Life Science in Japan Seen from Abroad

Speaker: Daniel Nathans
   Interm President, Johns Hopkins University

BROMLEY

 Let me begin by first of all saying how delighted I am to have this opportunity to join you this afternoon. I wanted to take the opportunity in the beginning to express to JSPS and to my old friend and colleague Toshi Koshiba my appreciation on your behalf for bringing together this particular forum which, in my opinion has been unique in telling those of us from the United States at least, much we did not know previously about Japanese science. So already this has been a real success.

 I'm delighted to have the opportunity to introduce two old friends and colleagues who are going to speak to you for the remainder of the afternoon about how they view science in Japan from here in the United States. The first of those speakers is Professor Daniel Nathans, who is the Interim President of the Johns Hopkins University. He was educated at the University of Delaware and Washington Universityi in St. Louis, and his work has been in the general field of biochemistry and genetics. For his work on the application of restriction enzymes to problems of moilecular genetics, a precursor to recombinant DNA and many of its facets, he was awarded the Nobel Prize. He is a member of our National Academy of Sciences and was awarded the senior award available to scientists in the United States, the US National Medal of Science. I had the great pleasure of working with Dan for three years during the Bush administration. He was a vary active member of the President's Council of Advisors on Science and Technology. There is no better equipped person in this country to speak on the general topic of Life Sciences in Japan : a Personal Perspective . Professor Daniel Nathans.

NATHANS

 When Allan asked me to participate in this conference, I said yes; then I began scratching my head about what it really was I was supposed to talk about. In the meantime, a strange thing happened to me. As Allan said, I went from being a professor at Johns Hopkins School of Medicine to being Interim President of the University. But I still look at science in Japan as a scientist, not as an administrator. I'm going to give you a very personal view. I conducted no surveys, no interviews; I didn't consult the citation indexes. I'm simply going to give you my impressions based on what has happened in my field, molecular genetics and biochemistry over the past quarter century. What I am going to talk about are some of the highlights of Japanese science in this area, and then I want to say something about the opportunities for young scientists in Japan vs. those in the United States.

 We can think of life sciences these days, and this is something rather recent, as little science and big science; however, none of it approaches megascience like particle physics or space exploration. We're not talking about billions of dollars for a big project, but rather tens of millions or at the outside a hundred million or so for one project, specifically the human genome project in the United States. Small science, which includes most research in the life sciences all over the world, is science directed usually by an individual senior scientist and a small team of junior associates, perhaps three, ten, fifteen, something in that order. One of the points that I want to make, one of the conclusions I want to come to, is little science is still where the creative action is in the life sciences; although, it is becoming more dependent on expensive instuments and collaboration than in the past. Nonetheless, there certainly is a place for larger projects which provide the substrate for more creative science.

 It's often said in Japan, and I, like many of you read about it periodically, that Japanese society in general is wondering, after their substantial investment, where is the international recognition - the Nobel Prizes - for Japanese scientists. I raise this because it is relevant to my conclusion that little science is still at the creative center of the life sciences.

 There is no doubt that there is what you might call “Nobel” quality research in the life sciences in Japan and there has been for some time. I want to cite four life scientists who I think fit this category. I have intentionally omitted present company in this audience, including my former colleague at the Rockefeller Institute, Professor Ebashi.

 First, let me tell you about some work done by Tsutomu Watanabe. Professor Watanabe was a microbial geneticist. He died prematurely at the height of his career. He worked out the mechanism of an important phenomenon that has plagued the world and will continue to plague the world for a long time to come, what's called infectious drug resistance in bacteria. A phenomenon was discovered in Japan just prior to Watanabe’s work (and this is what stimulated him) that certain forms of drug resistance among bacteria causing intestinal infection spread from one bacterium to another, and in fact, from one species of bacterium to another. Often this drug resistance is multiple, that is, resistance to a number of different antibiotics develops simultaneously.

 Watanabe, who worked out the mechanism of the spread in great detail, discovered what he called R-factors, little rings of DNA plasmids of a type that Joshua Lederberg had described years before in another context. Watanabe found that these little rings of DNA include genes that code for enzymes that either degrade the antibiotic or in some way keep the antibiotic from entering the cell, in any case, neutralize its activity. They also code for efficient transfer from one bacterial cell to another. This is really the essential problem of drug resistance that is now resurfacing throughout the world. You read about it in regard to organisms like the pneumococcus, staphyloccus, gonococcus, and enteric bacteria that cause diarrhea. It's what threatens to wipe out the benefits of the antibiotic revolution, and without the work of Watanabe, we would not understand the problem.

 The second person I would like to cite is Shosaku Numa. Unfortunateley, Professor Numa also died at the height of his career in 1992. He was at the Department of Medical Chemistry in Kyoto. Numa attended Harvard Medical School and then did research as a postdoctoral fellow in Munich at The Max Planck Institute with Feodor Lynen. He then returned to Kyoto and began a new field of investigation, which led to the elucidation of how ion channels work in nerve cells.

 Numa described in molecular detail, based on gene cloning, the structure of channels in nerve cell membranes, and in fact in many kinds of excitable tissues which gate the passage of ions like sodium or calcium across the membrane. Such channels are the basis of nerve cell communication. By changing certain aspects of the structure of those complicated proteins or ensembles of protein, Numa and his collaborators showed how they function. I think this has been one of the most exciting developments in the field of neurobiology.

 The third person I want to cite is Akira Kobata from the Institute of Medical Science at the University of Tokyo. His field is somewhat remote from my own, but I have heard about Kobata from colleagues and looked up his papers. He is a biochemist who studies the sugar molecules that are attached to proteins. Many proteins, particularly those on the surface of cells and proteins that get secreted like hormones, have very complicated polysaccharides attached to them. What makes them complicated is the different isomeric forms of the sugars depending on the linkages between the sugars and other variables. Kobata painstakingly worked out chemical methods for the analysis of these carbohydrates so that one could say precisely in chemical terms what the sequence of sugars is, what the linkages are, what isomers are involved in a particular case in these complicated sugar structures that often determine whether the protein to which they are attached has biological activity. He is a pioneer in the field and was recently honored by a Kobata symposium in Great Britain. According to my colleagues in this field, Professor Kobata has also been extremely generous in sharing materials and unpublished methods with the research community.

 The fourth person is Yasutomi Nishizuka, Professor of biochemisty at Kobe University; he is the only one I know among those I cite, because he and I overlapped during our postdoctoral fellowships in Fritz Lipmann's laboratory at the Rockefeller University shortly after Professor Ebashi left Lipmann's lab. When I knew him as a postdoctoral fellow, Nishizuka already had the marks of an exceptional scientist. Extremely competent in biochemical analysis and a clear thinker, he quickly cleaned up a problem that in my hands was in a very messy state. But what he is known for is the discovery of a family of enzymes called protein kinase C that are involved in the transduction of signals from the outside to the interior of the cell.

 Niahizuka not only discovered this class of enzymes he called protein kinase C, but did beautiful physiological work, showing how they were activated by membrane-derived lipids and calcium. He found different forms of the enzyme in different types of cells and described their function in intercellular signal transduction. He and his colleagues developed this entire area single-handedly.

 There are a number of others I could also cite, but I think this should be enough to illustrate the fact that there is quite a bit of very high quality science in biochemistry and molecular biology in Japan!

 Now let me turn to the one big life science project, genome sequencing, particularly of the human genome. I made some transparencies from a publication of the Human Genome Organization (Genome Newsletter, December, 1995) to summarize genome projects in Japan. This diagram shows the major research groups in Japan who are working on genome projects, mostly on the human genome. It is quite an extensive network. Although I don't want to go into this in any detail, I do want to point out that there are many universities and institutes that have groups involved in this kind of research. I do have to wonder from the things I read in Science and Nature whether this table of organization, which looks so neat, really applies on the ground. In any case, it is probably as well organized as the U.S. effort, and now there is about fifty million dollars invested in this in Japan.

 What's so important about the genome projects? Let's start with the human genome project. The human genome has about three billion base pairs of DNA, and something on the order of a hundred thousand genes. The work in Japan is part of a world wide effort to completely sequence the three billion nucleotides in the human genome. It is estimated that job will be done in 2005 or thereabouts. Although this seems a little optimistic unless there is a quantum jump in the efficiency of sequencing, in due time, there will be a complete sequence of the human genome. We'll know all of the expressed genes and therefore have the amino acid sequences of all human proteins.

 Not only can we deduce from the nucleotide sequences the amino acid sequences of all the proteins present in our bodies, we can also often deduce something of their function from the sequence, because even now, enough sequences have been completed to permit recognition of particular patterns in the sequences that are related to function. This has enormous significance for biological research, including understanding the evolution of our species as we compare sequences from different organisms, how the genome is organized, how individual genes are regulated, what some of the DNA that is now called junk DNA does. If some patterns can be discerned in the sequences of those regions that don't code for proteins, we may be able to get some clues to function to follow up on.

 And of course, identifying all human genes and proteins will have great medical significance. First of all, many human diseases are influenced by, if not caused by mutations in genes. We all know about cystic fibrosis, a disease that is rather common, in fact, one of the commonest diseases inherited in a simple mendelian fashion. An enormous amount of research on cystic fibrosis was done over the years with barely a clue to understanding the basis of the disease. But then the gene for this defective protein was finally cloned, a laborious long term effort by many laboratories throughout the world, and the sequence of the DNA was determined, from which the sequence of the protein was deduced. Suddenly, precise pre- and post-natal diagnosis was possible and understanding the molecular basis of the problem became solvable. More common diseases also have a genetic basis - cancer, atherosclerosis, diabetes, hypertension, schizophrenia - involving the interplay of several genes as well as environmental influences. Great advances will surely come from identifying these genes and understanding the functions of their encoded proteins.

 There is another medical aspect to the human genome project that has to do with drug development. A number of the genes will code for hormones, some of them hormones that were never imagined to exist. Others will be hormones that are members of a family of known hormones but have unique activities, for example some are now coming to market that stimulate blood cell formation in patients with anemia or in patients undergoing chemotherapy who become deficient in blood cells. Of even more general significance, human genome information will allow targets to be identified for drug development. Drugs, as you know, are compounds which attach to proteins (by and large) and perturb their function, e.g., inhibit an enzyme or affect a receptor on the surface of the cell. By having the primary structure of these proteins and ways to produce them in quantity, one can learn a good bit, and perhaps select or design compounds that bind the protein and affect its function.

 The major countries contributing to the human genome effort are the U.S., Great Britain, and France, I believe. Japan is a recent contributor. In 1989 Jim Watson accused Japan of scientific free-loading on the human genome project. His was a very blunt statement, indicating that Japan simply was not carrying its weight and was benefiting from all of the information that came from labs elsewhere in the world. I think it was accurate. But since that time, Japan has made a considerable effort, and you have seen the magnitude of their current investment in this effort. As a result, Japan has become an important contributor to sequencing the human genome.

 People are not the only interesting organism on earth. From the point of view of scientific or commercial value, there are lots of interesting organisms. The mouse is a close relative of ours, and experimentally tractable in many ways, and so a great deal of effort is going into mapping (and eventually sequencing) the mouse genome. In Japan, one effort that stands out is the analysis of the rice genome; in fact, the center in Japan is the leading group in the world in analyzing the genome of rice.

 You all may have read in Science magazine a month or so ago a report by Craig Venter, Hamilton Smith, and their colleagues about the first complete nucleotide sequence of the genome of a free-living organism, the bacterium Hemophilus influenziae. This report has excited scientists throughout the world because they used a novel sequencing strategy and completed the sequence in about one year. Now with the entire genome sequence available, they and others can do some extremely interesting fundamental and applied biological studies. We'll soon have sequences for many of the major pathogenic bacteria, providing in each case a jumping off point for more detailed understanding of how they cause disease and for developing new ways to control those diseases through vaccine development or drug treatment.

 This brings me back to the question of the relationship between little and big biological science. The big science I'm talking abouts sets the stage for little science. It sets the stage for the imagination of scientists to make use of new information which will be available electronically to ask new questions, devise new experiments, get deeper into the fundamental questions of biology as well as the medical issues. So I would say, although I'm all for Japanese participation in the genome projects, it should not be at the expense of what I'm calling little science, supporting individual investigators.

 Now I want to turn to the question of opportunities for young scientists that I alluded to at the outset, and also opportunities for women. John Vane wrote a very nice "News and Views" commentary in Nature in 1990 about endothelins, a class of peptides which are among the most potent blood vessel constricting agents known, and therefore are of intense pharmacological interest. I quote from Vane’s article:  The endothelin story is remarkable. Highsmith and his colleagues found that endothelial cells in culture elaborate into their medium a peptide vasoconstrictor substance. In searching for a topic for his PhD thesis. Masashi Yanagisawa, with Hiroke Kurihara, found Highsmith's papers and suggested to his supervisor at Tsukuba University, Tomoh Masaki, that he should take up the problem. Masaki agreed and, as the project developed, brought a sizable team into the work, including not only Yanagisawa as the molecular biologist but also Katsutoshi Goto as the pharmacologist and Sadao Kimkura as the biochemist. The result was that endothelin exploded into our consciousness in a paper published in Nature on 30 March 1988. It was so complete and thorough that one of my colleagues, who read it at the weekend, was convinced that it must have been intended by the editors as an elaborate scientific Aprils fool's joke...At a ceremony associated with the Tsukuba City meeting, Masaki and his colleagues were awarded the second Tsukuba Prize consisting of a huge silver medal and a research grant of ¥5 million. This recognition of a truly outstanding discovery will surely not be the last to do with endothelins. Oh yes, I should mention that Yanagisawa was awarded his doctorate.”

 The lesson is that here was a predoctoral student who had an idea, and he convinced his professor to let him work on the idea, even though it was not in the professor's range of interest scientifically at the time, a rare occurrence, especially in Japan I think, but a lesson for us all. The Japanese scientific community needs to take it seriously. You may remember that Susumu Tonegawa, who worked in Basel and Boston, said that in Japan he never could have done his post-doctoral work on the generation of diversity of antibodies for which he got the Nobel Prize.

 One other story. There was a famous husband and wife team of Japanese scientists who lived many years in the United States. Both were full professors at a leading university and received prizes jointly for their work. The husband was offered a professorship at Kyoto University; his wife was not. She told me that her mother said to her, "Don't you come back if they don't offer you a professorship also". I raise this issue of opportunities for women in science as part of Japanese science as I see it.

 My main point is that I think it is extremely important to provide opportunities for young scientists, including women, who are especially promising. Although there is waste in a system that takes risks with promising but unproven young scientists, overall, the rewards are great and after all, there is tremendous waste in supporting unimaginative science. You have to make your bets, and they don't all pay off, but this is where fundamental discoveries are going to come from.