things
that drew me to the article. One was, one of the
authors was Don Engelman. He was one of two
people at Yale who had offered me a post-doctoral
fellowship straight out of my PhD in physics. And I turned him down saying,
I don’t know any biology, and I need to learn
some biology before I could do that sort of thing. And the other was, I knew
the ribosome was important. And then the third thing
was that I thought, well, neutron scattering– I have a background in physics,
so I can probably pick that up. And so maybe I’ll
be useful to them. And so I wrote to Don
and I said, you know, you offered me a
job two years ago when I didn’t know anything. And now I actually
know some biology. So maybe you’ll
want me even more. So he put me in touch with his
collaborator, Peter Moore, who was really the ribosome expert. And that’s how I
ended up going to Yale to work on the ribosome. So at this time, really
nobody was interested much in ribosomes. It was a kind of niche interest. And let’s be fair, that
technique didn’t really work. Yeah. And it was suggested, in
the nicest possible way, that it was time to move on. Yes. And so I must just quote
this from your book, because I just think
it’s a wonderful phrase. So, “The universities
looked at my career– a bachelor’s and doctorate
in physics, neither of which were from a prestigious
university, two years studying biology without a
degree, followed by research using a technique
no one had heard of, to work on an old problem that
was already unfashionable.” It wasn’t looking
good, Venki, was it? No. So when I applied– so until then, it was a
sort of natural progression, except for this little
deviation into biology. You do a PhD, you do a postdoc. That’s all pretty natural,
except that I’d done a detour and switched
fields, by switching from physics to biology. But anyway, after
a postdoc is when scientists face the big crunch. It’s at that point
that they either have to get a
faculty job or they have to get a
different type of job or they have to
do something else. And I applied for 50 positions. And I applied to everything
from four-year colleges. So America has very good
four-year colleges– these are undergraduate
teaching institutions, which don’t do a
lot of research– as well as, sort of
mediocre universities and a few top universities. And out of those
50 applications I got exactly zero
interviews because of this. I bet it’d be like the man
who turned down the Beatles, isn’t it? Anyway. But I say in the book that
the four-year colleges were interested mostly in teaching. They probably looked at
my long Indian name and– they knew I had grown up in
India– they probably thought, we don’t even know
if this guy can speak English, let alone teach. So they didn’t want me. And then the top
research universities probably– you know, they
looked at my rather chequered CV and they said,
well, you know, this is some outlier and
not worth considering. I don’t blame them actually. I mean, probably if I’d had
been on the selection committee, I’d of done the same thing. And then you went to Oak Ridge,
which was a bit disastrous, wasn’t it? I did. There was 15 months. I went there– my
advisor, Don Engelman had called up this
fellow who was a physicist, who was
running a neutron scattering facility in Oak Ridge. And they wanted a biologist to
sort of help attract people. So in effect I was a neutron
salesman, if you like. You know, attract biologists to
come and use this instrument. So I said, I’m
happy to do that as long as I can do my own work. And they said, yes. We’ll set you all up with a lab. And then the lab
never materialised. So out of 15 months– well, three months after I got
there, I was looking for a job again. So the first decade of
your career as a scientist was not looking promising. No. It was terrible, because I
had started off in physics and then I’d sort of, you know– there’s an American
term called, “punting,” which is different from the
Oxford and Cambridge punting. I means, you know,
when you know you can’t score with your football,
you use your free kick and give up the ball
to the other team. But it means sort of
starting over, basically. So I had to start
over in biology. So it was effectively
my second career. Now I found my second career
wasn’t working out either, you know. So it was, you know,
how many lives did I have was the question. So let’s, again, park that. So Venki at this point is,
it’s not looking good, ladies and gentlemen. It really isn’t. Circling the plug
hole, is, I think what the Americans call it. So let’s turn to crystals and
the basic techniques which were around at the time for
looking at both– well, DNA people are very familiar with
the story of Rosalind Franklin and the crystallography. Just tell us why you
needed to have crystals in order to work out the
structure of a molecule. So normally, you
know, if you want to look at something
very small you would look at it with
a magnifying glass. Or if you wanted to look
at it in even more detail, you would use a
microscope, which is really a series of
magnifying glass lenses. And the way that
works is that light scattered from the object. And what the lens
does is it collects the rays that are scattered and
combines them into an image. And in fact all of you
are doing this right now while you’re looking at
us, because there are lenses in your eyes which are taking
the scattered rays from me and then recombining them
to an image in your eye. And that’s how you see. And with a lens you can
make the image much bigger than the object itself. So then you can look
at the magnified image and see details. But the problem is that if
you want to look at molecules, the distance between
atoms in a molecule is far too small to use light. Because there’s an
old theorem in physics that you can’t
distinguish objects that are further apart than
half the wavelength of the light you’re using. And light has many
thousands of times longer wavelength than the
distance between atoms. So you would need a much
shorter wavelength radiation. So if you take light and you use
light of the kind of wavelength that corresponds to the
distance between atoms, well that is what
we call x-rays. So x-rays and ordinary light
are both the same thing. They’re just different
energy and wavelength. But the trouble is,
there’s no lens for x-rays. And even if there were, x-rays
are unlike ordinary light. It’s actually damaging. So by the time you
were able to use x-rays to magnify
one single molecule, you would fry the molecule. You would destroy it before
you could even see it. So the way around that was
invented by Lawrence Bragg while he was a PhD student. And he was–
actually I believe he was the director of the Royal
Institution in the ’60s. Anyway, he figured out that
if you hit a beam of x-rays to a crystal, which
is essentially a three-dimensional
stack of molecules, then you could take
the scattered rays and you could computationally
do what a lens does. So if in effect you
do calculations, you’d measure the intensities
of the scattered rays and do what a lens does, but
you would do it in a computer instead. And you could then,
in a computer, calculate a
three-dimensional image. And that’s how
crystallography began. And it started off with
a very small molecule, sodium chloride– common salt,
which has only two atoms. That’s what Lawrence
Bragg started with. And then it went
to bigger molecules and Dorothy Hodgkin was
a big exponent of it. And she worked on molecules
which had a few hundred atoms, like vitamin B12. At the time it was
a tour de force and got her a Nobel Prize. And also a headline
in the Daily Mail which said, “Oxford
Housewife Wins Nobel.” [LAUGHING] An Oxford housewife
and mother of three. Mother of three. Yes. [LAUGHING] Yeah. I quote that in the book. But then if you get
to proteins, proteins have a few thousand atoms
instead of a few hundred atoms. The techniques of Dorothy
Hodgkin wouldn’t be useful. And Max Perutz was in Cambridge
was working on this problem. he worked on it for
23 years before he made his breakthrough. And he and his former
student, John Kendrew, but then his collaborator,
worked on the first two protein structures, which were
haemoglobin and myoglobin. And they won the
Nobel Prize in 1962. And they’d figured
out techniques to solve these much
larger molecules. And the third protein
structure was done here at the Royal Institution
by David Phillips, and that’s lysozyme. That was about six years
after Kendrew and Perutz won the Nobel Prize
for the first two. But you’re making
it sound a bit easy. And it’s– It wasn’t easy,
because, you know– Because the first– Yeah. So the first protein structures
took about 23 years, you know, because you had to figure
out all the methods, and even how to collect data. And there were also a bit
lucky in that digital computers were invented right around
the time when they needed it. And Kendrew, who doesn’t
get a lot of credit– I mean, he’s one of the more
under-recognised people. He also started
EMBL, by the way, which is one of the
big European labs. Anyway, he realised that
you needed to use digital computers. And in Cambridge there
was this huge computer called EDSAC, you know, which
would take up almost as much as this room, practically. And they would have to go there
to do all their calculations. Of course now I
have many millions more orders of magnitude more
computing power in my pocket, as do most of you. But that helped. And this goes back
to this technology, you know, driving science. And then it took another six
years to do the third protein structure. And for a long time protein
structures would take, you know, typically five to
10 years for each one to do. But then the pace accelerated. And the other thing that you
had to do, which is, crystals are pesky things. That’s right. I mean, really pesky things. Yeah. I mean, you might
think it’s easy if you left a bit of salt
out and it’s salty water and it sort of crystallises. But actually getting crystals– It’s a huge step. It’s really difficult. It’s a difficult step because
what you’re trying to do is you’re coaxing molecules
to form these very regular three-dimensional arrays. Now if you have spheres,
you know, regular spheres like marbles of the same size,
you can easily stack them up. OK. Well if you have some,
say, floppy teddy bears or something, it’s
much, much harder to make a very regular stack. They’ll all be
slightly different. They won’t lined
up very precisely. And so you can think of
proteins as sort of floppy– you know, this looks rigid,
but actually in water it’s in solution, and it’s actually
kind of slightly floppy. And to get this sort of– this has a few thousand
atoms– to get it to line up in crystals is very,
very difficult. And the idea that a ribosome,
which is a million atoms– so imagine, this is a
few thousand atoms. That’s a million atoms. So it’s actually many times
bigger than this lysozyme– to get that to
crystallise was not thought to be really
straightforward at all. But Ada Yonath, who was a
scientist who was, at the time, I think in Berlin, had
managed to get a crystal. That’s right. So Ada Yonath went to work
with Heinz-Gunter Wittmann, who ran a big department, almost
like an institute in Berlin. He was a Max Planck director. And he was interested
in all things ribosomal. And he actually had tried
to get a couple of people to give this problem a go,
which is to try and crystallise a whole ribosome. And one of them
turned out to be a bit of a charlatan, and the other– and he left. And the other guy wanted
to come to work on it, but his girlfriend was
German so he wanted to spend time in Germany. And his girlfriend at
some point dumped him. So he didn’t want to go anymore. So Wittmann had this fellowship. So when Ada Yonath
wrote to him, he already had a fellowship lined up. So he simply
transferred it to her. She came to Berlin,
and the first year she was working on something else. And then as she narrated,
she had a bicycle accident or something and she was
hospitalised for a while. And while she was
there she was thinking, well, maybe I should
give whole ribosomes a shot, because, you
know, the Institute is making lots and
lots of these ribosomes from different species. So when she told Wittmann,
he was naturally delighted because it had been on his mind. And he didn’t
think anybody would be willing to sort of
take on the project, because it seemed so impossible. But she, to her credit, not only
took it on, but stuck with it for quite a long time. So the ribosome is– it’s composed of a big bit, a
little bit, and some proteins. Yeah. So if you look up
there, you see there’s a bottom part in
yellow, and a top part, in sort of light blue. And so the top part is what’s
called the large subunit, and the bottom part
is the small subunit. They don’t have much
originality, scientists– the big bit, the little bit. Anyway, so the big bits and
the little bit, and they’re going to feature largely
in our story to come. So we’ve got– Ada Yonath has
got some crystals. You now decide that you’re
going to go to the Laboratory Molecular Biology in
Cambridge and you’re going to do a sabbatical for a year. So poor Vera gets
dragged across– Oh, no, no. I wouldn’t say
poor Vera for that. You know, Vera is an extreme
anglophile, you know. I call her the English
woman from Ohio. so I don’t think there was
any sort of imposition at all. In fact, she had spent a summer
in Durham when she was 17 and had been in love
with England ever since. So– Oh, so she was willing
on that occasion. No, she was always
willing to go to England. Yes. [LAUGHING] So you come to the LMB. Now the LMB plays a
big part in this story. And the LMB is a
very special place. The LMB, as probably
some of you will know– Laboratory Molecular
Biology in Cambridge, which was used to–
well it’s still right next to
Addenbrooke’s Hospital. And it’s an
extraordinary place that has an extraordinary record. It has more Nobel Prize
winners amongst its alumni than most developed countries. It’s absolutely astonishing. How many is it now? Well, the lab itself had its
16th Nobel Laureate, 12th Nobel Prize, because some of
them were shared this year with Greg Winter. But it also won the
Nobel Prize last year with Richard Henderson. And two in a row, for a
relatively small institution is unheard of. Yes. so tell me why, Venki,
it’s so extraordinary. I think the reason
is several-fold. First of all, Max
Perutz, who founded it, had this vision of
really a lab where you would have stable funding,
where people would be very collegial and
non-hierarchical, and they would work in small groups. And this has several effects. One is, if you
have stable funding you can afford to tackle very
large, difficult problems, because they’re not going
to pull the funding out from you if things aren’t
working right away. So it allows you the ability
to tackle hard problems. The collegiality– if you
have high level colleagues, it gives you critical feedback. So when you are
tackling a hard problem, you sometimes don’t know whether
you’re just wasting your time or whether you’re actually
sort of making progress, and you need to maybe try a
different technique and so on. And so if you have very
critical colleagues, that forces you to keep, sort
of focused on the problem. Having small groups is
also very important. If you have a huge
group, the reality is most scientists
don’t have more than one or two good ideas. OK. If you have a large group,
what you end up doing is having a lot of your
second-rate ideas distributed among your group. And then they all need papers,
and that takes away your time. You have to nurture them. You have to see them
through, et cetera. So all these bad
or secondary ideas are distracting you from
the one or two things you really want to do. OK. So by forcing you to
have small groups, it’s forcing you to
focus on the things that are most important
in your field, and not waste your time on sort
of these derivative problems. I think all of
these are important. And the collegiality, the fact
that there’s no hierarchy. We don’t have a senior common
room and a junior common– you know. We have a canteen where
everybody from the lab director to the
first-year graduate student or the cleaners or
electricians or whoever, they all sit together. And so there’s this feeling
that we’re all in this together. You know, everybody
feels invested. And so the result is,
we get terrific support from the machine shop, people in
the workshop or the electronics people and so on. Because everyone feels it’s
part of this grand effort. So it’s essentially
curiosity-driven research. And you’re not driven
so much by the need to published papers, which is– Right. –often the driving
force in science. I mean, Fred Sanger, who
won two Nobel prizes– he has about 40 papers. And today, if you just
counted his papers and what is called an H-index,
he wouldn’t even get tenure, you know at a middle
level university. So it just shows you, those
criteria are not that useful in terms of actual science. But I have to tell you,
it’s not actually a paradox. But this curiosity-driven
work at the LMB has generated billions for the
British economy– Greg Winter. –including Greg Winter’s
monoclonal antibodies, which is the basis
of six of the top 10 selling drugs are a result
of Greg Winters’ technology. Yeah. So Humera, the Medical
Research Council had an enormous amount
of funding every year, which came directly from
the Humera drugs that he– Yeah. In fact, our new building– you know, the
amount of money Greg raised for the MRC was
many times the cost of our new building, which
cost about $200 million pounds. So I often joke, it should
be called the Winter Palace. [LAUGHING] OK. So we’ve got you at the LMB. And you decide that you’re
going to go for the little unit. Yeah. So, you know, Ana Yonath had
crystallised the large subunit. And over the years she had
made the large subunit quality good so that the molecules were
all very precisely lined up so we could get an
atomic structure. But a Russian group
had done the same thing for the small subunit as
well as the entire ribosome. But the quality of these
crystals were not that great. So even if you were
able to solve it, you’d only get a fuzzy
image of the ribosome. You wouldn’t be able to
determine an atomic structure. And so I thought, well,
you know, people in Berlin have these great crystals
of the large subunit, so maybe I should work
on the small subunit. And one reason I wanted to
do that was first of all, I realised I wasn’t getting
anywhere by looking at little pieces of the ribosome, and that
they weren’t going to tell you how the ribosome worked, unless
you were able to look at a much bigger thing like
an entire subunit, or preferably the whole thing. And so I thought,
well, how would you even go about doing it? And it turned out I got
an idea, almost randomly as a result of a
conversation that had to do with a very
specialised technique in crystallography
that uses these very intense sources of x-rays
called synchrotrons, where you can choose the
wavelength of the x-rays very precisely. Anyway, I’ve described
it in my book. But it gave me an idea
that you could even, using this technique, tackle
very, very large molecules like the ribosome. So I thought, well,
I could do that, but I don’t want to go head
to head with Ada on the 50S subunit, even though it appeared
that work had sort of stalled, because those crystals had been
around for quite a long time and then no structure emerging. And I didn’t want to go
head to head with her. So I thought, well, rather,
I’ll pick the small subunit and see if I can
improve those crystals, and then I can try my idea
on those improved crystals. But actually that’s a very
important point in science, isn’t it? Because some people, they
choose the wrong thing. I mean, there is some luck. I mean, yes, you were
determined you would do that, but there is some luck about
choosing the right thing. Being in the right
place at the right time is a very important
point in science. Yeah. And I think if I hadn’t
done my sabbatical at the LMB for a year, I
don’t think I would have ever had this idea. If I’d gone somewhere else
to learn crystallography, I might have become a
competent crystallographer and done some pretty good
work, but I don’t think I would have had this idea of– first of all, it’s a
cultural thing too. After going to the
LMB, I thought, why am I wasting my time
doing these little, you know, bits and pieces of science? I should be tackling the most
important question in my field. So there was that
cultural motivation, you know, after having seen
how people worked at the LMB. And then the other thing
was this random conversation with a friend of mine, Phil
Evans, who actually was simply conveying a message
from Eleanor Dodson, who was a well-known
crystallographer at York. She and her husband
were both, you know Dorothy Hodgkins proteges. Anyway, so because of
this tip from Eleanor, I tried this technique. And then gradually I realised
it worked so well that maybe it could be used for
very large objects. So now you go back from LMB. You go back to America. And this is time you’re
now at Brookhaven or you’ve got to
Utah at the time? I was at Brookhaven. But when I went
back to Brookhaven, the trouble is the
administration at Brookhaven– it was run by a
Department of Energy, and they’re a bunch of
ex-physicists turned bureaucrats, and they really
didn’t have a good feel of how life sciences actually work. And they were really starving
our department of fresh blood. And I thought the
department was stagnating. There were very
good people there, but I just didn’t see that
this was a place that was going to be exciting in the future. So you’re off to Utah then. So I went off to Utah. I almost took a
job at Edinburgh. I don’t say that in
the book, but my son was just going to
university at the time. And according to British
immigration laws, because he was 18 he was
no longer my dependent. Obviously they hadn’t
talked to my bank. [LAUGHING] Anyway. So they wouldn’t
give him a visa. And anyway he had already
been accepted at Harvard, so he didn’t really
want to give that up. So I didn’t feel like
abandoning him at that stage and going off to a
different country. And that was one reason. But I also felt Utah had
some very good people working on RNA biology and had
absolutely superb colleagues. And I was very happy
to go there actually. Now by this time you think
that you’re on your own, doing your small unit, but
suddenly you realise that there is intense competition– Yeah. –and that you are
one of four teams. And you say in your book, I
had a near obsessive focus on the 30S structure. And I wonder, is
obsession essential? I think when– it
can go in phases. There are times when you
need to be relaxed and very open to new ideas, and
allow, sort of the world to sort of sink into you. But there are other
times when you’ve already decided this is
what you’re doing, and you just have to come
to grips with the problem and really obsess about it. | by obsessing, I
don’t mean you have to work on it 24 hours a day. If you do that you’ll
just wear yourself out and you won’t get anywhere. You have to take time off. You know, sometimes
actually you get your ideas when you’re away
from the problem, you know, going
for a run or going to a concert or something. But you do have to constantly
mull over it and be obsessive. So there you are obsessing. But it almost,
almost fell apart. Tell them the story
of the guillotine. Oh, that’s right. So you haven’t mentioned that I
actually left Utah and went off to the LMB. Oh yes. Yes. So what happened was, when I
started working on the 30S– I decided to work on the 30S. I went to a conference and
I realised that Tom Stites, who unfortunately
died about a week ago, had started to work
on the 50S, you know, going head to head with
Ada, using Ada’s crystals as a starting point. Because they had
sort of figured that, well, other people needed
to get into the act. So I thought that’s fine. Those people can
duke it out, and I wanted to work on the 30S. But then I got nervous. I thought, you know, Ada Yonath
had been doing it for 15 years and I thought, well, you
know, what if I’m doing it for three or four
years and get nowhere, because it’s a tough problem
and then my grant runs out and then they won’t renew it? So I wrote to Richard Henderson,
who was a director at the time. And I said, you know,
how about giving me a job at the LMB to come
and work on the ribosome. And of course most places
would sort of laugh at you. But the LMB being
what it is, he had me over on a visit to Sweden,
on the way to Sweden. And he talked it over
and then they gave me a job at the end of it. I went to Sweden and I realised
that Ada had then shifted her attention from the
50S to the 30S, because she had sort of ceded
the ground to Tom Stites and their colleagues. And so I had been trying
to avoid this race, and then found myself
in this sort of head to head race with Ada,
quite unintendedly. And then I went off to LMB and
there was this furious year when we all were trying to
pull out the stops to get this structure. And our crystals were
not like each other each. Crystal was slightly different. And we thought that
maybe the reason was the way we were freezing them. Because to freeze them you
have to look under a microscope and with a tiny loop,
fish out these crystals and then plunge them
into liquid nitrogen. And if you plunge them in
slightly different ways, maybe the crystals freeze
slightly differently and they end up being
somewhat different. I told you these
crystals were pesky. So, you know, a friend of
mine said, well, you know, we have this device, which
is like a guillotine. And what you do is you
fish out your crystal, you stick it onto
the guillotine, and then you press a
paddle and the guillotine drops down into the
liquid nitrogen. So every crystal will drop down
exactly the same rate and in exactly the same direction. So I had this very enthusiastic
graduate student, Bill Clemens. And he would sit
in the cold room. This all had to be
done at four degrees C. So he would put on his winter
jacket and set up a stereo and put on Johnny Cash. And then he would freeze
hundreds of these crystals. And actually if you want
to hear what he said– this is a little
self-advertising– you can hear it on Desert
Island Discs this Sunday. OK. But anyway, so he would
plunge all these crystals one after the other. Which he’d laboriously made. Yeah. And these crystals,
you have to realise, took about eight to
10 weeks to grow, after about 10 days
of preparative work. So about, say, nine
to 10 weeks overall. So he took about 200
of these crystals and stuck ’em on the guillotine. And he didn’t try one or two
to see if the thing would work. And I didn’t think to tell
him, you know, why don’t you try one or two? We all took it for granted. I think it was a failure
of communication. We all took it for granted
that this was a very standard device, et cetera. It turned out the device had
never been used for crystals. It was an EM for
electron microscopy. And this friend had just
been trying to be helpful, saying, well, maybe
you could try this. You know, but no
one had tried it. So in this desperate race,
in which every second counts, you’d just destroyed 200
of your best crystals. Yeah. So what happened
is the guillotine would plunge down in the liquid
nitrogen and stop with a thud. And in that thud, the crystal
would shoot out of the loop and disappear into the sort
of vat of liquid nitrogen. And so, you know, when they
took it to the synchrotron, all he had was like
200 empty loops, except for one loop which had
a crystal sticking out of it. And I sort of, in
a slightly lewd way say that it looked as if it
was giving Bill the finger. [LAUGHING] So this is a thoroughgoing
disaster that happened. Terrible. We probably lost about two
months in a very tight race. So you’re, by this time,
at the LMB in Cambridge, but actually some of the rest
of your team are back in Utah. So you are working– you have this kind
of shift system. Yeah. That’s at the beginning. That’s before the guillotine. So when I first
moved to the LMB, we had collected some data to
low resolution on the ribosome, just to see if the
strategy would work. And I had come to
the LMB with Vera, and I would do all the
computing at the LMB. And then at the end of the
day I would give the results– I would send the results
electronically to Utah. But there were
seven hours behind. And so they still had
most of their day left. And so we were effectively
working around the clock for those two or three months. And really, actually
instead of slowing us down, it probably sped us up a bit. So then you take your crystals
to the Argonne near Chicago, which is a beam there. And just tell us
about that, because I think this is the moment
when this story moves into Nobel Prize territory. Yeah. So the whole thing was that– the technique depends
on whether you can see certain special atoms,
which have different scattering properties for x-rays. And those are the
sort of magic signal that allows you to
calculate the structure, the signal from those atoms. So you take your crystals
to these synchrotrons and you do an experiment which
exploits the special scattering of these atoms. And then you do a
calculation to see, can you see the signal
from these atoms? So when you go to a synchrotron,
they give you 48 hours. And I have to tell you,
they give us 48 hours six months after I
had asked them for it. So they could have
given it to me anytime. And by this time they’d
given my competitors quite a lot of time. So that was sort of annoying. But anyway, we had 48
hours at the end of March. And if that didn’t
work, then effectively we would have lost
the first round. So we would be
Johnny-come-lately’s if you like. So at the end of
this 48 hours where we worked around
the clock in shifts, we did this calculation
to look for the signal from these atoms. And it just spat
out the results, and it didn’t look like
there was anything there. And I thought, oh
my god, something has gone terribly wrong. We must have chosen the wrong
wavelength or whatever it is. It hasn’t worked. And, you know, we’ve
basically lost this thing. And we’re going to have to just
regroup and do something else or do follow-up experiments. And then I realised there was
some mistake in the code that we had fed the computer. And I realised, actually
it needed to be rerun with the correct code. And when we reran it, it
spat out these results. And I could see
dozens and dozens of peaks, really strong peaks
from these special atoms. And I knew then that we
had cracked the problem. And in fact you say in
the book that you got up and you started dancing
around the room saying, “We’re going to be famous.” [LAUGHING] Yeah, I mean, you know, you
have all the stress of months and months of
stress, and then you have 48 hours of
exhausting data collection, and suddenly there’s just this
burst of relief, you know, that the whole thing has
worked and it’s going to be OK. And part of the reason
also is, you know, when you go to a
new institution you tell people like
Richard Henderson, I’m going to come here and
give the ribosome a go, you don’t want to sort of
be a failure, you know, and be an also-ran. And so it was just the
combination of all of that. It just sort of– there was
a sudden release, you know. So there’s this
intense competition. And actually people
think of science as being about collaboration. I mean, you think about huge
teams, you think about– Yeah. And science is always a
team effort, in that you build on the work of others. But actually there’s also a
fiercely competitive streak. Science has always been
fiercely competitive. I mean, you look at
Newton and Leibniz. Or actually there’s a very
famous example with Golgi and Ramon y Cajal, who
shared the Nobel Prize. And Golgi spent his
entire Nobel lecture completely trashing
Ramon y Cajal, although Ramon y Cajal turned
out to be right actually. But anyway, so science
has always been like that. It’s just– you know,
science is done by humans. Humans want to be recognised. They want to be famous. They want credit for
their work, and so on. And of course if you want
to work on the Higgs boson, nobody is going to give you
your own CERN to work on. So you have to collaborate. Or if you want to work on
the Human Genome Project, you have to collaborate. And that’s how a lot
of science works. But you can argue
that some by that time it’s more of an engineering
effort, you know. But if you have
a very good idea, you’re not going
to suddenly say, oh, well, I have this great
idea and let’s all share it. You’re going to want to
use that idea to show it works so that
people say, yes, this guy had this great idea. So I think that
drives the thing. And if you look
at the ribosome, I mean, to be very blunt
about it, while it was being done by just
one group for 15 years, not a lot happened beyond
getting the crystals. It didn’t progress
towards the structure, although it could have
at many different points. And suddenly you have
four groups working on it, and the whole field explodes
and things just take off. And it’s because, when
you have competition, you’re just forced
to work harder, but also to think harder. And it’s the same actually
in the marketplace, you know. It weeds out bad
ideas and it just creates better
products I would so. And things really began to get
a bit tricky at this point. There was a lot of rather
ill-tempered bickering between these groups. There is. And I think that’s
slightly unfortunate. So I say in the
book, collaboration is very good for
science, but it’s not so great for scientists,
because it’s very stressful. You have all this rivalry
and animosities and so on. But– And not helped by
the fact that now we are in Nobel Prize
territory, and there can only be three prizes. Yeah. So I talk quite a
bit about prizes. I can do this now. Well I’ve never liked
prizes, actually, you know. But if I’d said that before,
people would say, oh, well, this guy doesn’t have any,
so he’s just got sour grapes. But, you know– And now you’ve got quite a lot. Well, a few. But the thing about prizes is,
they apply a sports metaphor to science. And the thing I
don’t like about that is, in sports there’s a
very clear set of rules and a very clear way
to measure things. So if you have a 100-metre
race, the rules are clear and you can measure who came
first, second, and third. OK. Or in a football game you can
tell who scored the most goals, or at cricket who
scored the most runs. But in science it’s
not always obvious who did the big advance, because
science is multi-dimensional. We all depend on different
advances and different aspects of the problem. And so figuring that
out is not always easy. It can often be subjective. And I point out, in a very
big field like transcription, which is how DNA gets
copied into RNA to turn on certain genes, or to turn
them off in other cases, in a big field like that,
the Lasker Award, which is sort of the American
version of the Nobel went to one scientist. The Nobel Prize, for
exactly the same field, went to a completely
different scientist. Now how could it be that
two intelligent committees pick two different people? And it shows, to some extent,
you know, how subjective it is. But you had been
told– and I just think this is a
fantastic story– you had been told by Jim
Watson, no less, not once but twice that you were very
unlikely to get the Nobel prize, so quit dreaming, boy. It’s very funny. Right after the
structures were solved, I was invited to give a talk
at NIH along with Ada Yonath and Peter Moore, who was part
of the Moore-Stites duo at Yale. And I was then going off
to Cold Spring Harbour to give a talk at a
crystallography course that I’d actually
taken as a student to learn crystallography
before I went to the LMB. So at the airport I saw Jim
Watson was right ahead of me in the queue. So I introduced myself. And we spent the entire
time on the plane chatting with each other. At some point, apropos
of absolutely nothing, he said, well, you know,
there’s that guy in California, and there’s that Yale
group, and of course there’s that Israeli woman. So I don’t think– you shouldn’t worry about it. And basically what
he was saying was, you know, you should just
forget about the Nobel Prize. You’re just not in the running. And I sort of laughed
because, you know, I hadn’t brought
it up, you know. This guy was sort of
gratuitously telling me I was a loser. OK. [LAUGHING] And so– but, you
know, Jim being Jim– everyone in the
molecular biology field– we all admire Jim for his
huge contributions to biology, but we also know what he’s like. I mean, this is a
guy whose, you know– he’s got like, some strange
views about lots of things. Anyway, so I just
sort of dismissed it. But then nine years later–
fast forward nine years, about two months before the
phone call from Stockholm, I was at a Cold Spring
Harbour symposium on evolution, because it
was 150th Darwin’s Origin of Species and I was sort
of the token ribosome guy. Because the ribosome is ancient. It goes back to how life
evolved from chemicals like RNA. So, anyway, so Jim came
in just for my session. OK. And this RNA
biologist said, do you know Jim just came in for
your session and then left? And I said, no, I
didn’t notice that. He says, well, you must be
on somebody’s shortlist. And I say in the book, not
on Watson’s apparently. Because after this talk
I met him in the lobby and he started asking
me about how so-and-so was doing so-and-so
was doing and so on. And then he sort of
looked at me and he says, you know, look, not
going to Stockholm isn’t the end of the world. [LAUGHING] I didn’t know what to say. You know, again it was like
apropos of absolutely nothing. But it shows that
Jim is slightly obsessed about the
Nobel Prize, you know. And it’s just weird. But you’d also had a
blistering row with a person who was on the Nobel committee. Oh, yeah. How not to get a Nobel. After these structures
were solved, it sort of went into
some weird campaign mode. All of us were getting invited
to meetings all over the world. And for a few
years, every year we were getting invited to at
least one meeting in Sweden. And the last of these that
I attended was in 2004. And there’s a well-known
ribosome biochemist in Sweden, and he was at this meeting. And at the banquet he had
clearly had one too many. And he comes to me
after the dinner and starts haranguing
me about my talk. And he had a disagreement with
our model for how the code on the gene is recognised,
which is a very important part of my work. And he disagreed with it. And then he said,
you know, I know why you were trying to pretend
you’re doing something– you’ve done something new. We figured all this
out in the ’70s. So then I got really
irritated and I sort of gave it right back to him. And then his colleague
had to drag us apart. And then two months
later I read somewhere that he had been
appointed to the Nobel Committee for Chemistry. [LAUGHING] And so I thought,
well, you know, that’s that as far as
I’m concerned, you know. And actually it was a big relief
because I was absolutely sure that I was not going
to get a Nobel Prize. If the ribosome got one, they
would never give it to me, because this guy would tell them
that I was completely wrong, et cetera. But in 2009 you got the
call, which you thought was a prank call. I didn’t believe it. I didn’t believe
it because of that. And I said, well, you
know, if this isn’t a prank and you’re real– and I said to the
guy, you know, you have a very good Swedish accent,
but I’m not sure I believe you. [LAUGHING] And then I said,
well, if it’s true, I want you to put Måns
Ehrenberg on the line because he’s on your committee,
and he must be there. And there’s this huge
laughter at the other end. I realised then I was
on a speakerphone. You know? And then Måns came on the
line and that’s when I sort of realised it must be true. But what I love most
about this was that what Vera said when you went home. And she said to
you, “I thought you had to be really clever
to win one of those.” [LAUGHING] I know. So I quote– Marion Pearson was the
wife of Lester Pearson, who was a Canadian Prime Minister. And at some point she
was asked, you know, what she thought about Pearson
becoming prime minister. And she said, well, you know,
behind every successful man there stands a very
surprised woman. [LAUGHING] Now I want to let you
ask some questions, but I want to finish
off this story by coming back, as
I said, to the star of the show, the ribosome. So, briefly, what do we
now know about the ribosome because you’ve been able
to work out the structure? So there were several
questions when we started. First of all, how does
it recognise the code so accurately? Another is, how does
it actually join up the amino acids in the
other part of the ribosome? A third is, how does it actually
move from one group of three to the next group of three
along the genetic message? And then, how does it terminate? How does it know when to stop? How does it know what the
right starting point is? So in all of these we’ve
made tremendous progress. As a completely separate
issue, the ribosome happens to be the target
of lots of antibiotics. Almost half of known antibiotics
block the bacterial ribosome, but leave our ribosomes
alone to some extent. And so once we had
these structures we could figure out exactly
how these antibiotics blocked the ribosome. And that’s going to
help, and already has led to people using
these ribosome structures to try and design better
compounds, which might be more effective antibiotics. Now currently what
we’re trying to do is look at ribosomes
from– these were all bacterial ribosomes. But we’re now looking at
ribosomes from high organisms like up. To interrupt, sorry–
but bacterial ribosomes was a very important
part of this, because they were not
just any old bacteria. They were bacteria from extreme
environments, which helped you be able to use the crystals. Possibly. That used to be the dogma
until Jamie Kate, who was too young to be
swayed by current dogma, decided to give what we call
the bog standard bacterium of molecular biology,
which is e. coli a go and got fantastic
crystals, and therefore sort of proved that this
probably is a bit of a myth. But, you know, sometimes
myths are useful, because if you
believe in them, they help you sort of keep going,
you know, and give it a shot. Anyway, but those
were all bacteria, but now we’re looking at higher
organisms, so the ribosomes from our own cells,
and also the ribosomes from organelles within
us called mitochondria, which are actually remnants of
bacteria that were swallowed up by bigger cells two
billion years ago and have now become
their own thing. And so there are all these
classes of ribosomes. And then we want to understand
how ribosomes are regulated. How does a cell turn on
ribosomes, turn them off? How does it know when
ribosomes are stuck, and how does that then deal
with these abnormal situations? So those are all things
that we want to work on. And you understand them better
because you have the structure. We understand–
and the structures have made all sorts of
experiments possible that wouldn’t have been without
knowing where all the groups were on the ribosomes. It’s an extraordinary story. It really is an
absolutely terrific read. I mean, it’s that sense of,
we’ve got to get there, we’ve got to get there. And this huge competition. It’s terrific. And just to give you one last
thing about the ribosome. It’s so fundamental. It’s at the crossroads
between genes and the proteins that are
what the genes code for. And I like to say that
every molecule in every cell was either made by
the ribosome or were made by enzymes that
were themselves made by the ribosome. So you can think
of it as the mother or the grandmother of all the
molecules made in the cell. So that’s how important it is. And it goes back to a world that
existed before DNA or proteins, you know, from this
ancient RNA world. It sort of emerged
from the mists. [APPLAUSE]


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