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From Genome to patient: A new productivity paradigm for the pharma industry Dr. William A. Haseltine Chairman & CEO Human Genome Sciences Inc.

By Editor on Jan 25, 2001

From Genome to patient: A new productivity paradigm for the pharma industry

Dr. William A. Haseltine
Chairman & CEO
Human Genome Sciences Inc.

It's a pleasure to be here this morning to address the issue of the application of the enormous advances in understanding genes of humans, genes of other organisms to the pharmaceutical industry. This indeed has been a miraculous time. Over the past few years we have accumulated the complete genetic text of a number of microorganisms, many of those some of the most devastating pathogens that have affected our fragile species throughout the ages. We have been able to read the genetic text of yeast, of a worm, a fly.

Now, we are about to glimpse, for the first time, the assembled text of a human being. And then other mammalian species. These are accomplishments that will echo through the ages and it's our task at the beginning of this new era of understanding living forms, it's our task as members of the pharmaceutical industry, as members of the medical community, to begin to provide a framework for application of this enormous gift we'sve been given by our own efforts and the efforts of many of our most brilliant scientists. To apply this, to curing human ills, that is the task of the pharmaceutical industry, to take this knowledge, reduce it to a practical form. There is, in some ways, a number of debates underway as to how best to do that. And some of these debates go back deep in our history, our history of trying to understand the living world.

And as I see it, there have been 2 general schools of thought which, although intersecting from time to time, have different motivations and quite different consequences. When we come to observe the living world, one thing that has been remarkable is the observation that like begets like, that difference begets difference. That's a fundamental observation and throughout the ages it's been a very profound observation that allows us to understand and to manipulate the living world to our benefit. It is that observation that has led to the remarkable progress in agriculture and the rise of civilization itself. It's been that observation that leads to the domestication of our animal species, to the creation of virtually infinite varieties of animals that we use for economic and other purposes or for companions. Just look at the dog as an example of the practical implications of that knowledge. But that impetus to understand like begets like and difference begets difference, has not been regularly applied to ourselves, as a species. In fact, when we come to apply the concepts of pure breed, of strains, of genetic improvement, of selective breeding, to ourselves we find it repulsive. We find it something that ought not be done. We find enormous antagonism and I think justifiably so because where it has been the results have been nothing short of horrifying. And it is that reaction, in part, that we have to the work, this splendid work that's been done. It is not a pure good and it is not seen by our fellows as a pure good. It is seen as a mixed blessing because we know the power of this type of observation. We are being given ever more powerful tools to implement it and we are in fact afraid of ourselves.

Now, we have just been given or are about to be given, thanks to the concerted efforts of a number of us, the ultimate key to that knowledge of ourselves, to our inheritance. That

is, not only the complete genetic text of a human, but a beginning of an outline of a sum total of many, if not most, of our variations. And the question for the pharmaceutical industries, specifically, and a question for society at large is, what do we do with that knowledge? Now, many of you are practicing in the pharmaceutical industry, if not most of you. And you may well puzzle over that question because the answer is anything but obvious.

One answer is to begin to try to understand the consequences of genetic variation in our species for disease. And in fact we can look forward to a veritable torrent of information on that topic, pouring from laboratories around the world, enabled, speeded up and made possible by these remarkably powerful new tools. And the question then will be, what will medicine do with that knowledge? Can we predict without cure? And if we cannot cure or alter, do we want to predict? And, is there a practical business in the ability to predict without cure?'s Now surely it will not be all black and white. We already know there are some things we can do with some of our ability to predict. We can intervene early in some cases, but we should know from the present and you should know from your own observation that there are many genetic diseases we can predict today. There are some which we can alter through surveillance and medical intervention, but we do a very poor job of using even the knowledge we have. Take, for example, inheritable non polypoid carcinoma, the most prevalent inherited cancer in the western world. We'sve known for some time the 4 or 5 genes that lead to a very high incidence of that disease, yet we do virtually nothing with that knowledge.

I challenge anyone of you to go to your doctor and ask for a test, for your own genetic predisposition to that disease and see how long it takes you to get any kind of response. There is not a business there yet and it may be a very long time before we use this new power to see our genetic future for any sort of common good. Now we are hopeful, in general, that time will enable us to reach into the human body and change genetic destiny, once we have been born. Whether that comes from gene therapy, whether that comes from our ability to selectively alter specific nuclear tides or groups of nuclear tides, in the adult, possibly in the child, and more problematically in the unborn child, remains to be seen because that is in, at present, the distant future. We can begin to approach that in some animal models, but I believe it will be many decades before the full fruit of this knowledge of our genes and their implications for our health will see practical medical applications and it will not be, I predict, in most of your working lifetime. Some of us, particularly those in academia, will work diligently toward that. There will be those brave few pharmaceutical start up companies, biotech companies that embark on that long and difficult path, but most of us will not see that day, I believe.

What then is the pay off in our immediate future of this work? Well, another answer to the question is, if the insight doesn'st lead to our ability to change genetic destiny, it may allow us to define diseases with enough precision that we can use this marvelous machine we'sve created, which is the modern pharmaceutical company, which it's ability to generate millions and even tens of millions of chemicals, to apply those to discreet targets, to find drugs, to alter the biochemistry of our bodies and that the insight that is gathered from this understanding of inherited disease, whether it is a single gene or multiple genes that lead to that, will in fact be the key stone that unlocks a pathway that allows you and the pharmaceutical industry to use our extent skills to move forward in a clear path to find a new target. But we can already look to the present to see what kind of effort, what kind of yield that knowledge may have. And when you consider the kind

of knowledge that generally flows from studies of genetic disorders and their ultimate cause, we find a picture which is not particularly encouraging for the pharmaceutical industry, because we find that we can often answer the question, why's, why we get a disease, why one amongst us gets breast cancer or colon cancer or perhaps eventually schizophrenia or other diseases. But those answers of why's do not generally lead immediately or even after a great deal of effort in some cases, to a simple pharmaceutical resolution. We often have a question why's, for example, with breast cancer. The inherited genes for several forms of breast cancer, yet there is no obvious pharmaceutical remedy on the horizon. And as we do our diligent work and trace through the relevant biochemical contacts we can begin to accumulate groups of proteins that touch other proteins and go through the network, this elaborate network of cell regulation.

We are still at a loss, after 10 years of intensive work of having a point of intervention that may prevent those women from getting breast cancer and that is more the rule than the exception and those of you who work in the pharmaceutical industry know that's true. And so most of the effort that we hear about these marvelous breakthrough's in understanding our inheritance are indeed fascinating because they address one of the deepest questions we have about ourselves. Why are we the way we are? And why are we different from others? But as practical men and women who have a task of changing our health, that knowledge is at least to date of relatively low yield. Now I don'st believe that this knowledge is without practical end. There will be very specific and there are always going to be good examples, there are today, of how genetic causes can lead to treatments of disease and I am sure you can think of several examples. But you can probably count those examples today on all your fingers or possibly including some toes. So, it's not a lot.

There is another very deep tradition for trying to understand the living world. And it differs in many respects from the tradition of the geneticist, what I just summarized is genetics, of course. And the ultimate tool for genetics is the entire genetic code, the storage form of our genes, the form in which our genes are transmitted from generation to generation and understanding those variations and that is why geneticists are extremely pleased, as they well should be, with this new found power. But there is a different tradition in biology and that is the tradition of the anatomist. Whether it's studying the structure of a plant, whether it's studying the organs of an animal, whether it's studying the marvelous human body itself, it is a very distinct and different tradition from that of the geneticist. It is the anatomist, after all, that has provided us for one of our first systematic medical treatments, surgery. Where are the bones, where are the arteries, where are the muscles, where are the ligaments? And we can look deep into our history and see that people have been studying human anatomy. It is a study that says, regardless of how this structure came to be, regardless of it's inheritance, I can begin to understand a living system as a marvelous machine and people described it as a machine, of working parts that work together. I need not know its origin to understand it's function. They are, of course, in part related, but they are also quite distinct. In the last 2 centuries another form of that question has been the question of the physiologist, asking again, how does this body work? What is respiration? What is nutrition? What is the pulse? What is sensation?'s Physiology is a continuation of anatomy. It asks how this machine works. And biochemistry in the last 100 years has moved even further in helping us understand the marvelous machine that is our body. Understanding the chemistry, understanding the enzymes, and it's modern application of molecular biology,

understanding control of these genes in the hormone networks that make the body work, is an extension of that fundamental question, how does this machine work? And therein has been a cornucopia for medicine. If you look back over our medical progress, what we actually do in our hospitals today, what you do in your laboratories, it has it's origin, almost entirely in physiology, biochemistry and to some extent modern molecular biology. It rarely, if ever, has its origin in genetics, because when you study nerve transmission and look for new drugs to alter states of mind. When you look for new drugs to improve the functioning of the heart muscle and you look at specific enzymes, when you look at new pathways for bone degradation or bone deposition, you are generally not looking at genetics, you are looking at discreet parts. And therein lies another revolution which is related to, but distinctly different from, what you have mostly heard flow from the human genome project.

It is in fact a different definition of genome, not genome as it relates to this storage form of our genes, a form in which the genes are not actually used, they are passed on from one generation to the other, or passed on from one cell to the other, but the form in which the genes are used, those spliced, contracted, messenger RNA's that are used to make our proteins. And we are now in the process, well along in the process, of creating a new basis for anatomical understanding, a new basis for understanding physiology and a new basis for understanding pathology and development. That is, understanding the complete set of express genes. And in that sense, genome does not necessarily have to refer to the form in which genes are stored, it can also refer to that complete set of genes as they are used by our bodies. Genome means, of course, all genes. It does not only mean all stored genes. And it is in that context that this revolution is immediately and dramatically affected in the context of our industry. Because that change in our ability to handle most of these genes in the form in which they are actually used by the human body, has already transformed much of our industry and is rapidly transforming the rest.

What are the examples of that? Well, as most of you know, at the beginning of the last decade, the industry experienced a rare shortage. The shortage was on targets for discovery, what to work on. Seen more broadly, it was a problem of the desire to treat and cure disease and it's link to a rational starting point. The enzyme, the protein that you needed to modify, to treat a specific disease. There were perhaps 65, you might argue as many as 100 common targets, and if you took that 100 targets and you took the efforts of the pharmaceutical industry, they would largely overlap and there were many areas in which people wished to work in which there were great lacunae, great black spots. You could relate the desire to treat and cure a variety of diseases with a coherent and clear starting point and we had to rely, for the most part, on the efforts of the academic scientist. The academic scientist is like wild cat oil, explores, dig where they want, how deeply they want and when they want. We had no systematic tool. That has changed in the last decade. Not because of the genomic efforts to understand inherited genes, but by those of us who have compiled systematic collections of messenger RNA's related to organ tissue and pathological state. We can now reach into these collections and ask a series of rather straight forward questions to link our desire to treat and cure disease with a rational starting point. Those of you who are in the pharmaceutical industry know that that is the primary tool you use today and it is not a recent tool, it is a tool that has been acquired over the past 5 years. That transformation is driven deeply into the discovery process. If we want to start working on osteoporosis today, we look at the genes expressed in osteoblasts and osteoclasts, we make a

decision as to which of those are likely to either, if we modify them, retard bone degradation, or increase bone deposition. And I can think of 5 new targets in the last 5 years that have been discovered using principles of modern gene anatomy for that one disease alone. And we can go through the body. So, today, if we take the sum total of targets for small molecule drug discovery, there are literally several hundred new targets, widely distributed, throughout the pharmaceutical industry. So, we no longer have, for the most part, this bunching of all of the pharmaceutical discovery efforts on the same targets. We have a diversity, a richness which we have not experienced hereto fore in our discovery targets.

Now, as you also know, knowing where to start is only part of finishing the job. And what has been the shock, and I might say reasonably horrible shock, is that knowing where to start has not appreciably impacted as yet our ability to finish the job in terms of bringing new drugs to patients. And I would argue, the primary reason for that is that almost all the efforts the large pharmaceutical companies have focused on in the use of this new technology, is to use these splendid new tools for older purposes, chemical discovery. And it is the processes downstream after the target has been defined that are now the roadblocks. It is not having a large collection of chemicals, it is not the ability to screen through those chemicals, it is not structural biology or rational drug design, it is the complexity of fitting a novel chemical into the human body, not only into the human body in it's variable form, but in the human body in the forms in which it is now modified by other drugs. It is drug, drug interactions. The favourite target of our drugs is a 65-70 year old person, already taking 3-4, sometimes 5 or 6 other drugs. The industry will not experience the growth in productivity which is needed, despite these new and powerful tools, in my opinion, for another 10 or 15 years. So, we are looking forward to another 10 or 15 years of relative dearth in new products. Now those products will flow. We will have those products but in 15-20 years. That's how long it takes. And nothing that I have seen, and I would argue, little you have seen, has speeded that process.

Now I believe there is a better way to use this genetic information, this new information about our gene anatomy. It's the way we'sve chosen. Because the most direct way to use it is to use our human proteins, to use our human antibodies as drugs themselves. Now, with rare exception, that is not the favourite path of the large pharmaceutical industry. They would argue, 90% of drugs of the past have been small chemicals. Therefore 90% of drugs of the future will also be small chemicals. I don'st believe that will be the future. I think 20 years from now, half our new drugs will be human proteins and antibodies and half will be new chemicals. And those companies that understand that most rapidly, that incorporate that concept most thoroughly will be the winners 10 years from now, and those that stick to the chemical discovery paradigm will be the losers. And why is that? Because we all know that it takes the same amount of work to validate the medical utility of a novel human gene, whether it be a target for a small molecule or whether it be a protein itself or antibody target. Yet the subsequent path is dramatically different. From identification of the potential medical use of a novel human protein to it's initial clinical trial, can be a matter of 6-9 months and has been in our case and in many other cases. From the identification of a novel human protein as a target for an antibody to the initiation of a clinical trial of a novel fully human antibody, maybe 9-12 months and the types of diseases that these proteins and antibodies treat are exactly the types of diseases, degenerative diseases, diseases of the aging, that the industry today prefers to treat. Rightly or wrongly, those are the diseases we as an industry prefer to treat.

And so I don'st believe that it is any accident that the first fruits of this new revolution are 5 drugs, currently in human clinical trials. 4 from my company, small as it is, 1 from Amgen. And I believe the next fruits, the next 10 drugs maybe 1 chemical and 10 more proteins or antibodies. That is the route for success. It is based in anatomy, it is a path which we know can be fruitful. It is the most direct application of our new found knowledge.

So, to summarize. We certainly are in a marvelous age. We can use our new tools for a variety of purposes, to understand ourselves, our differences and the causes of our inherited diseases. Therein lie many problems, some of which have been eloquently expressed by our Chairman. Knowledge without end. But there is another and different tradition to which we have put this new found power to understand our genes. And that is a redefinition of human anatomy, physiology, pathology and development. It will and has already triggered a revolution in chemical pharmaceutical discovery, but the shortest, and I believe, most productive route to change, change in our lifetime, change in the next 10 years, will be the direct application of this knowledge to the creation of broad new sets of human therapeutic protein and antibody drugs. Thank you.