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Dr. James D. Watson
Nobel Laureate/Co-discoverer, DNA structure; President, Cold Spring Harbor Laboratory
In conversation with Roy Eisenhardt, Common Wealth Club Board of Governors member
The important issue which I think is in front of society is understanding and using the genetic information present on DNA, deoxyribonucleic acid. I never visualized we’d ever see it. It seemed too grand of an objective 50 years ago. But now we have it. And I don’t fear its misuse; I fear its disuse. That is, we’ll have it but not really use it as much as possible, as we can, for human benefit.
It’s hard now in this 50 years after finding the double helix not to speak about 50 years ago, so I’ll do that and say something about the climate of what science was like back then. And then I’ll try and end with today. There won’t be much in between, you know, 50 years ago and now.
It was in Dublin, Ireland, just 60 years ago, that the Austrian-born theoretical physicist, Erwin Schrödinger, gave a series of lectures under the title, “What Is Life?” In them, he made three important points: firstly, why we grow to be human, as opposed to, say, a dog or a tiger, comes from information that is present in our chromosomes. Second, the genetic information must be encoded as part of a stable molecule held together by covalent bonds. And thirdly, every time one chromosome becomes two chromosomes, this genetic information must be almost exactly copied. Now happily for me, Schrödinger transformed these lectures into a neat little book published by Cambridge University Press. I read it early in 1946 when I was still 17, a third-year student at the University of Chicago. It changed me from wanting to be a naturalist like Charles Darwin to becoming a geneticist searching for the chemical essence of the gene.
Just before I fell under the spell of What is Life?, the chemical bombshell appeared that Schrödinger or no one else really had foreseen. The fact that the molecule which carries genetic information is DNA. This major discovery was made in New York at the Rockefeller Institute by Oswald Avery, Maclyn McCarty and Colin MacLeod. Their experiments, published in 1944, were almost foolproof. But most biologists took little notice of them. They remained wedded to the idea that proteins, being the most complex of biological molecules, should be the bearers of genetic information. In contrast, by the time I had my Ph.D. from Indiana University in 1950, I was virtually obsessive about DNA, being convinced that the elucidation of the 3-D structure was at that time the most important objective for biology. By then the canny Scott chemist Alexander Todd, working in Cambridge, England, put the resources of his large laboratory toward establishing the exact covalent structure of DNA. Until then, DNA structure was only incompletely known. It was known to have contained four nucleotides (A,G,T and C), to be a very long molecule containing many of each of these four nucleotides, but how they were linked together, the exact chemical bonds, were not known. Todd established a so-called 5-3 phosphodiester linkage that linked together all the nucleotides. DNA had a very regular structure at the level of its sugar phosphate backbone.
The second person to take seriously the Rockefeller results was the Austrian-born biochemist Erwin Chargaff, working at Columbia University. He reported in 1950 that the number of purine bases in DNA was very similar to the number of pyrimidines. Even more important, the purine adenine was similar in amounts to the pyrimidine thymine, while the purine guanine was similar in amounts to the pyrimidine cytosine.
An equally crucial piece of information came from the Nottingham lab of the British physical chemist John Gulland. He found the purine and pyrimidine bases were located with DNA molecules in a way that prevented key hydrogen atoms from popping on and off as they would be expected. None of these chemists went on from their original results to try and think what DNA looks like at the 3-D level. Searching for the 3-D structure of molecules was then done by the technique of X-ray crystallography, still then the province of physicists. Proceeding from X-ray diffraction diagrams to molecular structures, however, was then not straightforward, even for small molecules like amino acids. So it then took a lot of intellectual courage to say that you were going to try and solve the structure of proteins or the nucleic acids DNA or RNA.
Leading the post-war molecular crystallographic world was a tiny group of physicists and chemists at Cambridge University supported by the UK Medical Research Council. They worked at the Cavendish Laboratory under the patronage of its head Sir Lawrence Bragg, the 1912 inventor of X-ray crystallography. Francis Crick had been on his staff for two years, working on new methods to attack protein structure, when I came there in October 1951 to try and make myself a crystallographer. Soon the 35-year-old Francis and I had desks in the same office and had set ourselves the task of building 3-D molecular models of DNA.
The great American chemist at Caltech, Linus Pauling, six months before had used molecular model building to find the alpha helical’s confirmation of polypeptide chains. In doing so, he used very little X-ray crystallographic information, but at the same time got the right structure. So Francis and I thought, Why not extend this winning approach to DNA? Conceivably, sufficiently experimental information already existed that model building would get us the answer in the absence of any further X-ray structure analysis. By then we knew through Francis’ friend, Maurice Wilkins, who worked at King’s College London, that the diameter of the DNA molecule was likely too large for just a single DNA chain. Maurice thought several chains were likely twisted around each other to form the multi-chained helix.
Our first DNA model conceived in late November proved all too soon embarrassing. It was incompatible with recent X-ray data also obtained at King’s College by the Cambridge-trained physical chemist Rosalind Franklin. In our model, the sugar phosphate backbones formed a central core with the purine (A+G) and pyrimidine (T+C) bases facing outward. Rosalind told us that the backbone, not the bases, were on the outside.
We only returned to model building after Linus Pauling made his own move on DNA. In December 1952, he designed a three-chain structure which also placed the purine and pyrimidine bases on the outside. When his manuscript arrived in Cambridge, Francis and I read it with great disbelief. Instead of scooping the Cavendish Lab, Pauling had fallen on his face to proposing the chains be held together by hydrogen bonds between phosphate groups. In our minds, his structure defied the basic laws of chemistry. So Crick and I rushed over to Alex Todd’s chemical laboratory to let him read Pauling’s paper. He also decreed the Pauling model impossible.
By this time, Crick and I were much better prepared chemically to move forward. The essence of DNA had to lie in how two, not three, intertwined chains were held together by hydrogen bonds between centrally located bases. Initially, we were held back by the wrong textbook assignment of where the hydrogen atoms were on the bases guanine and thymine. Only a day was to pass between actually knowing their correct locations and our finding of the double helix on February 28, 1953. Until that day, we never thought we’d find the DNA structure by ourselves. We anticipated that help from the people at King’s would be needed before we would know what DNA looked like. To our relief, we soon learned that their new experimental data fit our model perfectly.
The double helix instantly revealed the answer to the two key dilemmas posed by Schrödinger: How do you store and how do you copy genetic information? Instantly we knew DNA genetic information must be carried by the order of the four bases – A, G, T and C – along with sugar phosphate background. So just the order of the bases gave the information. DNA information was encoded in a sort of digital-like way. In turn, copying involved separating the double helix’s two strands. The resulting single strands then serve as molds, as templates for the formation of second strands using the base pair rules. Opposite an A, you have to have a T; and opposite a G, you have to have a C.
Our resulting three manuscripts – Watson and Crick, Wilkins and Herbert Wilson, and Franklin and Ray Gosling – went off to Nature on April 2, appearing in print three weeks later on April 25. In our brief one-page manuscript, a single sentence said: “It has not escaped our notice that our proposed structure suggests a scheme for copying genetic information.” I then sillily wanted to say nothing about the copying mechanism; to me it was so obvious we didn’t have to say anything. I wanted to ape the British in understatement. But Crick said some people might think we were stupid and didn’t see what our structure meant. So after writing the first paper three weeks later, we wrote a much longer second paper called, “Genetical Implications of the Structure of DNA.” It came out in late May. (Few reprints of this one still exist, so it’s much more costly to buy from a rare book dealer than the first paper. I never kept any.)
The ten years that then followed showed how DNA sequence information is used by cells to make proteins the main molecular actors of cells. The two strands of the double helix temporarily separate to let single DNA chains be copied into RNA chains of complementary sequence, using the same base pairing rules involved in copying DNA. The resulting single RNA chains provide the information for ordering amino acids. Successive groups of three bases along RNA chains specify successive amino acids along polypeptide chains.
The specific group of three bases which specified the 20 different amino acids was called the genetic code. It is universally used for all forms of life from bacteria to plants and animals. During protein synthesis, very large RNA-containing particles known as ribosomes function as molecular factories which spin out polypeptide chains in an assembly-line fashion. When we first worked on ribosomes, we thought their more than 100,000 atoms would preclude our ever knowing their precise structure at the 3-D level. Happily, a long succession of technical advances in X-ray crystallography recently let us see what they actually look like.
The first scientist to so visualize the ribosome in its entirety was Harry Noller at his lab in Santa Cruz. There he observed the complete absence of protein molecules along the ribosome site where peptide bonds are made. It’s atoms on RNA chains, not protein chains, that enzymatically promote the linking together of amino acids into polypeptide chains. So before our current DNA-dominated world came into existence, there must have existed a simpler RNA world. How this RNA world arose we shall never completely know. No surveillance cameras could witness how the first molecules of life came into existence several billion years ago. Earth’s chemical composition, moreover, has been constantly evolving.
What carbon- and phosphorus-containing molecules existed when the RNA world started will always be a mystery. So there is no way to disprove the creationist belief that life’s origin demands the assistance of some God-like force. I don’t believe this, nor do almost all my fellow biologists. As scientists, we only concern ourselves with ideas that can be experimentally tested. Truths only come from observations and experiments, not from revelations. Our principal concern now is to study life as it exists after roughly three billion years of Darwinian evolution. In doing so, we benefit from two major experimental advances of the 1970s.
The first was the working out of recombinant DNA procedures, which cut and paste DNA molecules. This powerful technology devised just 30 years ago, by Herb Boyer here in San Francisco and Stanley Cohen at Stanford, lets specific genes be isolated. Soon afterwards, Wally Gilbert at Harvard and Fred Sanger at Cambridge University devised rapid procedures to read DNA messages. Until these DNA sequencing technologies became available in 1975, only cells, not humans, could read DNA messages.
By 1988, improvements in DNA sequencing technology allowed the starting of the Human Genome Project. Its goal was to sequence the 24 very large DNA molecules present in each of our 24 different human chromosomes, a total of three billion base pairs. Before tackling the human genome itself, the genomes of a number of much smaller bacterial genomes were sequenced. Each such genome sequence reveals the precise number of genes involved in the growth and functioning of their respective cells. The smallest of the bacterial genomes – the smallest genomes of any form of life – code for only some 450 proteins. With time, we will know the function of virtually every molecular actor in such simple bacterial cells. The life of a bacteria will approach being as fully describable as a Swiss watch.
Obviously, the human genome, which contains some 25,000 different genes, presents a level of complexity that it will be a long time if ever – and I doubt it ever will be – that we will discuss human beings as if they were Swiss watches, or as, going further, a 747. On the other hand, now that we know sort of the location and function of virtually all the human genes, we can now scan the genome to see which genes go wrong when we come down with a disease. Soon we’ll have the potential to find likely more than 200 different genes whose mutated forms lead to human cancers. We know about 100 now. We’ll know them all, say, in five years. Equally explainable will be why and how some of us come down with Alzheimer-like brain dementias. Over the next decade, most of the major genetic changes that lead to schizophrenia, manic-depressive disease, autism and dyslexia will be worked out. Stopping many of these human tragedies at last has become a realizable human goal for medical research.
Though I’m already 75 years of age, I have reason to hope I may personally benefit from the Human Genome Project. When I helped start it 15 years ago, I thought my children would be its first major beneficiaries. Over a slightly longer time framework, improvements in DNA technology will lead to the sequence of the biologically important portions of many thousands of human genomes. This massive sequencing effort will let us find the specific DNA sequences to give to us our individual uniquenesses. Why some of us in this room are left-handed or have premature white hair or no wrinkles at 60 is due to our respective genes – as is, say, our predispositions to being either thin or fat. Likewise, many of our emotional differences – being predisposed to being happy as opposed to sad – are likely to arise from differences in DNA sequences. Increasingly, both what we as humans expect from ourselves and how we deal with other human beings will be affected by genetic knowledge.
Assigning genetic causation to human capabilities and disabilities almost always has ethical consequences. Before the Human Genome Project got going, when I was its leader at the National Institutes of Health, I said we would spend 3 percent of the money assigned to this project to discuss ethical issues. Geneticists no longer should have a largely hands-off attitude to how their results bear on the functioning of human society. Likewise moral philosophers, in their efforts to study the motivations behind human conduct, will best move forward by partnering with human geneticists searching for the genes that give to us our human nature.
The Scotsman David Hume, in his profound Treatise of Human Nature, said that humans are motivated by their passions, that is, emotional feelings, as opposed to reason. The main passion that led to the double helix was curiosity. All humans are curious to various extents about something or another. I, Francis, Maurice and Rosalind focused our curiosity on DNA. There likely exists differences – genetic differences – why some of us seem to have so little curiosity and others so much. You naturally want your children to have natural curiosity. With it they read books and read about phenomena that need explanations.
The passion for self-advancement also led to the double helix. Francis and I wanted to get there before Pauling. In his Wealth of Nations, the equally important 18th-century Scottish intellect Adam Smith argued that the freedom to work for your own self-promotion promotes the well-being of those about you. In our getting the double helix, we eventually created prosperity for others. Still highly argued today is the relative importance of nature and nurture in the expression of these human passions. Great differences in opinion exist, for example, as to whether human beings’ concern for the well-being of other humans is an innate or learned response acquired after birth. I come down on the side of nature, knowing that many acute observers of human behavior believe we help others largely because we anticipate that those helped, in turn, will help us. When I extend my hand to stop a nearby human losing his balance, I may be so doing because I was taught to so behave by my parents. Cultural instructions, however, cannot explain the feeding and caring of young birds by their parents. Such paternal behavior ultimately must go back to instructions encoded in their genes. The feeding and care by human mothers of their newborn children are likewise easiest understood as being gene-initiated.
Already back in the 18th century, the enlightened Presbyterian minister Francis Hutchinson, whose career took him from Ulster to Dublin to Glasgow, argued that we were born with a good feeling toward others. In Aberdeen, the moral philosopher Thomas Reid promoted a common sense approach to life, basing it on his belief that humans are born with an innate sense of right or wrong. Soon these ideas of the 18th-century Scottish enlightenment float across the Atlantic to the British colonies, giving to the American Revolution its intellectual independence – that human beings have innate needs for life, liberty and pursuit of happiness. To Tom Paine, common sense dictated that each human was entitled to make their own decisions and not receive them from kings or bishops whose authority did not come from those that they ruled over. Common sense tells me that humans should prevent as much genetic disease as science lets us.
The rare mistakes in the copying of DNA information that make evolution possible of necessity lead to much individual genetic injustice. Random throws of the genetic dice during the formation of sperm and egg take away from too many infants the opportunity to participate in a meaningful life. Those unfortunate individuals genetically programmed, say, to have cystic fibrosis, or muscular dystrophy, represent unambiguous tragedies lacking in any compensatory side advantages. Common sense tells me that no one is seriously harmed by steps taken to prevent the birth of such children. Once born their existences will by necessity generate too many moments of anxiety, pain and despair. Common sense also dictates that prospective mothers should make the decisions as to what lives are worth their bringing into the world. Obviously, they should share their thoughts with the fathers – that is, if they are still about. But men, however, should have no veto over women’s decisions. Few men willingly share the burden of looking after tiny infants. Likely, they are less genetically programmed to give the necessary care. All such decisions, like, Do I want to find out whether my future child will be badly handicapped? should be the choice of a woman. No one should force her either to be tested or not tested. But she should know what genetic tests exist and how respective genetic disease, say, Down syndrome, or Fragile X, will impact the future of those women that bear these children. How women will make these decisions will naturally depend on their own senses of right and wrong and from what culture and religions they come out of. Great care must be taken to keep governmental and religious bodies from directly entering into genetic matters. We all know too well what happened in Nazi Germany, when its government decided what lives are worth living.
Of course, women will occasionally make decisions that they later regret. Some of these may lead to governments, charities and religious groups caring for children whose disabilities prove too great for their parents to handle. We should count on good common sense coming from most women, particularly those with prior exposure to genetic issues. The power to the people idea really only works in dealing with educated people. Unfortunately, current gene discovery moves forward much faster than our genetic education programs for girls and their mothers. Common sense also dictates that individuals, as opposed to governments or other bodies, decide when our own genetic information is looked at. Our own DNA belongs to each of us as individuals. No one should have the right to examine it without our consent. In saying this, I know that the matter will prove more complex than we like. With time, we will know enough about our genes to be able to predict, say, whether we will likely have a long life. In which case we will probably decide not to take out large insurance policies at an early age. Insurance companies will know that we have this ability, and so they will demand the right to look at our DNA, say, if we wanted to take out a $10 million policy. Some compromise must be found; we don’t want insurance companies to go out of business. At the same time, it would be very unfair if someone has DNA which has a lot of bad signs when you look at it and that prevents you from getting an insurance policy that lets you buy a house. So we have to eventually, through a lot of discussions – and they won’t be simple – decide how we’ll handle the insurance matter. No discussions, I think, can reverse the fact that some people just are victims of genetic injustice, and their future lives will not be as simple or as healthy as those of others. No matter what we try and do ethically, we can’t reverse the harm to a person who carries a gene which will give him a short life. I think the only way we can sort of respond to this fact that some people are treated worse than others by their genes is to try and cure the diseases. Otherwise, we’re always going to be in a situation where no matter what we do someone who doesn’t deserve to has a worse fate in life than someone else.
We should also consider whether we should try and improve human life by adding new genetic material to our germ plasm. I’m in favor of so going forward, though most of my fellow scientists say they are against it. I believe they don’t want to alarm the public by possibilities which will never exist. On the other hand, by adding appropriate genes, we already can improve the memory of mice. Why not the same with humans? To me it’s common sense to take steps which might give our future descendents more effective brains. I don’t see who we’re truly offending by trying to enhance ourselves. To me it goes against human nature that people should not try to improve the lives of their children and those that follow.
