Note: On March 25, Haseltine announced that he will retire from Human Genome Sciences later this year. He will continue his not-for-profit work, some of which he discussed below.
As founder, Chairman, and CEO of the biotechnology company Human Genome Sciences in Rockville, Maryland, Bill Haseltine over the last decade has been associated with the Human Genome Project and with efforts to mint genomics data into a new generation of drugs. Known for his research on HIV and cancer, Haseltine has recently turned his eye toward neurodegeneration. Never a shrinking violet, this new friend of the field talks about his observations on Alzheimer's research, its progress, funding, and future outlook.
ARF: The idea for this conversation arose in the course of a budding partnership between the Alzheimer Research Forum and the New York Academy of Sciences. What is your connection to the Academy?
WH: I'm a member of the Academy, and of the President's Council. I suggested to them that Alzheimer's would be a good topic to take up. My private foundation has made a $100,000 donation over a two-year period to support a new workshop that the NYAS has initiated in Alzheimer's and neurodegenerative diseases.
ARF: What got you interested in neurodegeneration and Alzheimer's?
WH: I had founded an organization called the Society for Regenerative Medicine, and more recently, we've merged that into another society, now called the Regenerative Medicine and Stem Cell Biology Society. The concept is simple: We can create better, more cost-effective medicine by regenerating diseased, damaged, and worn tissues using human genes, proteins, and stem cells. Neurodegenerative diseases are a key component of our work. As part of trying to understand what was known, I systematically reviewed the Alzheimer's literature from about 1992 to 2004. I was pleased to note the remarkable progress that had been made in understanding the fundamental nature of the disease. There is enough fundamental science known that one can begin to create a systematic program to treat Alzheimer's. I thought it would be worthwhile assembling a group to think about how to apply new knowledge. We've had four meetings now, and at the last one, Michael Wolfe coordinated a session on Alzheimer's.
ARF: I noticed that.
WH: I think the time is right for a systematic assault on Alzheimer's. At least 10 or 15 different interesting points of intervention are now known. Systematic exploration of these opportunities ought to yield an effective way to treat and possibly cure disease within the next 10 to 20 years.
ARF: You're very optimistic.
WH: There's a lot known now. It may be 15 to 20 years, but I'm optimistic that we can make serious inroads in the foreseeable future.
ARF: Do you have a personal interest in Alzheimer's, as well?
WH: No. I was impressed by the quality of the science. But I always look for big problems where science can be systematically applied. It seems to me the problem of Alzheimer's is now where AIDS was in 1984.
ARF: In what way?
WH: In 1984, the fundamental nature of AIDS was known. A number of interesting targets had been outlined. It was a matter of developing systematic points of intervention. I think we can now make similar progress with Alzheimer's disease. A lot of the fundamental science is now known, and there are a number of approaches, which, if systematically explored, can lead to effective therapies.
ARF: Which points of intervention do you consider most promising?
WH: Inhibitors of the α, β, and γ proteases will probably be effective drugs. Passive and active immunotherapy approaches may be effective. There are a number of other approaches as well. A lot is known about the processing of the proteins and the phosphatases that are involved.
ARF: We cover these approaches extensively. When I saw the session devoted to Alzheimer's at the Regenerative Medicine and Stem Cell Biology Society meeting last November, it struck me that none of the presentations had to do with stem cells or regeneration, per se but with the approaches you just mentioned.
WH: That's not exactly true. We had a beautiful presentation by William Pardridge on blood-brain barrier and gene delivery.
ARF: That's true. But the others [Michael Wolfe, Cynthia Lemere, John Hardy] were not. The prospect of stem cell or regenerative medicine is extremely fascinating, yet in the area of neurodegeneration Parkinson's is the most studied of the common diseases. What is your sense of the potential of stem cells in Alzheimer's?
WH: I think once the damage is done, you'd like to be able to do some repair, and stem cells offer a potential source, but regenerative medicine is not synonymous with stem cells. The concept of regenerative medicine is the use of human genes, proteins, antibody cells, or stem cells—and materials—to repair damage by disease, trauma, or age. Regenerative medicine is a very broad concept.
ARF: By your definition, then, it's not just cellular therapies but really genome-based therapies in the broadest sense?
WH: Genes, proteins, cells, antibodies, stem cells, and materials. Part of the Society focuses on the whole area of biomatrices, nonliving mechanical supports, etc.
ARF: Have you given some thought to the idea of whether problems with adult neurogenesis contribute to pathogenesis of neurodegenerative diseases? In other words, that adult neurogenesis has a function in the brain, that it may become impaired by inflammation, and that problems with neurogenesis may contribute to the neurodegenerative process. That's a budding area in Alzheimer's.
WH: It could be. Yes, that's interesting.
ARF: From your experience as a scientist, do you see connections between cancer and Alzheimer's, or HIV and Alzheimer's, that you consider worth exploring?
WH: Well, I think what you looking for are analogies. I mentioned very broad analogies. When are problems ready to be solved? What struck me is, over the last 10 years from 1992 to 2002, the fundamental understanding of Alzheimer's disease advanced to the point where you could propose rational intervention. That process was similar to what happened once the HIV genome had been elucidated. What followed was systematic application by the pharmaceutical industry of approaches opened by genomic discovery. I think that's where we are with Alzheimer's today. So I'd say in general that's true. If you look at neurodegenerative diseases as a whole, they have a broad analogy to cancer. They both have common properties. Cancer can be considered to be one general class of diseases, but there are also a number of subcategories of the disease. So, too, with neurodegenerative diseases. There may be some very general approaches to treatment of neurodegenerative diseases, as there are general approaches to cancer. They are both, for the most part, diseases of aging.
ARF: Do you think that study of the mechanisms of AIDS dementia would enrich the study of Alzheimer's or other neurodegenerative diseases?
WH: It's possible, although I've yet to see any real breakthrough in the studies of AIDS dementia.
ARF: Another area I thought you might have found interesting in your literature review was that genes like p53 come up occasionally in Alzheimer's research, as well. Another area that's growing is the study of the upregulation of cell cycle genes in Alzheimer's neurons, so there is a kind of molecular…
WH: That's a little specialized. Certainly, knowledge of how cells behave, whether you get it from embryology, studies of differentiation, lineage specificity, or oncology, is going to be generally applicable, but I think it's a bit of a reach to say it's specifically related to cancer research. I think it falls into a broader category of, when you're working on a problem, look at all possible sources of knowledge.
ARF: How would you approach Alzheimer's research if you were setting up a lab dedicated to this disease with what you know today?
WH: I think the one thing we have now is some wonderful models. I would import the best models for Alzheimer's, which include mouse models using human genes, yeast models for the proteases, then begin a systematic study using the tools available to a large pharmaceutical company for discovery of drugs to inhibit the proteases in a specific way, and other drugs to arrest the process of human-like Alzheimer's in mice. Basically Alzheimer's in mice is very similar in some respect to the disease in humans. It's really the human genes that drive the mouse disease.
ARF: Many researchers have a major quibble that the mice only represent aspects of Alzheimer's; they're partial models. They are models of amyloidosis, mostly, but not of the full complexity of Alzheimer's. Is that true in other diseases, as well, and even so the models were adequate?
WH: That's true, but I think there's enough known to suspect that if you could abrogate that process, you'd abrogate the disease.
ARF: Yes, a majority thinks that, although the γ-secretase target has lost its lustre a little bit.
WH: That's only because people can't figure out yet how to work on it because of the specificity issues.
ARF: Exactly, yes.
WH: That doesn't inhibit people in a lot of other fields.
ARF: I'd like to talk about genomics and proteomics. You're known for your interest in bringing new technologies to the study of human disease, and I wonder how you envision genomics and proteomics as best applied to Alzheimer's. You mentioned one example when I asked you how you would set up an AD lab. Can you think of others?
WH: Yes, I'll give you a different answer to that question. I think the time has come to move Alzheimer's research into the applied stage. Certainly, there's always going to be room for more understanding, but it's time to go into high gear in terms of drug discovery. However, there are many, many other problems to do with the brain that call for a systematic genomic/proteomic approach. The first is to do a very careful analysis on, three or four levels. First is a much higher-resolution map of what cells are in the human brain akin to what was done with C. elegans. If you read what was done with C. elegans, it was mapping cell by cell.
ARF: That was beautiful work, but C. elegans only has about 1,000 cells…
WH: That should be done with the human brain. It's enormously more complex, but we have more capable tools, and it is a job that, in principle, could be automated. I would create a physical cellular map of the brain. Second, I would do a gene expression map of the brain. That could be done more readily than a cell connectivity map, but the two should be interfaced. Third, I'd do a proteome map. Create a map of where all the proteins are in the brain, and along with that, create a series of reagents that specifically bind to each protein. It is an enormous amount of work, which should occupy the next 30 or 40 years. And then, of course, proteome maps aren't only just proteins expressed one at a time, but proteins in living tissues that associate with one another—association of the proteins that are specifically expressed in the brain and in sub regions of the brain. We have the fundamental tools we need to create the basis for the next generation of brain research, which is a combination of a high-resolution physical structure map, gene expression map, protein expression map, and a dynamic protein-protein interaction map in the human brain. That's the program that should be sponsored by large government institutions or private foundations. That is what I would do if I were head of the appropriate institute in NIH or a foundation. I've already tried to do some of that, but not on this scale. It's a huge international undertaking, and I would try to arrange it on that scale.
ARF: A human brain project much analogous to the Human Genome Project? I've read about this.
WH: There are people thinking about doing it, but it's an enormous project.
ARF: Is it in planning stages somewhere?
WH: I haven't heard anybody express it quite the way I just did. I'd call for a human brain project, which includes especially the high-resolution cell-to-cell contact map.
ARF: Now, to clarify, were you thinking something like the developmental cellular lineage map that Bob Horvitz lab made for C. elegans?
WH: I don't think lineage, or developmental yet. I think just knowing where all the cells are and how they relate to one another would be extremely enlightening, and we have the tools and the computational capacities to do that now.
ARF: From my vantage point observing functional genomics and proteomics, they look like they're still largely about methods of development and refinement. Putting myself in the shoes now of, say, an Alzheimer's lab that wants to adopt some of this technology, I'm wondering which techniques would you say are mature and robust enough to make a real difference in neurodegeneration research, short of such a massive effort as you just outlined?
WH: I think the great advances have been to create the mouse models and now the yeast model of the proteases. Each of those is based on decades of study of particular pathways. What makes a difference in drug development is the simple reproducible assay that gives you some reasonable projection onto the reality of the disease. That's where I think you really need to work, no matter what field you approach it from, and it doesn't really matter what tools you have. People created the β-amyloid models from genetic linkage studies, recombinant DNA, and transgenic mice. Those are the fundamental tools. From those models, the first and foremost result has been active and passive immunotherapy. I say that's pretty good. And now, there are yeast strains that have the four genes necessary to reproduce the γ-secretase; that's not bad, either. There are the crystal structures of the β-secretase; also not bad.
ARF: It's interesting that you cite developments that came from neither functional genomics nor proteomics. In these areas, what I see in the Alzheimer's literature these days are, for example, microarray-based gene expression comparisons from, say, postmortem hippocampus of people who died with advanced Alzheimer's with…
WH: It is possible to obtain some information from that type of work. Cause and effect relationships are difficult to deduce, especially from samples of terminal disease.
ARF: Fair enough. But some studies use the brains of people who had died at early stages of Alzheimer's. And several independent studies in the literature now largely confirm the same clusters of genes as coming up quite consistently, including DNA repair, synaptic genes, glucose metabolism, and a bunch of others.
WH: In the early days of cancer research, people discovered that most of the genes for glucose metabolism and oxidative metabolism were activated in tumors. We now believe that that's largely irrelevant. Now it may be relevant to some aspects of cancer therapy, but it's certainly not relevant for understanding the origin of the disease.
ARF: Yes, that was my question: Where do you go next when you have just information about these gene clusters…
WH: ... very difficult.
ARF: … these 300 here are up and these 500 there are down and…
WH: … very difficult unless there are some very general lessons for what you can do to alter those.
ARF: These proteome maps that have been reported for C. elegans and Drosophila and yeast, when I see them in the literature I tend to cover them in our news section. I think that they could be a treasure trove of information for AD researchers looking for pathways and other genes active in neurodegeneration, but it doesn't seem to be happening quite yet. Why not? What's missing?
WH: It's the early days for that. The reason for that is, all that work does is generate testable hypotheses, which then have to be confirmed by genetic and biochemical analysis. So if you have an interesting pathway, say, for gluconeogenesis, and you've worked out that there are five or six new potential members based on protein-protein affinities. Each hypothesis must be tested experimentally before you have a reproducible assay to begin to look for new drugs to treat diabetes. You generate the hypothesis by the protein-protein association, but validating that takes time. We have seen that with the breast cancer genes. It has taken about 15 years to begin to trace through the associations pf the BRCA-1 and 2 genes with other cellular proteins, and we're still at a relatively early stage in the work. Even so, the research has been interesting and in some cases revealing, both with respect to possible function of the genes, as well as the link between those pathways and pathways that lead to spontaneous breast cancer.
ARF: There are also more specific maps in Alzheimer's, for example, interaction maps for specific AD-relevant genes such as APP. Cellzome and Takeda have such maps and I believe they have generated at least potential new drug targets but, of course, these companies keep them private…
WH: Other people will find them; they won't be private for long.
ARF: Do academic labs need such maps? Are they valuable?
WH: Sure they are.
ARF: How can they get them?
WH: They have to make them. They have to do it themselves. It's not that hard.
ARF: From your perspective, what are the questions in Alzheimer's that could entice the best minds from outside fields to sink their teeth into this disease?
WH: All you need is more money. As we found with AIDS research, people who said it was an uninteresting problem got interested when money became available for research.
ARF: Is Alzheimer's underfunded?
WH: Yes. Let me ask you a question: Is $2.7 billion being spent on Alzheimer's research by NIH?
ARF: No, the NIH spent 600 million in 2002.
WH: It is on AIDS. I would suggest we take two-thirds of the AIDS research budget, because nobody knows what to do with it anymore, and put it into Alzheimer's research.
ARF: Would you elaborate?
WH: You want better people to work on it. Just put a lot more money there and they'll come. It's not hard to get scientists to work on problems. You just put the money out and the best guys come. That's how modern biology got started with tumor viruses. The special virus cancer program put a lot of money in, the best people came, recombinant DNA emerged, and then a lot more money went into cancer. And the same thing happened: We've watched the budget go from $1 million a year to $2 billion a year, and saw the academic community respond very quickly.
ARF: What does it take to change the budget allocations in that way?
WH: It's got to be a political process, done through Congress. It cannot be done through the scientific community, because the scientific community now has a vested interest in doing things the way they are.
ARF: If you were charged with bringing scientists from other types of fields into the study of Alzheimer's, what backgrounds would you call upon?
WH: There are several ways to do it. I'll tell you how we did it for HIV because that's exactly what we needed to do. The first thing we worked on is getting significant budget for NIH. In 1985 they had proposed $1 million for HIV/AIDS research, and we were able to increase it in a single supplementary round to $260 million. Those were special circumstances, but that's the first thing we did. The second thing we did was found the American Foundation for AIDS Research. It was just being put together by Mathilde Crimm and Elizabeth Taylor. My role was to give it a mission of providing seed grants—rapid turnaround seed grants—to investigators who wanted to begin research in the field. We would give a startup grant enough to fund a postdoc for a year with the possibility for one and only one year renewal to almost any qualified researcher who had a concept for how you could work on AIDS. Through the combination of giving them money so that they could get into the field, plus making sure there was money for them once they were in the field, we were able to build that field of HIV/AIDS research from nothing to a major research enterprise in about three years.
ARF: In Alzheimer's, some foundations do similar work.
WH: But that only works if there's a big new pot of money and you want to get people into the field fast. There's no point in getting people into the field if they can't get funded later on. Actually, the idea came previously from the Leukemia Society. There it worked for a little while, but it didn't work that well because there was no big, growing pot of money behind the seed grants.
ARF: Other than money, what are the things that slow down progress in research?
WH: Basic knowledge slows it down. No amount of money applied to a problem that's not ready to be solved can solve it. Certainly, we see in the problem of regenerative medicine restrictions on the kind of research you can do.
ARF: Many baby boomers these days are caring for a parent with Alzheimer's and they're increasingly aware of the looming threat to themselves, much like middle-aged people were about heart disease 20 years ago. This is penetrating public awareness, and I wonder what you envision for them in terms of diagnosis and treatment in 10 or 20 years.
WH: I would say 10 or 20 years from now—especially 20 years from now—we should be able to effectively treat and prevent most Alzheimer's disease.
ARF: The pharmaceutical industry has long considered Alzheimer's difficult. One of many reasons was that trials are long and costly, and there wasn't a surrogate biomarker with strong consensus in the field to persuade the FDA to accept it. The industry is more active now. What has changed?
WH: I think the state of the science has changed enormously. The imaging technologies have changed so you can see what's happening. PET scanning gives you a reliable biomarker.
ARF: As Human Genome Sciences is transforming itself from more of a genomic sequencing company into a broad-based drug discovery company, has it started its own neurodegeneration or Alzheimer's program?
ARF: Has it licensed some of its target genes to other companies?
WH: Yes, we have. I think we were the first to discover the β-secretase.
ARF: Just the sequence?
WH: No, its role, too, although that's not widely known.
ARF: No, it's not. I associated it with the Amgen team and another, academic, group.
WH: I think we have priority over all those groups. It's been worked on by one of our partners.
ARF: Do you hold intellectual property over BACE?
WH: I suspect we do, yes.
ARF: BACE therapies?
ARF: BACE is a difficult enzyme to inhibit with small-molecule drugs. There was a spate of a half-dozen papers on BACE inhibitors in the literature about 2 months ago but I think those are experimental.
WH: Yes. We're not doing that work directly ourselves.
ARF: Why hasn't HGS entered into it?
WH: We are focusing on oncology and immunology, that is immunology as related to infectious diseases.
ARF: Are you not interested in neuroimmunology and the inflammatory component to Alzheimer's?
WH: I'm interested in it, but HGS does not work in it.
ARF: Would you like to add anything else?
WH: No, it's been an interesting conversation.
ARF: Thank you.
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