00:00:00 Michael E. Charles is an Austrian-born molecular biologist who received the 1962 Nobel Prize in Chemistry.

00:00:30 It is my privilege to introduce our next Nobel Laureate speaker, Professor Christian

00:00:57 de Duve, who is currently the Andrew Mellon Professor Emeritus at the Rockefeller University

00:01:05 and the President of the International Institute of Cellular and Molecular Pathology in Belgium.

00:01:13 Professor de Duve is best known for his discovery of lysosomes, and these are subcellular particles

00:01:21 that function in many ways as the digestive system of the cell. He was awarded the Nobel

00:01:29 Prize in Physiology or Medicine in 1974, jointly with Dr. Albert Claude and Dr. George Palladi,

00:01:38 for discoveries concerning the structural and functional organization of the cell.

00:01:46 Dr. de Duve discovered lysosomes in 1949 while working at the Catholic University of Louvain

00:01:54 in Belgium, using an elegant but simple cell fractionation technique of centrifugation,

00:02:02 that is, spinning the cells. In this technique, I'm sure most of the scientists understand

00:02:10 he didn't actually spin it with his hand. The cell parts were broken open and carefully

00:02:19 separated by centrifugation, and Dr. de Duve found that more than a dozen different hydrolytic

00:02:27 enzymes were contained within bag-like particles, which is called lysosomes, and these apparently

00:02:35 behaved like the digestive tracts of the cell. Over the years, Dr. de Duve and his colleagues

00:02:44 have made significant contributions to the development of techniques and instrumentation

00:02:50 for the study of cell biology. Among the achievements of his Rockefeller Laboratory was the discovery

00:02:58 of peroxisomes, organelles, which involve, among other functions, in the metabolism of fats,

00:03:05 and I'm sure we have an understanding implication of that discovery. Recent work in his laboratory

00:03:13 on both sides of the Atlantic have devoted to the application of basic research in cell biology to

00:03:21 problems of medicine and therapeutics, including cancer, immune defense mechanism, and genetic

00:03:27 diseases. Dr. de Duve has summarized his vision of the cell in his book, A Guided Tour of the Living

00:03:38 Cells, published in 1984, and most recently, he just completed a book on the origin of life and

00:03:45 the evolution of the cell, which I expect we'll hear more about in this lecture. In the past two

00:03:54 days, I have gotten to know Dr. de Duve a little better, and I've come to appreciate that his

00:04:00 personality and his approach to science really, I think, reflects the higher ideals of scientific

00:04:08 research. At the personal level, he is always quick to give credit to his mentors and his colleagues,

00:04:17 and is extremely modest about his own achievements. In his work and in his personal life, he is an

00:04:25 international person. He speaks four languages, at least fluently, and as we will hear, English is

00:04:33 certainly one of them, and he has worked on both sides of the Atlantic, collaborating with scores

00:04:40 of colleagues around the world, demonstrating that scientific research really knows no geographic

00:04:46 boundary, nor political boundary, or sociological boundary. He has concerns for educating and

00:04:54 mentoring young scientists, and in 1975, he created the International Institute of Cellular and

00:05:02 Molecular Pathology in Brussels, which maintains close ties with the Rockefeller University. Dr.

00:05:10 de Duve has been the recipient of numerous international awards, but he did not want, but he

00:05:15 did want me to mention that he received a special award of merit from the Gairdner Foundation here

00:05:21 in Canada in 1967. He is a foreign member of the Royal Society of Canada, and he holds honorary

00:05:29 degrees from numerous universities, including the University of Sherbrooke and University of Montreal.

00:05:36 Dr. de Duve will speak to us on life as a cosmic imperative. Let us welcome Dr. de Duve.

00:05:45 Thank you very much, Dr. Ling. It's always nice to listen to such glowing introductions. It's like

00:06:12 reading your obituary without having to deserve it.

00:06:23 But like obituaries, such introductions have to be taken with a grain of salt.

00:06:28 It's a great honor, great pleasure to participate in this unique, extraordinary event honoring

00:06:38 John Polanyi, who's not only a very great scientist, but also a great humanist. And this

00:06:47 morning, you heard that he had really two personalities. And I must say that I haven't

00:06:57 had much contact with his personality, number one, that is, as a chemist, I think mostly because we

00:07:04 live on different time scales. He's a man who works in the picosecond, femtosecond scale that

00:07:13 you heard about this morning from Lord Porter. And as you will hear later, my time scale is

00:07:20 measured in billions of years. But I had several opportunities to interact and get acquainted

00:07:30 with John Polanyi in his other personality, the humanist. Many of our talks being

00:07:42 conducted in the gardens of the Vatican Palace in Rome, and I think we've had an opportunity to

00:07:53 sympathize in those days. I don't know whether those interactions are responsible for my being

00:08:00 here. I hope they were. In any case, I'm very grateful for this opportunity to participate,

00:08:06 John. Thank you very much. By some coincidence, which may not be a coincidence, my talk

00:08:15 has been sandwiched between two high-powered scientific lectures. And I think I'm

00:08:25 expected to provide you with some relief.

00:08:33 I hope it won't be comic relief. It's going to be cosmic relief.

00:08:40 I'm going to speak about very general matters, and I will use very simple language, maybe

00:08:48 simplistic for most of you. And if you think it's simplistic, please excuse me. I'm not

00:08:56 trying to underestimate your scientific expertise and knowledge.

00:09:07 My talk will deal with very general questions that all of us, I suppose, ask. What is life?

00:09:17 How did it start and evolve? What is its meaning, if any? How do we humans fit within this

00:09:27 general scheme? Now, these questions, until recently, have been addressed mostly by philosophers

00:09:36 and theologians. But in recent years, they've become concerns more and more for scientists

00:09:45 because the increasing knowledge we have acquired and are acquiring concerning the nature of life

00:09:55 and its evolution, and concerning many other aspects of cosmology, geochemistry, and so on,

00:10:03 provide us with information on which we can try to base more rational or meaningful answers

00:10:13 to these questions than philosophers can. And first, what is life?

00:10:25 Well, as you know, books have been written on the topic. There's one famous,

00:10:31 which is written by Erwin Schrodinger, a famous physicist, and it's called What is Life?

00:10:38 Now, my own answer to this question is life is what is common to all living beings.

00:10:52 I don't know why you're laughing.

00:10:56 Because this is not, this is not one of those sayings by this famous Frenchman,

00:11:02 Monsieur de la Palice, of whom it is said that 15 minutes before his death, he was still alive.

00:11:17 He's famous for such sayings. Well, my definition of life is not a tautology,

00:11:24 because it allows us first to exclude a large number of properties. To be alive,

00:11:30 you don't need green leaves, you don't need wings, you don't need a brain, you don't need

00:11:35 shells, you don't need hands and feet. In fact, you don't even need to have many cells.

00:11:42 So, what is left is really what is common to all living beings, excluding what is not common.

00:11:49 And in fact, it is really what is common between us and the lowly coli, bacilli, we

00:11:57 harbor in our gut, and in between, of course, fungi, plants, animals, and other living beings.

00:12:05 And this still leaves a lot. This still leaves a lot. First of all, all living beings

00:12:11 are manufactured, are built, with the same basic constituents, the same

00:12:17 molecules, proteins, nucleic acids, carbohydrates, fats, and so on. Not exactly the same, because

00:12:23 otherwise they would all be identical, but similar molecules. All living beings use the

00:12:30 same, or similar, chemical pathways to build their own constituents, to break down their foodstuffs.

00:12:39 All living beings use the same basic mechanisms to retrieve energy and convert it into

00:12:49 work. Of course, there are differences. The green leaves Dr. Porter talked about this morning

00:12:54 use chlorophyll, and other beings, we use different systems. But basically, when you look at

00:13:02 the molecular mechanisms, they are built according to the same principles. And of course, especially,

00:13:10 all living organisms, all living beings, use the same language, the same genetic code.

00:13:18 In fact, all these similarities are so strong that we can now state, with a

00:13:27 considerable degree of certainty, or at least assurance, there's no certainty in science,

00:13:35 but assurance, that all living organisms are descended from a single ancestral form of life.

00:13:44 And the evidence supporting this is, first of all, all the similarities that I have already

00:13:50 emphasized, but the evidence, even stronger evidence, comes from the sequence similarities

00:14:01 between proteins that perform the same function in different organisms, and between the genes

00:14:09 that code for these proteins that perform similar functions in similar,

00:14:13 the same organisms. And the preceding lecture, of course,

00:14:20 has provided already a very good background to that. We know that we can now sequence proteins,

00:14:27 we can now sequence nucleic acids. In fact, Fred Sanger got his two Nobel prizes,

00:14:33 one for sequencing proteins and the other for sequencing DNA. And now that we have so many

00:14:40 sequences of proteins that do the same thing in different organisms, whether they be bacteria,

00:14:45 plants, or whatever, or for the genes that code for these proteins, we find that there is

00:14:50 unmistakable evidence that these molecules are descendants from a single ancestral form

00:14:59 that evolved in slightly different ways during evolution, because some mutations

00:15:06 changed the sequence in one way or another without destroying the

00:15:14 biological activity of the molecule, of course. And in fact, this technique of comparative sequencing

00:15:20 has become a major tool for reconstructing the pathways of evolution. And here, this is the kind

00:15:30 of simplistic vocabulary that I'm using. Instead of showing beautiful DNA sequences the way Dr.

00:15:37 Smith showed you, I'm showing something very much simpler. Now, imagine yourself in a world

00:15:46 in which words change in different parts of the world, change mostly by copying mistakes,

00:15:55 so that one letter is replaced by another. And so suppose that you are now sampling

00:16:02 the languages of different parts of the world and comparing different words with each other,

00:16:07 and you find that in one area, one word is spelled professor, and the other area,

00:16:14 it's spelled processor. Well, now that you know the rule that words evolve and change by

00:16:22 means of copying mistakes or accidents of one sort or another in the spelling, you can

00:16:28 readily conclude that, or at least assume, that these two words originate from a common

00:16:35 ancestral word, which may be professor, in which case the F was changed by a C in this

00:16:44 line, or it could have been processor, in which case the C of processor became an F

00:16:49 by mutation in the other line. Now, suppose you find protector and projector somewhere else,

00:16:57 and again, you can assume that these are descendants from the single ancestral form

00:17:04 in which either T was replaced by J or J by T. Now, comparing the four words, you can

00:17:11 go back a little further in time and say that all four are descendants from a common ancestor

00:17:21 that has in common with the progeny P-R-O-E and O-R, but has undergone changes in three positions

00:17:30 and three different kinds of changes. Well, this, in a very simplistic way, illustrates

00:17:36 the strength of this technique of molecular sequencing for reconstructing evolution.

00:17:45 That is, the whole history of life is really written into the sequences of our proteins,

00:17:52 of our nucleic acids, and by analyzing extant living organisms, you can go down to the common

00:18:00 ancestor of all life on Earth, and here, in a very simplistic fashion again, is shown the kind of

00:18:09 tree that people have come up with. Here you have, in the ordinate, you have a time scale. It starts

00:18:18 at 4.5 billion years ago, which is the approximate time when the Earth was formed.

00:18:33 The Earth is believed to have been inhospitable for life during about half a billion years,

00:18:41 and very soon later, life appeared. Now, we know this, we know this, well, I'll tell you in a minute

00:18:49 how we know this. I just, first, I want to point out the general shape of this tree. You see that

00:18:55 very soon, two bacterial lines separated, the Eubacteria and the Archaebacteria, also called now

00:19:07 Archaea and Bacteria, separated, in fact, very early, and a third line, which is really extremely

00:19:15 important, led from a bacterial ancestor through a very large succession of extremely complicated

00:19:24 steps, led to the ancestor of the eukaryotic cells. The eukaryotic cells are big cells with a

00:19:33 real nucleus that divides by mitosis. They have lots of membranes inside, organelles,

00:19:39 very much more complex than bacteria, and they evolved from bacteria through a succession of

00:19:48 steps. I could give you my idea of how this happened, but there is no time, and then finally,

00:19:54 we end up here very, very late at the formation of the first multicellular organism. We have to

00:20:04 realize that this little green square includes, in the history of life, all that we used to know

00:20:11 before from fossils of plants and animals, and comparative sequencing has allowed us to reconstruct

00:20:21 in much greater detail, I mean, when I say us, the people who do this work, because I haven't done it

00:20:27 myself, to reconstruct this tree in, of course, infinitely more detail than you see here, and the

00:20:36 reason why, now I'm going to tell you why we have a time scale. Here, we have a time scale that's

00:20:41 given by the fossils and the geological strata in which the fossils were found, but here,

00:20:48 fortunately, in the last 10, 15 years, microfossils have been found, that is, fossilized traces of

00:20:56 bacteria that are found in very old rocks up to 3.5, 3.6 billion years old, and in which one can

00:21:05 recognize the traces of bacteria, of the shapes of the cell walls of bacteria that lived 3,500

00:21:16 million years ago, and that looked, in fact, very much the same as some of the bacteria that exist

00:21:24 today. So, what is also shown here is that up to about 2 billion years ago, there was no oxygen

00:21:33 on Earth, and then oxygen appeared through the activity of these microorganisms that have

00:21:40 photosystem II, we heard about this morning, and that split water to release molecular oxygen,

00:21:48 and this created quite a drama. Some people talk about the oxygen holocaust, all these organisms

00:21:55 that were very happy in an oxygen-free environment suddenly were exposed, or not fortunately, not too

00:22:03 suddenly, to a substance that is really very toxic to living organisms, which is molecular oxygen,

00:22:10 and so probably many, we don't know how many, many died, but some adapted to oxygen and became

00:22:19 the ancestors of present-day aerobic bacteria and of present-day aerobic multicellular organisms,

00:22:26 and it is at this stage that some bacteria were taken up by this primitive phagocyte-eating

00:22:35 cell and were adopted as permanent endosymbionts, first the mitochondria, or perhaps first the

00:22:42 peroxisomes, but we don't know too much about that, were adopted in this way and provided the first

00:22:49 ways of dealing with oxygen, peroxisomes having a very primitive system of utilizing oxygen,

00:22:56 then came the mitochondria that utilize oxygen in a much more

00:23:00 efficient way, and finally came the chloroplasts, which are the green bacteria, they came from

00:23:10 cyanobacteria, the green organelles that are responsible for photosynthesis in green plants.

00:23:17 So this is the kind of results that one can obtain today from comparative sequencing. It is a

00:23:29 completely unexpected offshoot, fringe benefit, if you might say, of these revolutionary developments

00:23:36 in molecular biology, but they may really allow a glimpse, or perhaps even more than a glimpse,

00:23:43 in the whole history of life on Earth, in our own history, and in this respect they are, of course,

00:23:50 of tremendous value. I would now like to spend the rest of this talk

00:23:58 to a discussion of the origin of the common ancestral form.

00:24:06 And here is where I'm going to be very general. I'm not going to go into any chemical details,

00:24:15 although I could do some.

00:24:21 First statement.

00:24:26 Life arose naturally. Now, this is a postulate. I mean, it's not something that I can demonstrate,

00:24:36 but if I do not accept this postulate, then we can just go, I can stop this lecture. In fact,

00:24:44 everybody can stop working on the origin of life because it ceases to become, it ceases to be a

00:24:49 scientific problem. If science is going to try and explain the origin of life, we have to accept as

00:24:57 a postulate, and I think something that's not easy to believe, not difficult to believe, that life

00:25:02 arose naturally. Now, this statement excludes creationism. Creationism, which is the name that

00:25:15 we give to literal interpretation of the biblical account. And obviously, if things happen the way,

00:25:31 I mean, literally the way it was described in the Bible, then we can stop doing work on this.

00:25:37 Next, this excludes vitalism. Now, vitalism is a doctrine that was quite popular, let's say,

00:25:44 a century ago. Today, I think very few biologists still believe in vitalism. Vitalism is the

00:25:52 doctrine according to which living organisms are made of matter, animated, between quotation marks,

00:25:59 animated by some kind of vital spirit, a vital force. And this was very popular in the last

00:26:09 century, but nowadays we, most of us, I would say a very large majority of scientists believe that

00:26:19 living processes can be explained entirely in terms of physics and chemistry, and we don't

00:26:26 need a special force. And this definition also excludes finalism, which is really something very

00:26:34 similar to vitalism. Finalism assumes that living organisms are driven not only by

00:26:45 antecedent causes, antecedent causes, that is by phenomena that have occurred before,

00:26:53 and that pushed them, but that they're also pulled by future events, that is they're pulled

00:27:00 by some kind of purpose. For instance, a finalistic view of, well, let's say that the

00:27:11 stomach is to say that the stomach evolved in order to digest food. That's finalistic.

00:27:20 The scientific way of looking at it is say that the stomach is such that food is digested in it.

00:27:26 It's a different. We remove the purpose, even though we know that living organisms behave

00:27:36 very much as though they were accomplishing a purpose, but they did not evolve, they were not

00:27:44 pulled by the special kind of cause that involved purpose, design, or whatever. All right.

00:27:56 Next statement.

00:28:01 Life arose naturally. Now we now add through the succession of chemical steps.

00:28:09 Life is chemistry. Virtually everything that happens in a living organism is based on chemical

00:28:19 interactions and chemical reactions. Of course, this includes some physical interactions, but

00:28:25 the borderline between physics and chemistry is not very clear. There are four kinds of chemistry

00:28:34 that have become interested in living organisms. There's the old organic chemistry, which owes its

00:28:42 name to a vitalistic attitude because it was the chemistry of compounds that were made by living

00:28:51 organisms and originally were believed to be made only by living organisms, thanks to the

00:28:57 intervention of a vital force. Now, of course, we know that they can be made in the laboratory.

00:29:04 Then comes space chemistry. Space chemistry in the last 20 years or so has provided extremely

00:29:10 interesting information about the origin of life because it has revealed that, in fact,

00:29:16 carbon compounds are present all throughout the universe. There is, in fact, organic chemistry is

00:29:24 not an esoteric kind of chemistry. It's the most banal kind of chemistry in the universe, and

00:29:33 there is small organic compounds that are found on interstellar dust. They're found on comets.

00:29:40 They're found on meteorites. Even some meteorites that fell on Earth have been analyzed and shown

00:29:48 to contain amino acids and other typically biological compounds. Although nobody or very

00:29:55 few people believe that they are made by living organisms on those bodies, they believe that

00:30:00 they're made by natural forces that probably were important in seeding the first reactions

00:30:08 that led to life. Then there's abiotic chemistry. Abiotic chemistry, that's chemistry without life,

00:30:15 was started almost exactly 40 years ago by Stanley Miller when he did his famous experiment,

00:30:21 which differs from organic chemistry in that the organic chemist tries to manufacture a compound

00:30:29 and devises the best possible procedure for making the compound in the laboratory. The abiotic

00:30:36 chemist tries to reproduce in the laboratory physical and chemical conditions that were likely

00:30:43 to obtain or to have obtained or prevailed on Earth 4 billion years ago to see what comes out.

00:30:50 Now, most abiotic chemists have a little idea of what they want to come out, and they tip the

00:30:56 scales in favor of the product. They use some finalistic techniques, but Stanley Miller did not.

00:31:04 Stanley Miller really wanted to reproduce prebiotic thunderstorms, electric storms,

00:31:12 in his little machine, and he found amino acids and other lactic acids, glycolic acids, many

00:31:19 typically biogenic compounds. And finally comes biochemistry, which is the kind of chemistry that

00:31:26 I've done all my life, and which tries to understand what is happening in real living

00:31:32 organisms, how they behave, how they do what they do. And let us say that in my own little excursion,

00:31:39 you know, this topic has become a sort of hobby, an old age hobby, which keeps me out of mischief,

00:31:46 as my wife would say. And I differ from my friends in these other areas of chemistry in believing,

00:31:54 and I don't have the time to tell you, but I think I have strong arguments for that, in believing

00:31:59 that biochemistry has more to tell us about the origin of life than we think. That in fact,

00:32:06 that even the history, the chemical history of life, is written largely into the basic chemistry

00:32:13 and the chemical reactions of metabolism. I wish I could tell you more about it, but

00:32:19 I don't want to make this too long. I want to move on to the next statement.

00:32:27 Let me see, I still have a few minutes. The next statement adds something more.

00:32:34 Life arose naturally through the succession of chemical steps. Yes, of very many chemical steps.

00:32:42 Now, this is obvious. You can't imagine, you can't assume that a living cell would emerge

00:32:53 in one shot, or even a molecule of DNA. You can't expect a molecule of DNA to arise spontaneously

00:33:01 in one shot. And Sir Fred Hoyle, many of you know, famous astronomer, and also a man with sort

00:33:10 of rather original ideas about a number of topics, including the origin of life, has said it very

00:33:18 well. He says a Boeing 747 cannot arise spontaneously, ready to fly, from a junkyard

00:33:28 swept by a hurricane. Well, that's obvious. Well, a living cell, believe me, is very much more

00:33:34 complicated than the Boeing 747. So we need a very large, a very, very large number of steps,

00:33:41 millions of chemical steps that follow each other, to lead to something as complicated

00:33:48 as a living cell. And so now we come to what is really the most important statement,

00:33:55 that, at least in my opinion, life arose naturally through the succession of a very

00:34:02 large number of chemical steps, most of which had a high probability of taking place

00:34:10 under the prevailing conditions. Now, in other words, the view that I'm defending and proposing

00:34:19 for you is that life is a highly deterministic process that was bound to occur under the

00:34:28 conditions that prevailed on Earth four billion years ago, bound to arise, and therefore that

00:34:35 would be bound to arise anywhere or anytime in the universe where the same conditions would

00:34:42 obtain it. How much time do I have left? Does anybody?

00:34:47 What? 10 minutes? Oh, God. It's much too much, but never mind. I'll fill the gap.

00:35:01 Okay. Well, maybe this gives me an opportunity, because I think this is really,

00:35:06 this is the crux of the whole argument, and this is the message. Highly probable.

00:35:15 Deterministic phenomena. Okay.

00:35:20 This view is not accepted by many of my eminent colleagues. I don't know how

00:35:28 impopular or popular it is today, but certainly 10, 20 years ago, very eminent people like Jacques

00:35:36 Monod, Francis Crick, and many others who all wear the same little crown that you can see on

00:35:42 my head if you look very closely, they said just the opposite. They said life is an extremely

00:35:50 improbable phenomenon. It's something that happened that arose by an extraordinary combination of

00:35:58 circumstances, in fact, such an improbable combination of circumstances that it could

00:36:04 very well never have arisen anywhere in the universe. In fact, it's almost a cosmic joke.

00:36:12 In fact, they use that term, and Jacques Monod, in this beautiful book, Chance and Necessity,

00:36:19 Le Hasard et la Nécessité, just to show you that I can speak French too, Jacques Monod has

00:36:28 written, the universe was not pregnant with life, so that was the point.

00:36:41 The argument is the following. Highly improbable events occur all the time without our even being

00:36:48 aware, and to give you an example, probably not many of you play bridge. I like bridge,

00:36:54 but anyway, bridge is a card game that is played with a deck of 52 cards, and four people play it,

00:37:01 so the cards are shuffled and dealt around the table so that each player gets 13 cards,

00:37:07 and the deck contains 13 spades, 13 hearts, diamonds, and clubs. Now, suppose that you

00:37:16 sit at a bridge table, the cards are dealt, and you look at your cards, and there you have

00:37:22 13 spades, and the next player looks at his cards, and he finds 13 hearts, and the other one finds

00:37:31 13 diamonds, and of course, the last one gets the 13 clubs, there's nothing else left.

00:37:37 Okay, so it's pandemonium, you know, they sort of shout and say, we've never seen anything like this,

00:37:44 they call conference presses, and television, and the media, the newspapers are filled, some,

00:37:53 I mean, the 13 spades, hearts, clubs, diamonds were dealt, and they would be right. This is indeed

00:38:02 an extraordinary event. It's a highly improbable event. I calculated the probability, and I'll tell

00:38:08 you, it's one in 50 billion, billion, billion, which guarantees that if it ever happened, it will

00:38:19 never happen again, or almost. So indeed, they witnessed what you might say almost a miracle,

00:38:26 something that at least has a very, very low probability of taking place. That's very true.

00:38:34 But this is true of any other bridge hand. That is, every time a hand is dealt,

00:38:42 it's probably never been dealt before, and may never be dealt in a foreseeable future.

00:38:50 Every bridge hand is unique. Every bridge hand has a probability of 50 billion, one in 50 billion,

00:38:57 billion, billion. But bridge players don't always exclaim whenever they take their hands, oh,

00:39:08 I just witnessed a miracle.

00:39:13 So this is what happened with life, says Jacques Monod, says Francis Crick. In fact, in his book,

00:39:21 Life itself, he actually uses the card analogy. Life is just one of these highly improbable events.

00:39:31 Maybe, you know, it could very well happen that bridge could be played for billions of years,

00:39:36 and never anybody would see this particular kind of distribution. Same thing with life.

00:39:42 All right. This argument is impeccable, as long as it applies to a single event.

00:39:56 But we've just seen that life arose by the succession of a very large number of successive

00:40:04 steps. So we're not dealing with 13 spades, hearts, diamonds, and clubs once, but twice,

00:40:15 ten times, a hundred times, a million times in succession. And that, my dear friends, is

00:40:23 impossible. Unless, unless the cards are doctored, the deck is doctored. And in a particular case of

00:40:35 the origin of life, a doctored desk is a universe pregnant with life. It is a matter that has

00:40:43 properties such that, given the opportunity, life will arise, which leads to the conclusion,

00:40:50 which is not this, don't start applauding yet, it's not the conclusion to my talk, but

00:40:58 it leads to the conclusion that life must obligatorily arise wherever conditions are

00:41:05 suitable. The universe was pregnant with life, contrary to what Jacques Manon has said.

00:41:12 All right. Now, there remains one problem. Granting that maybe I'm right, and that life is

00:41:23 indeed a deterministic phenomenon, there still remains the possibility that the conditions

00:41:29 that prevailed on Earth four billion years ago, the chemistry, the physics, the temperature, whatnot,

00:41:36 are highly improbable. In other words, that the opportunity for life to arise in the universe,

00:41:46 a universe pregnant with life, are almost zero, and that, in fact, life did arise through a cosmic

00:41:53 accident, a cosmic joke, not because life is not, is itself improbable, but because the conditions

00:42:00 needed for life to arise are improbable. And here, I have no answer, because this is not my field.

00:42:08 I ask the question to planetologists, cosmologists, the geochemists, the experts who have looked into

00:42:16 this problem, because there is a great interest in the search for extraterrestrial intelligence,

00:42:22 and of course, if there is intelligence out there, there must be life, at least, I suppose so.

00:42:28 And so they've made estimates. Unfortunately, so far, there is no answer, because we don't know,

00:42:37 we have no evidence of there being life elsewhere, or no evidence of the conditions elsewhere being

00:42:43 suitable for life. But the consensus, or the almost, I would say, the consensus of these experts

00:42:51 is that our planet is not so terribly extraordinary, and that the history of planet Earth,

00:42:59 the physical, chemical history, probably is being repeated, or has been repeated, or will be

00:43:05 repeated, in many, many other places in the world. An estimate of one million planets per, or life,

00:43:13 not life-bearing, but planets capable of bearing life, one million per galaxy, has been suggested

00:43:20 as a reasonable, acceptable, well, even if that is off by a number of orders of magnitude, that

00:43:26 still implies millions, billions, maybe trillions of living planets. So the message is, tonight you,

00:43:38 even earlier, you look around, and anywhere you look in this vastness of the universe,

00:43:44 there's some life out there. Is it thinking life? Is it conscious life? Well, again, there is no

00:43:54 answer, and I really have no time to go into that, because it can be argued, but there really, again,

00:44:01 there are two ways of looking at the tree of life. Here, I hope you can see, well you can't see it

00:44:10 all, so just look at the trunk below first, you see it's a beautiful drawing, it was made for my,

00:44:17 now I can plug my book, it's going out in a few weeks time, it's called Vital Dust, and anybody

00:44:23 who wants to know the publisher, I'll tell you, but this was drawn by Ippi Patterson, who's a

00:44:30 very nice artist, who's the wife of my, not the publisher, but the man who was my publisher before,

00:44:38 and you look at this tree, this is the tree of life, and you see this wonderful canopy with

00:44:47 millions of twigs, and leaves, and so on. What you see is biodiversity, and what strikes you

00:44:58 is the extraordinary diversity of life on earth, the bacteria, and the protists, and the plants,

00:45:04 the fungi, the animals, and so many different species, and so many varieties, and so on,

00:45:09 so many that are now extinct, and that lived before, I mean there's millions of different

00:45:14 species that make up the whole universe, and what, not the universe, the biosphere, and what

00:45:22 strikes us, and strikes many biologists, many of the leaders of evolutionary biology,

00:45:29 is contingency, that in many respects, if you should start all over again, you would not get

00:45:37 exactly the same canopy, because so many factors of chance, and so on, are involved in these little

00:45:44 bifurcations that give you more and more different twigs elsewhere, everywhere, and that therefore

00:45:50 there is a lot of chance, and contingency that is involved in shaping this tree, and

00:45:59 I don't know whether you can see, there on top, there's a little red dot, a little red part,

00:46:07 that's you and me, that's in this tree, the human species, a very, very small, and you might say

00:46:16 Stephen Jay Gould, for instance, who's a well-known paleontologist, and science writer

00:46:21 of the United States, from Harvard, and he says, well, contingency is everything, and he says,

00:46:28 if we start all over again, we would not be here, and he, in fact, he says, just an afterthought,

00:46:36 that's talking about the human species, just an afterthought, a bauble on the Christmas tree of

00:46:42 life. Now, this is the last, because I think I'm using more time than you gave me, trim this tree

00:46:55 of all its diversity, and here is what you see, the trunk, and there you see this rise

00:47:09 toward increasing complexity, of the bacteria, the protists, the primitive eukaryotes, and then

00:47:16 you go over the fungi, the plants, the animals, and the humans, and 10 million years from now,

00:47:22 there will be another tree, maybe here, or maybe here, with more advanced than we are, I think the

00:47:27 mistake we make is to believe that we are the final product of evolution, that would be very sad,

00:47:34 because I think there is still room for improvement, but anyway, and I don't have the

00:47:42 time to go into the details, I think I can defend on scientific grounds, and not on the ideological

00:47:48 grounds, the theory that there is within, I mean, that allowing for the interplay of chance and

00:47:56 necessity all through this evolution, that there are reasons for believing that there are constraints

00:48:03 that will force life to develop toward increasing complexity, so there are really two

00:48:13 ways of, say, deriving a sort of philosophical attitude from scientific data, Jacques Monod

00:48:22 derived a sort of rather despairing kind of philosophy, stoically despairing, or despairingly

00:48:31 stoical philosophy of life, now let, I'm going to try to tell you, or to

00:48:41 recite the last sentence of his book, and I'll do it in French, and I'll translate it later,

00:48:46 although this is a bilingual country, of course, this is the last sentence of his book,

00:48:54 l'homme sait enfin qu'il est seul dans l'immensité indifférente de l'univers

00:49:01 d'où il a émergé par hasard, pas plus que son destin, son devoir n'est écrit nulle part, I translate,

00:49:10 man finally knows, I don't know exactly how he knows it, but anyway, man, for humans, finally knows

00:49:17 that he is alone in an indifferent universe out of which he emerged by chance, no more than his

00:49:34 destiny, his duty is written anywhere, it's not written anywhere, Stephen Weinberg,

00:49:42 famous physicist, in his book, the last, the first three minutes, says something quite similar,

00:49:49 I forget, I can't quite quote him, but one thing that he says is, the more the universe appears

00:49:54 understandable, the more pointless it appears, well, they derived this kind of philosophy from

00:50:02 the kind of scientific view that I have told you about, and I think the same data,

00:50:14 the same information can be looked at in the different ways, the way I've looked at it,

00:50:19 and therefore I think I'm entitled, if they are entitled to derive despair and absurdity from

00:50:27 the data, I think my interpretation of the data leads to a more hopeful and a more

00:50:34 meaningful attitude to the universe, and I would like to leave you with this message, thank you.

00:51:27 My name is Michael Charles, and I'm Dean of the Faculty of Applied Science and Engineering here

00:51:43 at the University of Toronto, and it's my great pleasure to introduce Dr. Max Perutz.

00:51:51 When I identified myself to Dr. Perutz yesterday, as the one that would introduce him today,

00:51:58 his immediate response was, well, please keep your introduction short, because I have a lot to say.

00:52:07 Dr. Perutz, I'll do my best to oblige.

00:52:12 Proteins perform a variety of different functions in the body,

00:52:16 for example, hemoglobin transports oxygen from the lungs to the tissues,

00:52:21 and carbon dioxide from the tissues to the lungs.

00:52:25 The functions of specific molecules are related to their structure,

00:52:29 but determination of such is a major problem, especially in the case of large proteins.

00:52:36 Nevertheless, knowledge of their structure is basic to the understanding of protein action,

00:52:41 as well as to the possible design of other proteins with useful properties.

00:52:47 Max Perutz, together with his colleague John C. Kendrew, was awarded the Nobel Prize for

00:52:53 Chemistry in 1962 for his use of X-ray diffraction techniques to solve the very

00:53:00 complex structures of protein molecules, and specifically, hemoglobin.

00:53:05 Originally from Vienna, Dr. Perutz has spent most of his scientific career in England.

00:53:12 He did his graduate work in the Cavendish Laboratory in Cambridge, studying the then

00:53:19 new technique of X-ray diffraction for structure elucidation.

00:53:25 As a graduate student in 1937, he started work on the first X-ray diffraction technique,

00:53:32 and as a graduate student in 1937, he started work on hemoglobin.

00:53:38 It was 19 years later, while director of the Unit for Molecular Biology,

00:53:44 that he finally solved its structure.

00:53:48 Along the way, he developed techniques and approaches that many others would apply later

00:53:52 to other proteins. The recognition of the importance of this work was immediate.

00:53:59 The Nobel Prize in 1962. The consequences are far-reaching. Today, taken together with

00:54:07 site-directed mutagenesis, for which Michael Smith won the Nobel Prize in 1993,

00:54:14 and with advances in computing, the crystal structure of a protein serves as a starting

00:54:20 point in understanding its mechanism of action, as well as in designing inhibitors and mimics.

00:54:27 Max Perutz has been honored with the Royal and Copley Medals of the Royal Society,

00:54:32 and with the Order of Merit by Her Majesty the Queen.

00:54:36 Dr. Perutz continues at the Medical Research Council's Laboratory of Molecular Biology in Cambridge.

00:54:44 He's more concerned now with the effect of science on society, and has expressed his

00:54:49 views in a book entitled, Is Science Necessary?

00:54:54 Max Perutz, please address us on the topic, living molecules.

00:55:02 Dr. Charles, thank you very much for your introduction, but may I correct one little

00:55:24 point? You said the structure of hemoglobin came out 19 years after I started my work on my PhD

00:55:31 thesis in 1937. Actually, it was 22 years, and if my examiners had insisted on a solution of

00:55:42 the structure, I would have had to remain a graduate student for 22 years. Now today,

00:55:50 I want to tell you about one of my heroes. This was the man who discovered what genes are made of.

00:56:00 He was born in Halifax, Nova Scotia, 130 years ago. His father was a poor English Baptist minister

00:56:10 who had emigrated from England with his wife. Now when Oswald was 10, his father became pastor

00:56:20 at a Baptist church in a poor quarter of New York, and my first slide shows the boy.

00:56:29 So may I have the first slide, please? And perhaps the lights down a bit, because they make it hard

00:56:36 to see for people. So yes, that's the family, Avery, you see, and they are really solemn Victorians.

00:56:52 You wondered whether they ever smiled, but look, there's a sort of little mischievous glint on the face

00:57:00 of Oswald Avery, which shows that there was some talent in him.

00:57:16 Now, at first, Oswald wanted to become a minister like his father, but after taking

00:57:24 his bachelor's degree, he changed his mind and decided to become a doctor to read medicine.

00:57:30 Now, the medical students here will be interested to know that at that time,

00:57:34 he didn't have to know any science, whatever. He just started his medical career trained in

00:57:44 literature and the Bible and such like. So Oswald became a doctor, but medical practice didn't

00:57:53 satisfy him. He turned to bacteriology and to research, and aged 36, he was appointed bacteriologist

00:58:02 at the hospital of the Rockefeller Institute for Medical Research in New York, the best of its kind.

00:58:10 Now, at that time, pneumonia was a common and a deadly disease. About a third of the people who

00:58:18 contracted it died from it, including Avery's mother. In 1881, Pasteur discovered that it was

00:58:26 caused by a bacterium which he called the pneumococcus. Now, Avery wondered why did the

00:58:36 pneumococcus kill some people and leave others alive, and devoted his entire life to the solution

00:58:46 of this problem. His first discovery was actually made by his collaborator, Doshes, who found that

00:58:55 the blood and the urine of the moribund patients contained a soluble substance which is not

00:59:04 normally there and which was not present in the blood of the urine of the patients who recovered,

00:59:11 and they isolated this substance, but neither of them were chemists, and they misidentified it as a

00:59:18 protein, and it wasn't until years later when a very good chemist, Michael Heidelberger, came to

00:59:23 join them that he showed that it was a sugar-like substance, what we call a polysaccharide, that it

00:59:31 was made of chains of sugar-like molecules. But what was the significance of it? That

00:59:43 became clear through the discovery of Fred Griffiths, a bacteriologist at the laboratory

00:59:50 of the Ministry of Health in London who would have become famous if he had not been killed

00:59:56 by a German bomb in 1940. Now, Griffiths discovered that the pneumococci were of two types.

01:00:05 May I have the next slide now, please?

01:00:09 Dimitri, you see on this slide here, you see that there were these little ones which were naked,

01:00:19 and these big ones which were covered by a sort of mucus, slimy shell, and now it turned out

01:00:30 that this slimy cell was made of the same sugary substance that Doshes and Avery had found in the

01:00:39 blood and the urine of these infected patients. So, after this, Avery kept on talking about

01:00:46 sugar-coated bacteria, but he tried to make a vaccine of the sugar coating, but it didn't work,

01:00:54 and he didn't really get much further until another extraordinary experiment was done by

01:01:02 Fred Griffiths in London. He did an experiment which every sane person would have told him was

01:01:09 useless and absolutely crazy. Now, let me tell you what he did. He infected mice with a mixture

01:01:18 of the live, rough bacteria and of the dead, smooth bacteria which he had killed by boiling.

01:01:25 He made quite sure that they were all dead because he tried to culture them and they wouldn't grow.

01:01:30 So, he injected mice with a mixture of these two kinds of bacteria, and a couple of days later,

01:01:39 all the mice were dead, and they were full of this virulent, smooth bacteria. So, what had happened?

01:01:51 The dead, smooth bacteria had transformed the live, rough ones into smooth ones.

01:01:59 They had induced a heritable change in the rough bacteria, an extraordinary, inexplicable thing,

01:02:06 unbelievable. In fact, very few believed it, and Avery himself didn't believe it,

01:02:12 and wouldn't work of it, but then one of his collaborators took advantage of his

01:02:17 being at home sick, and while Avery was away, he repeated the experiment of Griffiths,

01:02:24 found that it worked, and found that the mice were unnecessary because you could do the same

01:02:29 thing by growing this bacteria in a broth, that is, you grew the rough bacteria in a broth

01:02:36 together with killed, smooth ones, and that would transform the culture into smooth ones.

01:02:43 So, after this, Avery was convinced, and he was determined to find out what the transformation

01:02:51 was due to. You see, he argued it must be due to a single substance, but how to find it?

01:02:57 You see, as you heard from Professor de Duve, a bacterium can contain thousands of different

01:03:07 proteins, thousands of different substances. How were you going to find the one that produced this

01:03:12 transformation? Well, one obvious candidate was this mucus shell itself, but they found, of course,

01:03:21 that it was inactive, but then they discovered that there was at least a way of breaking the

01:03:30 bacteria open so that they spilled out what was inside them, and then you could have a look,

01:03:36 and they did an experiment, which I now want to show you and repeat.

01:03:42 So, let's see, where have I got my, oh, yes, here, okay. So, you see here, it's a very simple

01:03:52 experiment. Here, I have a bottle of distilled water, and I'm going to measure out 300

01:04:03 cubic centimeters of this, 300 milliliters, like so, and put it in this beaker,

01:04:18 and then here, I have a bottle of deadly bacteria,

01:04:23 and I'm going to spill these into the water here, so a bit more, I think.

01:04:42 So, we'll stir them up a bit.

01:04:46 But that doesn't give you a sufficiently smooth suspension, usually, so I'm going to

01:05:02 pour it into here. You see, I've got this kitchen blender. Now, the one thing,

01:05:11 you have to put a lid on it, otherwise it will spill. Now, gosh, this is all automated.

01:05:25 So, let's turn it on.

01:05:30 So, that should have made it smooth enough, you see, and now,

01:05:36 and so, we just have a smooth suspension, you see, now, and now, Avery and his colleagues

01:05:45 actually added to this suspension of bacteria deoxycholate, which is essentially bile juice,

01:05:54 but that was before the invention of detergents, and now, you see, we can just take some

01:06:01 kitchen detergent and get the same result. So,

01:06:11 we'll stir it up a bit, and you see, as you stir it, it gets more viscous, so I can

01:06:24 stir it for a while.

01:06:26 You see, I have to stir it for a while to make sure that I break up all the bacterial walls.

01:06:44 So, I think that should do it, yes, and now, I add to it about twice the volume of alcohol.

01:06:57 So, I've got that here, ethanol, so that will be 600 milliliters.

01:07:16 All right,

01:07:21 and now, look what's come out. Do you see this, this white fibrous stuff,

01:07:34 the sort of, you know, I can actually,

01:07:40 so now,

01:07:56 McCarthy and Avery dissolved a little of this in water and added it to a culture of this

01:08:05 rough bacteria, and would you believe it, it transformed it into smooth ones,

01:08:12 and when they made a chemical analysis to find out what it is, they found it was made, it was DNA.

01:08:20 Astonishing and totally unexpected result, but then, of course, the worry started. Is it really

01:08:26 pure DNA? Could it not have impurities in it of the other nucleic acid, ribonucleic acid,

01:08:35 or could it have an impurity of proteins that actually caused this astonishing transformation?

01:08:41 So, they used enzymes which, in turn, split any of these substances, so they added

01:08:52 the enzymes from the stomach, you know, pepsin and trypsin and chymotrypsin, which split proteins,

01:08:59 and it had no effect, and then they were lucky, really, because at Rockefeller Institute,

01:09:05 there were the pioneers, Nothrop and Kunitz, who had isolated and purified these enzymes for the

01:09:12 first time so that they could get, Avery could get them from these people, and again, there was,

01:09:21 Kunitz himself had purified an enzyme that splits ribonucleic acid for the first time,

01:09:29 and they could get it from him, so they were very lucky being in that environment,

01:09:33 but none of these enzymes had any effect, but so now they wanted an enzyme that splits DNA,

01:09:44 deoxyribonucleic acid, but that nobody had isolated themselves, and they had to isolate it

01:09:51 laboriously from animal intestine, and it took weeks or months to get a pure preparation of that

01:09:58 enzyme, which you can now buy at Sigma or any other of these firms by the gram,

01:10:04 and when they tried that, it completely inactivated the transforming activity.

01:10:10 Now, Avery, it was, what does it mean? I mean, nowadays we say, well, it's clear the DNA

01:10:22 was a gene that coded for the production of this mucous shell in the bacteria, but then this idea

01:10:30 was so revolutionary that Avery himself, who was extremely cautious and meticulous,

01:10:37 didn't want to accept it, and it took him months before he actually finally wrote up the paper

01:10:43 and published it in January 1944 in the Journal of Experimental Medicine in New York,

01:10:51 the journal which was read by medical people, but not, say, by chemists, and very little

01:10:57 read by biochemists, so the news didn't get around very much, and most people were skeptical,

01:11:03 and afterwards, years afterwards, people, yes, he was so cautious, he never even mentioned the

01:11:10 word gene in this paper, so that people afterwards, historians of science, wondered whether he was

01:11:16 actually himself had been aware that he'd isolated the gene, but Robert Olby, an English historian,

01:11:24 found a letter from the Australian biologist Macfarlane Burnett, written to his wife after a

01:11:34 visit to Avery's laboratory at Rockefeller, in which he writes, Avery has discovered a gene,

01:11:43 he has isolated a gene, so then, you know, from that letter, it's clear that Avery himself was

01:11:50 aware of it. Now, of course, Avery should have got the Nobel Prize for this, but you see,

01:12:00 you must imagine at that time, everybody had been convinced that genes are made of protein,

01:12:07 and the discovery that it was made of DNA, which was regarded as a chemically dull substance,

01:12:15 an unreactive molecule, a molecule that really provided the scaffolding for the chromosomes,

01:12:22 while the genes on the chromosomes were likely to be made of protein, the idea was so new that it

01:12:28 was unacceptable, and I think the Swedes, especially, had their eyes fixed on protein,

01:12:34 and they never gave him this very well-deserved honor, so Avery, who made the discovery at the

01:12:41 very end of his career, when he was ready to retire, died without ever receiving the prize,

01:12:48 but the Royal Society of London, to their credit, gave him their highest honor, the Copley Medal.

01:12:57 So, there was, among the small band who believed Avery, was a young American,

01:13:08 and, can I have the next slide now? One day, oh yes, yes, I wanted to show you, this was Avery,

01:13:18 can we have the lights a bit away from the screen, you know, it's hard to see, yes, that's better,

01:13:24 that was Avery at the later part of his career, he was a bachelor, a meticulous scientist,

01:13:33 a man, he never went on lecture tours, he wrote no books, he took out no patents,

01:13:39 he lived entirely for his research, and he hated traveling, he didn't even go to London,

01:13:51 when they made him a foreign member of the Royal Society and gave him the Copley Medal.

01:13:58 Now, can we have the next slide, please? So, one day in 1951, the door of my office at the

01:14:08 physics lab in Cambridge opened, and a head with a crew cut and bulging eyes popped through it,

01:14:19 and asked without as much as saying, hello, can I come and work here? And,

01:14:26 luckily, I said yes, because that was Jim Watson, who was the first lecturer yesterday, and

01:14:37 he, in his book, The Double Helix, he describes himself as a kind of western cowboy coming into

01:14:49 Argentine English circles at Cambridge, but in fact, he had an electrifying effect on us,

01:14:56 because John Kendrew and Francis Crick and Hugh Huxley and I, who formed this small group of

01:15:03 people working on the structure of large biological molecules, we all thought that the

01:15:08 secret of life was in the structure of proteins, and that's what we put all our energies in. And

01:15:15 Jim persuaded Francis Crick, whose thoughts were already moving in that direction, that the first

01:15:23 and more fundamental problem, even, was the structure of DNA, and that this is what they

01:15:28 should go for. Now, about not quite two years later, Crick and Francis Crick and Jim Watson,

01:15:39 one Monday morning, called me into their room to show me their newly constructed model of DNA,

01:15:47 and this is, can I have the next slide now? So, I think, let's have the next one and then go back

01:15:58 to this. So, there they are, you know, Jim on the left, Francis on the right, and there's this model

01:16:07 looking not like this elegant thing there, but made from brass rods and thin plates, screwed

01:16:21 with retort clamps to a large sort of retort stand, which reached from the floor to the ceiling.

01:16:31 An extraordinary edifice, but it looked dead right from the very start. Now, let's go back

01:16:39 one slide and let me explain to you a bit about the chemistry, which Michael Smith

01:16:48 already introduced. You see, DNA is a long chain, and really a rather simple one, because

01:16:57 the main chain consists of an alternation of phosphates, so that stands for phosphorus,

01:17:04 oxygen, oxygen, linked to a sugar ring called deoxyribose. So, it goes phosphate, sugar,

01:17:14 phosphate, sugar, phosphate, sugar, and so on, and to each of the sugars is attached what we call a

01:17:21 base, that is a ring of carbons and nitrogen. So, this is carbon, nitrogen, carbon, nitrogen,

01:17:28 carbon, nitrogen, and so on, and these bases are, as Mike has already said, there are only four kinds.

01:17:38 You see, there's adenine and cytosine and guanine and thymine. So, this is why people thought DNA

01:17:49 was such a dull molecule. Now, Chagas discovered, again as Michael told you, when he analyzed

01:18:01 DNAs from various biological tissues, he found his astonishment that the ratios of cytosine to guanine

01:18:13 and of adenine to thymine were always one to one. He published this in an obscure Swiss journal,

01:18:20 Experiencia, which none of us had ever read, and it was only because he was friendly with my colleague,

01:18:27 Kendrew, who invited Chagas to dinner together with Watson and Crick when Chagas visited Cambridge,

01:18:34 that Watson and Crick got to hear of this result, which they would never have otherwise, but you see

01:18:41 it inspired Watson to take the crucial step. So, let me now, I brought these models,

01:18:58 and let me now show you how this works,

01:19:06 and what Jim discovered.

01:19:18 Models always fall to pieces in the wrong places, just the way you don't want them, but okay, now.

01:19:27 Right, so you see I've got these models now, where the blue balls signify nitrogen, the black ones

01:19:36 carbon, the red ones oxygen, and the white ones hydrogen, and so this is guanine, and if you like,

01:19:49 you can say that it has two prestids here, male prestids, looking for a partner, and this is

01:19:59 cytosine, which is another of these prestids here, they are hydrogens, and these two slots of

01:20:09 prestids fit together like that, this you see, so that cytosine can pair with guanine, but it can't

01:20:23 pair with thymine, because the prestids are in the wrong places, and similarly you see adenine,

01:20:37 which we have here, can only pair with thymine, in the meantime this has dropped off, right,

01:20:51 so, where's thymine, here, yes, right, so it can only pair with thymine like this, and not with the other,

01:21:08 so Watson and Crick then postulated that in the structure of DNA,

01:21:17 these two bases must always be paired by forming hydrogen bonds, now Crick argued that DNA must be

01:21:28 a helix, this was actually based on an idea of Pauling, Pauling argued that in a long chain

01:21:35 molecule, where each of the individual building blocks are the same, the surrounds of all the

01:21:43 building blocks must be equivalent, and this is possible only in a helix, so Crick knew this,

01:21:51 and so they postulated it must be a helix, and then on the basis of one of Rosalind Franklin's

01:21:58 results, Crick argued that it must be, there must be two chains, and the two chains must run in

01:22:07 opposite directions, actually there was great argument, would there be two chains linked

01:22:14 together, or three chains linked together, and Watson lodged with a French lady who kept a

01:22:31 boarding house where there were a lot of girls, you see, and she saw Watson walking up and down

01:22:41 muttering to himself, there must be two, there must be two, and of course she thought this referred to

01:22:47 some of his relationships with the girls, but in fact, you see, he argued that for genetic reasons,

01:22:54 there must be two chains in the molecule of DNA, so may I have the next slide now please, so,

01:23:03 the next one, that's one, yes, yes, so this, you see, is a simple replica of the model they built,

01:23:13 and in which you see the double helix, you see there the two chains winding around each other,

01:23:21 and here you see the sugar, the phosphate, sugar phosphate and so on, and they are the basis,

01:23:29 so if you like, you can look at this as a spiral staircase, in which the basis are the steps and the

01:23:38 phosphate sugar chain, the banisters, so if you look at the model here,

01:23:43 in this, you can't, of course, see the individual atoms so well in this, but this is

01:23:49 when you, what it looks like when you give the atoms their real sizes, so these are all the

01:23:55 oxygens of the phosphate, which carry negative charges, and are directed outside towards the

01:24:01 water, which can, water molecules can put these charges, and you see inside are the bases,

01:24:11 which are water repellent, and which are linked together in pairs, and now,

01:24:17 you see, the miraculous thing about this discovery, which quite unexpected to Watson

01:24:25 and Crick, as well as to all of us around, was that this structure immediately gave away the method

01:24:32 of replication of the genetic information, or the nature of the genetic information, because it was

01:24:38 now clear that if this is the gene, then the only information which the gene can carry is the

01:24:45 sequence of these different, four different bases along the length of the chain, and if the bases

01:24:53 are paired in this way, then there was a simple way in which the genetic information could replicate

01:25:02 itself. May I have the next slide now, please? So, there it is, you see the bases I've just

01:25:08 shown by letters, A for adenine, et cetera, so they are A and T and called C and G, and so here

01:25:18 you would see the parent double helix, which now separates into two separate chains, each of them

01:25:26 becoming a template for the formation of a new double helix, in where G is always paired with

01:25:36 C and A with T, so that from this parent helix you generate two double helixes with the same

01:25:48 sequence of DNA. Well, Mike Smith told you of the enormous length of DNA in a single human

01:25:56 germ cell, a meter containing 5,000 million such base pairs. The fantastic thing is that when

01:26:07 every time a cell divides, this whole amount of information equivalent, so I said 3,000,

01:26:14 it's 5,000, 3,000 million, I beg your pardon, 3,000 million, so every time a cell divides,

01:26:21 this enormous amount of information equivalent to a library of 5,000 volumes

01:26:27 is copied with the probability of only a single misprint.

01:26:34 No printer could possibly do this, and this is because of an elaborate proof reading mechanism

01:26:44 which exists. Now, so what does it do? The DNA is chemically inert, it has only a single function,

01:26:54 and that is to code for the sequence of amino acids in proteins. Proteins are the workhorses

01:27:01 of the living cell. All chemical reactions in living cells are catalyzed, that is, speeded up

01:27:08 by proteins, and there's a special protein for each chemical reaction, so that you contain,

01:27:15 each contain something between 10,000, perhaps 100,000 different proteins, and each coded for

01:27:25 by a separate gene, and each having its specific function. So the proteins are also made of long

01:27:34 chains, but of long chains of amino acids, and I've actually brought you some models of amino acids

01:27:42 to make this more vivid. So here you see you have one of them, and the characteristic feature that

01:27:52 is common to them all is this part here. You have hydrogen, oxygen, oxygen, carbon, carbon, nitrogen,

01:28:01 hydrogen, hydrogen. So, and this has then two carbons, three carbons, and another two oxygens.

01:28:09 That is, it has an acid group here. It's called glutamic acid, and there you have another amino

01:28:16 acid. You see, this again has got the same nitrogen, carbon, carbon, oxygen, oxygen as the first one,

01:28:23 but then attached to this carbon is another group, a benzene-like ring with an oxygen here.

01:28:30 It's called a phenolic ring, and that's the amino acid tyrosine, and there you have a third one,

01:28:37 and again you see the same grouping at the bottom, and then attached is a carbon, and a cipher atom,

01:28:46 and a hydrogen. Now, these link together in a very simple way. Each amino acid loses a

01:29:00 oxygen and a hydrogen, and the next amino acid loses a hydrogen from this nitrogen,

01:29:11 if I can pull it off, yes, and then the two link together like so, you see. So now we have two

01:29:21 amino acids linked together, but that still leaves this grouping here at one end, the other group at

01:29:30 the other end, so this can combine with another amino acid. So if I pull this oxygen off, which

01:29:37 has lost its hydrogen, and then pull the hydrogen off this nitrogen here,

01:29:55 like so, so I've pulled this hydrogen off, and push it in here.

01:30:00 All right, now, let's go in.

01:30:10 Oh yes, okay, so you see now I've linked these three amino acids together, but if you again look

01:30:18 at these things as press studs, you see it still has a male press stud at one end and a female one

01:30:23 at the other end, so it can link up to more and more amino acids, and people have now discovered

01:30:32 proteins which contain thousands of amino acids in a single chain. One of these is called

01:30:38 titan, appropriately, it is an amino acid in muscle, and now the next kind of astonishing thing

01:30:48 is that you see, as Mike Smith has shown you, the unique codes for the sequence of amino acids,

01:31:00 there's these long chains that are synthesized in the cell, and once synthesized, they hold up

01:31:06 spontaneously to a particular shape, which then determines their biological function. So to give

01:31:13 you an idea of what these things look like, I'm now going to show you a movie, and the movie is of

01:31:20 my pet molecule, hemoglobin, so can you turn the slide projector off, please, yes, and can you turn

01:31:29 the lights right off, and also all the lights, please, can you turn these down, right, so there

01:31:38 you have the hemoglobin molecule, and what it shows is just the main chain with all the other

01:31:44 atoms, and in the chain, as you see, these red molecules, there are the hemes, which I'll show you a

01:31:52 model of in a moment, which link the oxygen. Now, so hemoglobin carries oxygen from the lungs to the

01:32:05 tissues, and releases it, now every time it takes up oxygen and releases it, it changes its structure

01:32:17 in the way that you see here, it's made of 44 protein chains, and they rotate relative to each

01:32:27 other every time oxygen is taken up and released, the way you see here, so you see it's not an

01:32:36 oxygen tank, it's a molecular mechanism, it's a breathing molecule, and it's immensely complex, it

01:32:47 contains 10,000 atoms.

01:32:49 So, you see, this is the pigment, which makes our blood

01:33:19 red, the hemine, and there's the iron atom, which is linked to the amino acid histidine by a strong

01:33:28 chemical bond, and now you see what happens when the oxygen combines with the iron, so when the oxygen

01:33:42 combines with the iron, the iron pops into the plane of this ring, and this represents the oxygen, so

01:33:50 there would be one oxygen atom here, the other oxygen atom. So this is what happens at the heme, when oxygen

01:34:07 combines, you see, every time this combination takes place, the iron pops into the plane of the pigment,

01:34:16 and oxygen is released, it pops out again, and that transmits a force to the rest of the molecule, which

01:34:24 actuates that change of structure, which you saw in the early part of the film. Thank you, that's enough for the film.

01:34:38 Now, you see, this is the model of the heme, so this is the pigment that makes your blood red, so the ring of

01:34:48 carbons, carbons, carbons, four nitrogen atoms here, and an atom of iron in the middle, and the oxygen combines,

01:34:58 there's an oxygen molecule, you see, and it combines with the iron atom like so, but, so why do we have to have

01:35:08 this big molecule with 10,000 atoms? Because the iron has to be ferrous, two valent, in the absence of the

01:35:18 protein, oxygen really oxidizes the iron to the trivalent, to the ferric state, and that reaction is irreversible,

01:35:28 it would be useless, but by keeping this molecule in the protein, the oxygen combines with the two valent,

01:35:38 with the ferrous iron, and the reaction is reversible, so that oxygen is taken up in the lungs, where it is

01:35:46 plentiful, and released in the tissues when it's scarce, and then by another elaborate mechanism, the hemoglobin

01:35:54 actually promotes the return transport of carbon dioxide from the tissues back to the blood, so this is wonderful,

01:36:03 great discovery, but is it any use? And for many years, I was doubtful whether my life's work on this problem

01:36:17 would actually produce any results of benefit to medicine, but recently my colleague, Yoshi Nagai,

01:36:29 has used Mike Smith's method to modify the gene for the hemoglobin molecule, so that it can actually be used as a

01:36:42 blood, as a substitute for blood for transfusion, so that instead of transfusing whole blood, where there's this terrible

01:36:52 danger of being infected with the AIDS, or the hepatitis, or goodness knows what other virus, you would have a sterile

01:36:59 solution of hemoglobin, which you could give patients in emergencies, and that is now in phase two clinical trial,

01:37:12 and so far the results look very hopeful. But what about all this business of protein engineering in general, I mean, has it really

01:37:26 cured anybody? Well, I'll show you, it actually has. One of the really terrible inherited diseases is called adenine deaminase

01:37:45 deficiency, so if we have adenine, where's my adenine, it's molecule, what have I done with it? Yes, there it is, so you see this

01:38:03 enzyme splits that nitrogen of the adenine ring, and this is an essential step in nucleic acid synthesis, so these children that have

01:38:20 inherited a fault in the gene for this enzyme, adenine deficiency, have no immune system, they're as badly off as patients with AIDS,

01:38:33 in having no defense against infective diseases, so as this is a really hopeless inherited illness, French Andersons and others in the

01:38:48 United States summoned up the courage to try and treat these people with a gene for the missing enzyme, so this is called somatic gene therapy

01:39:01 as opposed to germline gene therapy, which would be criminal in humans, somatic gene therapy, they're trying to introduce a gene into, in this case, a child,

01:39:16 and so I think the next slide shows the principle of French Andersons method, well we'll skip this now, yes, so you see he takes some, well initially he treated the baby

01:39:36 with just the enzyme, and that, you see this is ADA, stands for the adenine deaminase enzyme, and that helped a bit, but of course it's very short lived,

01:39:50 you have to inject that every few days, but now you see he took some bone marrow from this little girl and then infected the, yes, introduced the bone marrow

01:40:08 into a retroviral vector, so into a plasmid, which Mike Smith talked about, you see, by just the method he demonstrated earlier this afternoon, and then introduced this plasmid into a virus

01:40:25 from which he had removed the gene for the reproduction of the virus, and he then put this virus back in touch with the virus, yes, and so this is a contradiction, it doesn't work like that, he put the virus,

01:40:44 yes, I'm sorry, but I said it wrong, excuse me, he then infected the child's bone marrow with this virus, and cultured it, you see, hoping that the DNA would be freed, and that the gene for the enzyme would be multiplied,

01:41:05 and would actually be joined into the chromosome of the white blood cells in the bone marrow of the child, so essentially you see what he did, he infected the bone marrow cells of the child with this gene for the enzyme,

01:41:30 and then injected the bone marrow back into the child, and now the next slide shows you the result, you see, there is the adenine deaminase concentration in the blood of the child, which started with zero here,

01:41:51 you see, and the arrows indicate successive transplantations of the child's own bone marrow infected with this virus, you see, and after, on here are plotted days, so the whole length of this is 600 days,

01:42:13 and you see that after three, six, eight of these injections over the course of a year, there is a steady production of the enzyme by this child of about half the level of that in a normal carrier, which is enough, you see, to keep the child healthy,

01:42:38 and I think my last slide, the next one, actually shows French Anderson, here he is, you see, with the two little girls, whom he treated like this, who can now lead normal lives, they go to school, they can go skating, they can dance, they can do all sorts of things, so this is really a great success for somatic gene therapy.

01:43:02 Now, after this, let me read you my final message to this great meeting here.

01:43:13 To those who watch the signs of the times, it seems plain that the 21st century will see revolutions of thought and practice as great as those with the 16th witnessed.

01:43:29 Through what trials and sore contests the civilized world will have to pass in the course of this new reformation, who can tell?

01:43:37 But I verily believe that come what will, the part which Canada may play in the battle is a grand and noble one.

01:43:45 She may prove to the world that for one people at any rate, despotism and demagoguery are not the necessary alternatives of government, that freedom and order are not incompatible, that reverence is the handmaid of knowledge, that free discussion is the life of truth and of true unity in a nation.

01:44:05 Will Canada play this part that depends upon how you, the public, deal with science?

01:44:12 Cherish her, venerate her, follow her methods faithfully and implicitly in their application to all branches of human thought, and the future of this people will be greater than in the past.

01:44:24 Listen to those who would silence and crush her, and I fear our children will see the glory of Canada vanishing like Arthur in the mist.

01:44:34 Now what I read you today was the end of a lecture which T.H. Huxley gave in London 135 years ago, and all I did was to change the word England for Canada.

01:44:49 Thank you.

01:45:21 Ladies and gentlemen, it just remains for me to thank Dr. Perutz for his remarkable presentation in which, among other things, he's taken us into his laboratory.

01:45:35 This, ladies and gentlemen, is the concluding presentation by the nine Nobel laureates in the series on science and society.

01:45:51 Which helps inaugurate the John C. Polanyi Chair in Chemistry at the University of Toronto.

01:46:05 Thank you all so very much for coming.