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Genetic artist with an edge William Haseltine sneers at genome project, emphasizes new drugs Sunday, June 25, 2000 By Byron Spice, Science Editor, Post-Gazette
Wearing a ruffled shirt and a bow in his hair, Luis Egidio Melendez holds a paintbrush in his right hand and a sketch of a man in his left. Garbed in a business suit with his thinning black hair slicked back, William Haseltine holds a pen in his left hand and a chart of human proteins in his right.
These images -- a 1746 self-portrait by the Spanish painter and a photo of the biochemist -- are juxtaposed in the annual report of Haseltine's company, Human Genome Sciences.
The symbolism isn't hard to grasp. Haseltine is redrawing the human body, one protein at a time. And Haseltine, a man not noted for his modesty, no doubt savors the biochemist-as-artist analogy.
"There's a new medicine being born under everyone's eyes," said Haseltine, speaking in a calm, soft voice at his Rockville, Md., headquarters. The source of what he calls "regenerative medicine" is brewing in fermentation tanks on the floor below: natural proteins, including hormones and antibodies, that will help the body heal itself or compensate for deficits.
Think of what insulin has done for diabetics and imagine that approach being applied to afflictions ranging from bedsores to osteoporosis, from high blood pressure to lymphoma.
It's all made possible by the ability to discover genes, identify the proteins they make and then find how the body uses those proteins. In 20 years, Haseltine predicts, half of all medicines will be proteins, hormones and antibodies that strengthen muscles, thicken skin and repair nerves.
Peering through wire-rimmed glasses, Haseltine takes a dim view of the Human Genome Project, of which Human Genome Sciences is a spinoff. "Techno-folly" is how he describes the quest to map and sequence all of the human genes.
Completing the genome project, he said, "will have a marginal impact on what we do and it will have a marginal impact on the pharmaceutical industry." Most of the DNA in the genome is junk, he argues, and doesn't mean a thing. The crucial part of the genome is the tiny fraction of DNA that comprises the genes, and he claims that his company already has identified most human genes.
The Human Genome Project, he says, may be like putting a human on the moon: "Quite an achievement, but what does that let you do?" The practical applications of the Apollo program were nil, he said, in contrast to military and spy satellites, which helped spawn the global telecommunications network.
"What transforms life? Going to the moon, or being able to make a cell phone call?"
Keeping secrets
That kind of talk irritates geneticists such as Aravinda Chakravarti of Case Western Reserve University, who led development of the Human Genome Project's latest five-year plan. "I wish him well, since if he succeeds that is good news for all of us consumers," Chakravarti said. But he's leery of many of Haseltine's claims, noting that many are based on data that have yet to be published.
Chakravarti, who specializes in the genetics of complex diseases such as hypertension, maintains that the approach that he and his colleagues have taken is sound -- that understanding the mechanisms of disease will eventually lead to better treatments.
"I cannot fruitfully disagree with Bill Haseltine because I publish my data and discuss my ideas along with all of my colleagues in the scientific community," Chakravarti said. "He does not."
Haseltine, 55, hobnobs in celebrity circles in Washington, D.C., and New York with his glamorous wife, Gale Hayman, a former model who runs a New York cosmetics company and developed the fragrance known as "Giorgio."
But his roots are in the California desert, where his father was a physicist at the Naval Weapons Center at China Lake, and much of his life has been spent in the lab. In graduate school at Harvard University, he worked in the labs of James Watson, who won the Nobel prize in 1962 for discovering DNA's molecular structure, and Walter Gilbert, who won the prize in 1980 for developing a method for sequencing DNA.
He stayed at Harvard for 17 years after earning his doctorate in biophysics, performing cancer and AIDS research at Dana-Farber Cancer Center in Boston. He collaborated with Robert Gallo of the National Institutes of Health to develop the theory that AIDS is caused by the human immunodeficiency virus, and he was the first to sequence HIV.
Then, in 1992, J. Craig Venter, a National Institutes of Health scientist involved in the Human Genome Project, persuaded Haseltine to go into business with him. Human Genome Sciences was the result.
Finding active genes
Venter had developed a scheme for rapidly identifying "expressed" genes.
Though the genome contains thousands and thousands of genes, only some are expressed -- actively functioning -- in any given cell. Some cells express the genes for producing insulin, for instance, while others express the gene for producing a brain chemical such as dopamine.
Venter planned to identify these expressed genes by looking for messenger RNA -- the molecule that helps the gene produce a working protein. There would be no need to figure out the sequence of the entire gene, which includes material not directly involved in protein production. To make pharmaceuticals, they only needed the machinery for producing the protein.
"He was right," Haseltine said. Using their highly automated process, Venter was able to identify thousands of genes and Haseltine was able to figure out what they did. By 1996, they had found virtually every human gene, he contended. "The technology worked much better than we thought it would."
In fact, Haseltine contends, the success of their technique has upset his old colleagues in academia, who he claims are all but obsolete. "Scientists are now being replaced by machines," just as surely as typewriters have been replaced by computers. "People said this would never happen ... We've created assembly lines to produce knowledge," and the cottage industry of academia simply can't compete.
Not long after discovering the gene identification technology, though, the interests of Venter and Haseltine diverged. Venter left in 1997 to create the nonprofit Institute for Genome Research and, later, the for-profit Celera Genomics, an information services company that is independently sequencing the genome. Haseltine focused on using his company's genetic resources to develop pharmaceuticals.
Haseltine said the company has focused its attention on those genes with the most pharmaceutical potential -- a subset of genes that makes about 15,000 secretory proteins. These are proteins that send signals to cells to grow and divide, move or commit suicide.
To figure out which ones might have therapeutic potential, the company has created systems that make it possible to test a cell culture against 10,000 to 15,000 of these signaling proteins at once, measuring 200 ways that the cells can respond to each of the proteins.
A healing protein
One protein, for instance, was found to induce healing in skin and mucosal cells that had been damaged, but had no effect on healthy cells. Dubbed keratin growth factor 2, or KGF-2, it is the most advanced of the Human Genome Sciences drugs now in clinical trials. In late May, company officials announced that KGF-2 had proven safe and effective in a 94-patient trial on treating chronic venous ulcers -- large wounds that form where blood pools in the legs, often near varicose veins.
The same drug might be used to treat bedsores, burns and diabetic ulcers, Haseltine said. Clinical trials are being conducted now to test its effectiveness in treating burns to the mouth and intestines caused by chemotherapy taken by bone marrow transplant recipients. Other trials may start soon to test it for treating ulcerative colitis, a disease in which the intestines become inflamed, causing diarrhea, cramps and fever.
Another promising product identified through this testing is B-lymphocyte stimulator, or BLS, which was found to increase the activity of disease-fighting white blood cells called lymphocytes. BLS might be used to boost antibody production in the elderly, in AIDS patients and patients recovering from chemotherapy and organ transplants, Haseltine said. Trials could begin this summer.
And, by coupling BLS with a radioactive isotope or toxin, he added, the company may be able to use the protein to treat B-cell tumors, such as multiple myeloma and B-cell lymphoma.
Conversely, designing an antibody to attack BLS might provide a way to dampen the immune system, providing treatments for diseases such as lupus and rheumatoid arthritis, in which people's immune systems attack their own tissues.
The same automated system of discovery, Haseltine said, has found a brain chemical that affects the desire to eat and to sleep. This might lead to treatments for obesity and narcolepsy, he added.
These proteins aren't as convenient as a pill; for now, they must be sprayed, injected or inhaled. And though they are natural, they can have side effects. Following a patient death, the Food and Drug Administration this spring halted clinical trials by Vascular Genetics, a company that had licensed one of Human Genome Science's discoveries to treat heart disease by gene therapy.
No Human Genome Sciences drug has made it to market yet, but Haseltine says this process -- discovering a gene, isolating its protein product and then finding how the protein is used -- will speed pharmaceutical development.
And displaying the acid edge he is known for, Haseltine concludes that using the exploding wealth of genetic information to produce drugs is far better than using it to devise genetic tests to tell whether someone has a condition or is susceptible to it.
Genetic tests, he said, make both doctors and patients uncomfortable. They often provide too much information, such as predicting increased risk of cancers and other diseases, without necessarily giving patients an opportunity to do much about it.
"The questions that geneticists ask are not helpful for medicine," he said bluntly. "They ask why things happen. But why doesn't necessarily tell you what to do. Our focus is on what you do about a disease."
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