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From: Research Universities and the Academic Disciplines AAU Centennial Meeting October 16, 2000 University of Chicago
"Biology's Revolution: Opportunities and Challenges for Universities"
Good morning. It is a special pleasure to be back in Chicago, the city where I was born, and at the University of Chicago, where I have enjoyed many fine events through the years and have many colleagues. In fact, two former students from my laboratory became tenured faculty members here at the university. It is also a thrill for me to be able to talk about the future of education and research at universities with the people who are guiding these great institutions in the twenty-first century. We are already into this century, of course, but we still have ninety-nine years to make good on whatever we decide to do. Our invitation requested that we each talk about the past, present, and future of our own research disciplines. I was asked to speak before I had become president of the Howard Hughes Medical Institute, so I planned to give you a view "from the trenches," drawing on my twentythree years of carrying out research, teaching general chemistry and biochemistry to undergraduates, and teaching graduate students at the University of Colorado at Boulder. Now, having taken on the Howard Hughes position, I feel inclined also to address some higher-level issues. So this is going to be a discussion of what biological research is like and how it is changing, mixed in with a look at some of the ways that institutions might respond to new challenges. I am going to give a particular slant on my research. Instead of talking about the work that led to the Nobel Prize, I'll talk about something more recent--our work on the ends of chromosomes. This will connect with some of the points that I will make in the more general part of my presentation. Let's start with a view from Newsweek magazine, from an article examining scientific advances that supposedly might enable people to live to be 150 or 200 years old. You are all familiar with one of these ideas, organ replacement. As the century progresses, more of us may be walking around with replacement parts in our bodies--more than just a new heart. The Newsweek article also featured telomere therapy, the "age-enhancing idea," which is what I am going to talk about. What is this? My parents' view is: "We don't know what it is, but we want to be the first ones to get it." I don't know if you'll share that view when I am done. Let me start by describing telomeres, the ends of chromosomes. The same DNA sequence is located at the very tips of all of the twenty-three pairs, or forty-six total, of human chromosomes. The sequence--TTAGGG--is very simple, not nearly elaborate enough to code for a protein. This block is repeated a large number of times, (TTAGGG)N, where the subscript N can be in the thousands in the case of a human or mouse chromosome. If the sequences are too simple to encode a protein, what are they doing? It turns out that they act as a kind of a cap at the ends of our chromosomes. It also turns out that the molecular machines that copy DNA can handle vast stretches in the middle parts of our chromosomes but cannot copy the telomeric sequences at the very tips. The simple explanation has to do with the nature of DNA replication, in which one strand of the double helix serves as a template for the other. When you are at the end of the chromosome, there is no strand to "template" the other one. Nature solves this problem using a completely different molecular machine called telomerase, discovered by Liz Blackburn and her student, Carol Greider, at the University of California, Berkeley. Liz is now at the University of California, San Francisco, and Carol is at the Johns Hopkins University. This telomerase machine carries around a stretch of RNA that templates the addition of those short sequences. If there' is a C in the RNA template, there will be a G opposite it on the end of the chromosome. When there is an A in the template, a T will be inserted at the chromosome end. Blackburn's laboratory discovered the RNA subunit, but the key protein subunit remained elusive until a Swiss postdoctoral fellow named Joachim Lingner came to our laboratory in Colorado. Lingner decided to try to find the protein that was the catalytic heart of this RNA-protein complex, this telomerase. He studied the protozoan Euplotes aediculatus. The reason for choosing this organism was that instead of having just 46 chromosomes, it has about 50 million in every nucleus, all of them very short. We figured that if you want to study chromosome ends, why not choose an organism that has lots of ends and therefore a correspondingly large amount of the telomerase enzyme that is responsible for filling out the ends? Fortunately, the type of telomerase in Euplotes is very similar to that in humans. Lingner devised a purification scheme in which he "went fishing" with a complementary DNA sequence to pull out the telomerase enzyme in an active form. Next, he purified a little of the complex, just a few picomoles worth. We couldn't do anything with it, though, until we learned of a group at the European Molecular Biology Laboratory in Heidelberg that was able to derive amino acid sequences--and to figure out the linear order of the monomeric units in the protein--using nano-electrospray mass spectroscopy. In collaboration with the German laboratory, we were able to determine parts of the protein sequence, which enabled Lingner to clone and sequence its gene. Then the wonders of bioinformatics came into play. Sitting in one of the genomic databases was a related sequence--not from the human genome, but from yeast. Of all the genes and proteins that had ever been sequenced, what most resembled the new Euplotes protein turned out to be a yeast protein. This is the same yeast, Saccharomyces cerevisiae, that we use to make beer and bread. It is a wonderful experimental organism because even undergraduate students in the laboratory can be taught to change or delete one gene, leaving the rest of the genes in the cell the same. So you can rigorously test the importance of a particular part of a chromosome and determine its particular function. In this case, in collaboration with a group at Baylor College of Medicine in Houston, we mutated the yeast version of the Euplotes telomerase gene. We found that, indeed, the chromosomes shrank from their ends like clockwork because the cells could no longer replicate the very ends of their chromosomes. Shortly thereafter, Toru Nakamura, a graduate student in the laboratory, was working with Lingner early one morning, mining DNA sequence databases, when they found the human version of the same gene. So several years of biochemistry with a ciliated protozoan, a few months of work with yeast, and a few seconds on the computer combined to find the human gene--a wonderful illustration of the changes taking place in biology. Not only did we have access to the sequence database that contained this human homologue, but so did every pharmaceutical company in the world and every other academic laboratory. There ensued a great race among scientists in many parts of the world. In a two-month period, our paper on the human gene was published, as were similar papers by an MIT group and groups in Australia, Canada, and Japan, all using the Euplotes sequence to locate the corresponding human gene. This human telomerase gene is now being investigated as a way of extending the life span of human cells, and it works beautifully in cell culture. You can immortalize human cells that would normally grow for only 50 generations. They will now grow indefinitely without becoming cancerous when this gene is added to them. Before you all get too excited, I will say that the immortalization of individual human cells extracted from the body and growing in a petri dish is a far cry from immortalization of the human organism. Don't hold your breath for the telomere therapy that Newsweek predicted. We were asked to extrapolate our field of research twenty years into the future, and I have little faith in my own abilities to extrapolate so far. But we can predict some events that are likely to come into play in our research universities to drive this sort of research to the next level. It is clear that these genome databases are not yet nearly as useful as they are going to be twenty years from now. Our computational techniques are still primitive. Informatics will take off in a major way, so that many experiments in the biological sciences will be done in front of a computer terminal--experiments that will be rigorous and important, not just computer games. More and more, this is what a Ph.D. thesis in many areas of the biological sciences will entail. In the future, computational techniques will allow us not just to compare primary sequences--the order of As, Gs, Cs, and Ts along a DNA strand or the order of amino acids in a protein--but also to predict the three-dimensional structure and the activity of proteins. They will even allow us to do what we have been trying to do for the last twenty years with only limited success--design pharmaceuticals on the computer to specifically antagonize the activity of some of these proteins, including telomerase. Cancer cells are immortal, and the telomerase enzyme is activated in 90 percent of human cancers. A drug that would inhibit its activity is very much sought after as a possible cancer chemotherapeutic. Another area that will accelerate in the next twenty years is imaging technology--visualizing the three-dimensional structures of cellular components all the way down to individual molecules. There has been a revolution in X-ray crystallography over the last twenty years that has allowed the structures of many proteins and nucleic acid molecules to be determined at the atomic level. That revolution is already largely behind us. In the next two decades we will see more scientists building up from the level of one protein, or one protein-nucleic acid complex, to bigger and bigger complexes. To give you an idea of what kind of information we might obtain, consider the current model of telomerase, which includes the RNA component, the protein, and the end of the chromosome--the telomeric DNA. Although this is just a model, not an accurately determined structure, it represents the critical level that molecular biologists want to achieve: to visualize all of the atoms in such a complex, see how the components all fit together, see where the active site is, and see how the chemistry allows, in this case, the chromosome end to be extended. Our capability to determine atomic-level images of biological components is increasing from the 100-angstrom scale all the way to the micron scale, which is roughly the size of a cell. The resolution of high-voltage electron microscopy is improving, while X-ray crystallographers are cracking the structures of larger and larger assemblies. So, although it still sounds a bit like Star Wars, we really do think that within the next twenty years one could locate every molecule of a living cell and even all of the billions and billions of atoms within it. Of course, just having one such snapshot would not be the final goal. One would want to see how the molecules and atoms moved with respect to each other over time, in different disease and nutritional states, and when mutations occur in the collection of genes. That is what the future may bring, perhaps within our lifetimes. Because of my recent move to Howard Hughes, it is appropriate for me to try to give a broader perspective on some of the issues that involve science and universities. I picked out four trends that I thought would be of special interest to this audience. They all will challenge universities to devise new approaches to research and education. The first is the way in which new technology is transforming biomedical research. A similar transformation began earlier in astronomy and physics--biology came rather late to the game. But from the story that I just told, I think you can see how a new level of technology made possible our project. If not for the nano-electrospray mass spectroscopy, we would not have been able to do anything with our picomole of telomerase. There wasn't enough to analyze by standard chemical techniques. I also showed how bioinformatics enabled the jump from the Euplotes gene--which, frankly, few outside our laboratory cared about--to the yeast gene, which was of somewhat more general interest, to the human gene, which has a lot of medical interest. Such biological breakthroughs will continue to occur within the limits of existing technology. But looking ahead ten or twenty years, the type of instrumentation, its cost, and the level of technical expertise needed to run it appropriately will reach the point where single universities will have great difficulty in supporting the technologies. I would suggest that universities and other institutions, including perhaps the for-profit sector, will need to collaborate to establish facilities that none could afford or maintain alone. Ideally, that sort of facility would not just enable the use and broad distribution of new technologies, but also develop the next generations. My second point is that biological research and many other kinds of scientific endeavor these days benefit from new forms of teamwork. My story about discovering the human telomerase gene involved a Swiss postdoc and a Japanese graduate student, a laboratory of collaborators in Texas, and a mass-spectrometry facility in Heidelberg. In addition, when we were trying to quickly sequence the human homologue, we collaborated with a biotechnology company in Menlo Park, California, aptly named Geron. We see more and more papers in biological journals where the list of authors is as long as the abstract. In a few cases, it even takes up the entire first column of the article because there are huge international consortia involved in making these projects work. What is the challenge for the Research University in dealing? In the past, we have always thought that it was critical for each of our Ph.D. students to have their own project. They have to develop the ideas. They have to do the experiments themselves. They are allowed to talk to other people in the laboratory and encouraged to interact a lot, but ultimately they write a sole-author dissertation to get their Ph.D. Then many of them go to the biotechnology industry and find out that things don't work that way at all. Instead, they become members of a team, which many find to be incredibly exciting and invigorating. But they struggle, because they have never learned to apply their expertise in a team context. This is a challenge for the universities. Rudyard Kipling said, "The strength of the wolf is in the pack. The strength of the pack is in the wolf." Modern university education has focused on the latter half of that aphorism--the part about the strength of the pack being in the wolf. Just educate really good wolves, we seem to believe, and you'll get a good team of individuals without having to do anything more. But the other half of Kipling's truth is that the strength of the wolf is in the pack. We have not done much to nurture teamwork in most of our universities. So universities may have to consider developing new systems that reward personal achievement in a group context. Third, the integration of research and teaching is something that research universities have been struggling with for a long time, and it is something that is very important to me personally. I was teaching undergraduates while the research story I just told you was unfolding. I have always found positive reinforcement in both directions of this two-way street. The things I do in the classroom and the questions my students ask influence my research, just as my being able to bring ideas and discoveries from the research laboratory into the classroom is important to their education. I do this in the form of hands-on experimental demonstrations or just stories, such as: "Okay, I am not going to talk to you about carbon-hydrogen bonds today. Instead, there's a much bigger molecule that a colleague of mine down the hall discovered last week that we're all very excited about, and I want to share this with you." This gives them much more of a feeling about what it is like to do science and to be a scientist than they can get from a textbook. The most vibrant science education experience that research universities can foster comes not from classroom teaching, but when undergraduates enter research laboratories. That is where they get personalized education. They work with state-of-the-art equipment on questions whose answers are not yet known. Those experiences are the ones students remember five and ten years after they have left the university. That is what transforms their lives. They rarely will remember a single class where they sat in straight rows and listened to a professor lecture. Obviously, undergraduates are doing research at all of your institutions, but such research is often seen as desirable rather than as essential, and it is not broadly available to students in their first two years. Wouldn't it be fabulous if we could make a much cleaner break from high school education to university education and tell entering freshmen: "We hope you had a great high school career. Now we're going to think about things differently here at the university." As a subtext, we may need to consider new ways to hire, promote, and support our faculty on the basis of their teaching as well as their research. I could talk at length about biology becoming more interdisciplinary and globally diverse. I already mentioned interdisciplinary science, so I will not go over that ground again. Let me just say a few words about the globalization of science. Obviously the Internet and the Web have allowed scientists from many parts of the world to connect with each other almost as easily as they can connect with a colleague down the hall. The ease of connection could enable a new level of international collaboration on a level playing field. Instead, we see a disparity of opportunities, with the best minds of Asia, Russia, Eastern Europe, and other regions migrating to the United States. Global science will be healthier if we can get scientists from different nations to the point where they can collaborate as equal partners. At the Howard Hughes Medical Institute, we contribute by giving grants to international scientists to work in their home countries, including Russia and countries in Eastern Europe, Latin America, and Africa. This helps keep alive the science infrastructure and the opportunity to educate the next generation of scientists in those countries rather than contributing to what is already a substantial brain drain in the direction of the United States. Disparity in opportunities extends to the diversity of people engaged in science. I have become familiar with a few institutions--the University of Maryland, Baltimore County; Xavier University of Louisiana; the University of California, Berkeley; and others--that have demonstrated remarkable success in retaining more minority students in science and then seeing them go on to earn the Ph.D. at other institutions. Although the three campuses I mentioned are very dissimilar geographically and in the demographics of their student bodies and other features, their programs share several elements. These include intervening early in a student's career, creating a sense of community among students from underrepresented minorities, and providing role models and exposure to career paths along with education. They are powerful models. We need to learn from them and implement their ideas more broadly. With that, I thank you for your attention.
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