William Haseltine, Founder, Chairman of the Board and CEO, Human Genome Sciences
What would it take to be able to engineer an unlimited human life span? Although nobody knows for sure, being able to manipulate the complete "parts list" of all the molecular building blocks of the human body would be a nice resource to draw on. Human Genome Sciences claims to have something very close to that-a copy of almost every human gene in test tubes, and the ability to use them as drugs. Dr. William A. Haseltine is the Founder, Chairman of the Board and Chief Executive Officer (CEO) of Human Genome Sciences, a powerhouse biotechnology company that claims to have discovered over 90,000 human genes and to have filed patent applications on many of the most useful ones. Human Genome Sciences (ticker symbol, HGSI) aims to create a new era in medicine, in which its gene-based products are used as specific, non-toxic, non-allergenic medicines that replace many drugs. Along these lines, Dr. Haseltine coined the term "regenerative medicine," and then a newer term, "rejuvenative medicine," to describe the expected medical revolution that, in his view, could lead to human immortality. Dr. Haseltine talked to us in an exclusive interview conducted by Gregory M. Fahy, Ph.D. on Sept. 10, 2001.
Life Extension Foundation (LEF): Can you tell us how big Human Genome Sciences is?
William Haseltine (WH): We have about 1,000 employees. We have about 450,000 square feet, including about 350,000 square feet of manufacturing space. We have six products in clinical trials. Our income is about 25 million dollars a year from transactions. We have income from interest of about 100 million dollars per year. We have about 1.7 billion dollars in cash assets. We are very well capitalized.
WH: Yes. This approach offers a number of advantages. First, it is a way of reducing the complexity of finding genes by more than a hundred-fold. Only one one-hundredth of the genome gives rise to messenger RNAs.
Second, if a messenger RNA exists, it means the cell has transcribed the corresponding part of the genome [actually used a gene to make an active mRNA; see sidebar-Ed.] and is ready to use it to make a protein. In other words, there is no doubt that the information in the messenger RNA is relevant to the cell.
Third, because we can isolate messenger RNAs from specific tissues, we can gain some idea of where in the body and under what conditions those messenger RNAs are being used. That gives us a clue about the roles they may play in the body.
Fourth, we can copy a specific messenger RNA into DNA [thereby making "complementary DNA," or cDNA, which has the same information content as the mRNA being copied-Ed.], and then we can use that DNA to program a cell to make more copies of the original mRNA and therefore, more copies of the protein it normally produces.
One cannot do that from genomic information alone. We knew in 1992 that genomic information would not easily lead to whole genes, because the genes cannot be read from the genome in a direct way.
Between 1993 and 1995 we isolated at least one copy of what we believe to be more than 95% of all human genes. There is still a dispute over how many genes humans have. We think there are close to 100,000, and we have actually isolated 90,000 unique genes. About 60,000 genes remain to be found by others analyzing the human genome.
LEF: Have you isolated all those genes from adult tissues?
WH: We have also looked at fetal tissues, embryonic tissues, tumor tissues and other diseased tissues. We have looked at more than 1000 primary human tissues.
LEF: How sure can you be that the RNAs you've isolated are full-fledged RNAs and not just fragments or pieces of bigger mRNAs that are being recycled? You might translate meaningless fragments into proteins, but they might not be proteins that are actually made in cells.
WH: We have tested that possibility thousands of times. Typically, we look at the longest messenger RNA in our collection, then analyze it. In most of the cases we were able to make fully functional proteins, the same as those found in cells and tissues.
LEF: What about different alleles [variations of given genes, like brown and blue as variants of the eye color gene]? Is that a problem? Do you get all of these?
WH: For the most part, we ignore allelic variation. Alleles usually represent minor variations in function. We often have a choice of which alleles to take. We usually make proteins from the predominant allelic type.
LEF: If you were to give that dominant version of the protein as a therapeutic agent to a patient who did not make that version of the protein, is there a chance of an allergic response or an attack on the foreign protein?
WH: Generally, no. That is why insulin works for most people. That is why human growth hormone, g-CSF, gm-CSF [bone marrow related proteins] and many other proteins, work for most people. Humans tolerate proteins with non-self allelic variants. The moment we stop tolerating the alleles of others, we will no longer be members of the same species.
Even human antibodies can be used as drugs. Antibodies are created by individuals in response to a particular set of circumstances. Today those antibodies can be created in the test tube. They are extremely well tolerated when injected into the body. One might expect the body to make antibodies against the injected antibodies, but this does not appear to happen.
LEF: As you know, what we generally hear these days is that there are only 30,000 to 40,000 human genes, not 90,000 to 100,000.
WH: One of the first human genome publications said there were 26,000 genes. And another publication said there might be 30,000 genes. Then a paper (Genome Biology 2001 2(7): research 0025.1-0025.18) reported that most of the genes referred to in those publications were not the same. The new paper estimated that there are 65,000 to 75,000 human genes. So are we to believe there are 26,000 genes? Or 70,000 genes? The detection of different numbers of genes by different groups shows just how poor the methods of identifying genes from chromosomal DNA really are.
LEF: I've heard it said that there may be an average of three different splice variants of [different ways of using] each gene, and that might amplify the total effective number of genes.
WH: Such analyses fail to consider that almost all splice variants have the same function. That means it is still usually true that one gene corresponds to one function. Most of the time, for drugs based on human genes, the rule to remember is still one gene, one protein, one drug.
LEF: Are you personally responsible for the mission of Human Genome Sciences? Is the company fulfilling your dream?
WH: I am the one who shaped its formation and direction.
Our original mission was (and still is) to improve human health by bringing a wide variety of new products to patients and to treat diseases that could not previously be treated. Specifically, we seek to bring new protein and antibody drugs to market. Our goal is to become an independent global biopharmaceutical company. From the outset, we established four specific objectives.
First, to be the first in finding most human genes in useful (that is, in cDNA) form. We accomplished that objective in mid-1995.
Second, to create systematic means to turn knowledge of new genes into medical uses. We wish to do that both for ourselves, so we can create new human protein and antibody drugs, and for our partners, so we can enable them to create new small-molecule drugs.
Third, to share our newfound knowledge with large pharmaceutical partners, which we have done.
We had a seven-year relationship with a group of pharmaceutical companies led by Glaxo-SmithKline. During that period, our partners used our technology to initiate about 460 different drug discovery programs. The most advanced of these is the first small-molecule drug developed through genomics to enter human trials, a drug that Glaxo-SmithKline is using to attempt to treat heart disease. The drug inhibits an enzyme called PLA2 that creates inflammatory reactions in blood vessels.
Part of the third objective was to obtain substantial payments from pharmaceutical companies to support our own research, as well as to participate in the sale of products after they are developed. Human Genome Sciences is entitled to a substantial portion of the sales of drugs developed by our partners.
The final objective was to build the infrastructure necessary to discover and bring to market our own human therapeutic protein and antibody drugs. We are well along on that path. So we have executed plans to accomplish all our original objectives.
LEF: I understand that you have singled out a subset of genes that you consider to be particularly interesting for patenting.
WH: We are focusing on genes that control external signaling pathways. Those pathways instruct our cells, from the outside, to perform one or more of several simple actions.
The signaling proteins can be on the surface of cells or can leave the cell surface and circulate. Such proteins generally are exported from cells by a common pathway, which involves the use of "signal sequences." We have used that common pathway to isolate (in cDNA form) about 10,000 human messenger RNAs that have the ability to make proteins with a signal sequence. We believe that these 10,000 human proteins comprise most of the proteins that will be useful as drugs.
These proteins signal the cell to grow or to remain static, to differentiate or to remain unspecialized, to live or to die, to stay stationary or to move. Those are the basic functions that cells perform.
This set of proteins also includes the targets of most antibody drugs. Antibodies work on the outside of cells, not on the inside, and therefore must recognize structures that are either in the blood or other body fluids, or on the surface of cells. Proteins that can be targets of antibodies almost all have signal sequences.
That's why we have focused on this subset of about 10,000 genes. In their cDNA form they are stable, and we can use them to make proteins. We are systematically analyzing their functions through biological experimentation.
LEF: One of the things I understand you've done is to use a sort of robotic system to proceed from simply finding the original proteins to getting information about what their functions are. How can you do this when there are so many possible functions?
WH: We do analyses for one disease at a time. In one case, we were interested in diseases that could be treated by stimulating the immune system-either cell-mediated or antibody immune responses. We examined the ability of our set of 10,000 proteins to influence those processes. We have found several proteins that influence immune system function, which then became candidate drugs. One example is a drug we call B-Lymphocyte Stimulator, which stimulates cells that make antibodies. We have initiated two safety trials in patients with serious immunological disorders that leave them susceptible to a variety of infections. One group suffers from Severe Combined Immunodeficiency Disease; another group has Immunoglobulin A deficiency. B-Lymphocyte Stimulator might boost the immune system in ways that are beneficial in patients with AIDS. We believe that this protein has the ability both to boost the immune system's ability to fight ongoing infections and to potentiate vaccine activity. It seems to be the most potent stimulator of antibody production the body has.
LEF: So you simply search through the proteins until you find the best ones for accomplishing various predetermined tasks?
WH: Yes. We concentrate on substances with activities that fit a medical need.
LEF: In the past you've also talked about using genes as drugs. How do you make a gene into a therapeutic product?
WH: We view genes as specialized delivery vehicles for proteins. Genes, when injected into cells, can induce those cells to produce proteins. If one wishes a protein to persist for a longer period, one might inject a gene for that protein into a tissue. To date, the only tissue that works is muscle. Typically, a muscle cell will produce the protein for several weeks. Eventually, the injected gene will be degraded or otherwise inactivated, and production of the protein will stop.
We licensed one such gene to a company called Vascular Genetics, Inc. The company has attempted to create micro-vasculature in heart muscle by direct injection of DNA into that muscle. In preliminary experiments, the gene seems to have had some beneficial effect on cardiovascular disease in about 100 patients. There do not seem to be serious side effects associated with the use of this drug.
LEF: Are you using temporary rather than permanent gene transfer just in case something goes wrong?
WH: No. One does not necessarily need a protein to persist for a long
LEF: Are you also working on permanent insertion of genes?
WH: We are not pursuing that strategy. We think that for a variety of reasons, our purposes are best served by focusing on proteins and antibodies as drugs. The technologies and methodologies for gene therapy have not yet been adequately developed, in my opinion.
LEF: Even limiting yourself to therapeutic proteins, can 10,000 proteins really be exploited within the 20-year life of a patent?
WH: That number is not achievable even by the entire pharmaceutical and biotechnology industry working in concert. But we already have partners who are developing 460 drugs based on genes, and typical drug sales today for large pharmaceutical companies are $500 to $700 million per year.