An Ego in a Lab Coat Seeks Genetic ‘Fountain of Youth’
He is French cuffs and monogrammed shirts, slicked-back hair and chauffeured cars. Mogul Mort Zuckerman is a friend and Princess Firyal of Jordan is a party companion. Beverly Sills sits on his company’s board.
William A. Haseltine is not known for modest living or modest ambition. He was one of the brightest students at UC Berkeley and one of the world’s most important AIDS researchers. And he is quick to let you know it.
But for the scientist-socialite, all that was a warmup for what he plans as his great legacy: conducting a medical revolution that adds decades to the human life span--and puts the 55-year-old Haseltine at the helm of a new pharmaceutical empire.
The grand thinking is possible because of a tiny feature of the human anatomy: the gene.
Long before this summer’s news that scientists had mapped nearly all human DNA, a new breed of entrepreneur began racing to turn genes into breakthrough medical treatments--and big profits. In the process, one of the most crucial sectors of the medical world--the pharmaceutical industry--has undergone revolutionary change and is now on the verge of producing a bonanza of gene-based drugs. For many people, these new medications will be the first tangible benefits of the new gene era.
The race for gene drugs is a high-stakes scramble, bankrolled by investors who are now snapping up biotechnology shares the way they once bought dot-coms. “The opportunity is huge, and the one who hits it right has the chance to create the next Microsoft or Cisco or Intel,” said Jonathan Rothberg, chief executive of CuraGen Corp., a Connecticut-based gene research firm. “The person that has the right business model and the right execution is going to do really, really well.”
Human Body as Medicine Chest
Of all the businessmen laying bets, Haseltine is one of the most ambitious. A look at his work so far illustrates exactly how genes are bringing big changes to medicine. While many researchers focus on the genes that go awry in the body and cause disease, Haseltine was one of the first to pursue a novel idea: that genes also contain cures. To him, the human body is its own medicine chest, full of substances that genes already fashion to heal wounds, strengthen bones and fight infection.
As a result of that insight, computers throughout the pharmaceutical industry are scouring the genetic code systematically to find the genes that produce these natural medicines. Automated machinery runs hundreds of experiments at once to sort out the best candidates. Gone is the lone researcher following a hunch at the lab bench, pipette and test tube in hand.
Already, Haseltine’s Human Genome Sciences Inc., based in suburban Maryland, claims to have found hundreds of potential new drugs at a fraction of what big pharmaceutical companies spend on research. None is ready for pharmacy shelves but four have proved promising enough to move into human trials, more than any other company known to be using similar methods. Investors have heartily bought into Haseltine’s vision, giving the California native shares and options worth more than $330 million.
Biology has become an enterprise of big computers, big data sets, big money--and often, big egos. “Very, very large ego,” Jim McCamant, editor of the Medical Technology Stock Letter in Berkeley, said of Haseltine. “It’s an ‘I’m right and everyone else is wrong’ view of the world.”
Haseltine shrugged off the comment. “Eventually, everyone else will do this,” he said of his drug-finding method. “It’s so utterly logical and absolutely sensible. Everyone will realize that this is what you have to do. And in my experience in science, they’ll say, ‘We were doing it all along.’ And they haven’t been.”
Stumbling Through a Darkened Room
For all their success, pharmaceutical researchers often have investigated the body as if stumbling through a darkened room.
What they look for are “targets,” or specific places in a cell where a drug might have some effect. Most targets have turned out to be receptors, or proteins on the cell surface that receive messages telling the cell to do something.
In the 1970s, for example, James W. Black discovered a chemical that blocks a histamine receptor, stopping cells from producing stomach acids. The result was Tagamet, the blockbuster anti-ulcer drug. Another Black discovery binds to a beta receptor and has the effect of lowering heart rate and blood pressure. It led to the big-selling hypertension drug Inderal.
But finding a novel target and a drug to affect it is difficult, often the result of inspired guesswork. Decades of research have turned up fewer than 500 targets in the body, maybe one-fifth of what exists. With targets so scarce, companies spend huge resources on “me too” drugs that might work a bit better on a known receptor. Tweaking Black’s discoveries led to Zantac, which competes with Tagamet. Inderal spawned Lopressor and Tenormin. They give more options to patients, but all are aimed at the same targets in the body.
Now, drug makers have something unimaginable in Black’s heyday: a list of thousands of possible drugs and drug targets. In essence, it is the constantly growing list of human genes, each of which creates a protein that might be a new drug or drug target.
“That’s why they’re all excited. That’s why Wall Street has gone nuts,” said Dr. David Flockhart, a pharmacology specialist at Georgetown University in Washington. “It’s not irrational. It’s real.”
Today, a full catalog of human genes is more or less in hand. But, as Haseltine launched his company in 1992, many researchers thought it was decades away.
A Child of China Lake
Haseltine is a product of China Lake, Calif., a Mojave Desert community that is home to Navy weapon designers and fighter pilots. Spurred by the scientists around him and by sickness in his own family, he trained with DNA pioneer James Watson and other famous scientists, eventually winning a faculty appointment at Harvard Medical School.
At Harvard, Haseltine became one of the most prominent researchers in the early years of the AIDS crisis, helping lead the effort to find the genes of HIV and to understand how they did their deadly work. He also started several drug and vaccine companies, earning enough money to erase financial worries from his life. An art aficionado with a fondness for 11th century Indian bronzes, Haseltine became known for sizzle as well as science. His reputation only grew with his second marriage in 1991 to Gale Hayman, a ballet student turned cosmetics entrepreneur.
They made an attractive pair: He was trained by Watson, she was trained by choreographer George Balanchine. Together they threw dinner parties for business leaders and European celebrities. Hayman exuded glamour. With her first husband, she had built the boutique Giorgio of Beverly Hills into an icon of the 1980s, then scored again with the blockbuster Giorgio perfume and sold the company in 1987 to Avon Products Inc. for $165 million.
“Haseltine was a big personality, and that’s sort of an understatement,” said Lydia Vorsteveld, a former research assistant at the Boston cancer facility that was home to Haseltine’s lab. She remembered asking her boss once how to pronounce the scientist’s name. “It’s ‘Hazzle-teen,’ ” came the reply. “Rhymes with razzle-dazzle.”
Haseltine’s move into gene-based drugs came when a venture capitalist teamed him with Dr. J. Craig Venter, who had developed a way to find genes quickly. At the time, all the researchers in the world had turned up only about 2,000 human genes, while Venter in short order had found twice as many on his own.
Venter’s insight was to look not for the genes directly but for telltale molecules that cells create to “read” genes when it is time to make a particular protein. Haseltine said he realized that Venter could quickly find all the genes in the body, which could become the central asset of a new pharmaceutical company.
Human Genome Sciences, or HGS, was founded in 1992, with Haseltine as chief executive. The partnership lasted only five years before Venter left and went on to make his mark by founding Celera Genomics Group, one of the two teams that has mapped out nearly all the human DNA. But well before his departure, Venter helped HGS find parts of tens of thousands of genes, representing what Haseltine said was 95% of all that exist in the body. Haseltine said that the company has found about 120,000 genes, a claim that irks some scientists who believe that could be more than exist.
With a list of genes in hand, Haseltine set out to develop drugs. He decided to focus on the limited set of genes that make proteins involved in cell-to-cell signaling. He reasoned that many medically interesting phenomena, such as hunger, immunity and healing, must at some point involve cells giving instructions to other cells.
Using software, HGS scientists trolled through their list of genes to find those with a chemical sequence that suggested they were involved in relaying signals among cells. About 14,000 genes turned up and HGS decided to synthesize the actual proteins encoded by about 10,000 of those genes.
Then the company ran massive experiments to determine what job each protein performed in the body. They put a variety of cells into tiny dishes--skin cells, blood cells, immune system cells--and using automated machinery exposed the cells to each of the 10,000 proteins. Did the cells multiply? Did they die? Did they differentiate into other types of cells?
By measuring changes within the cells, HGS scientists generated a huge database of information about how each protein functioned. Now that database is a tool for discovering new drugs.
At HGS offices recently, Haseltine demonstrated how the database works. He showed a visitor how to turn up a protein that boosts the immune system by spurring the growth of T-cells, a type of immune cell. Scientists already have found one such protein, called IL-2, but its medical use is limited because it acts on more than just T-cells, causing side effects.
“So, we want to find a better IL-2,” he said. “We start out with the assumption that the body makes one,” as people do not naturally suffer side effects every time their bodies grow T-cells.
With a few keystrokes at a computer, an aide told the database to show every protein ever tested by HGS that caused T-cells to grow vigorously. Four genes popped up on the screen. A few more keystrokes brought up data about how the four proteins had performed in tests on more than 100 other cell types. That information is key, Haseltine said. If a protein affects a large number of cell types, it likely will cause side effects if turned into a medication.
Of the four proteins Haseltine showed, only one stimulated the growth of T-cells and only of T-cells. “So now we have a new drug candidate,” he said. “We’re conducting studies on its suitability for human use and, if we’re lucky, we’ll have clinical trials by the end of next year or the following year.”
It was through similar methods that HGS found the drugs that are now in human trials.
Company scientists wondered whether any proteins in their database had the effect of making skin cells grow. They found 10, but nine also made other types of cells grow. The one that stimulated only skin cells is being developed as Repifermin, a drug that may one day help people with bedsores and other persistent skin wounds.
In another experiment, HGS scientists found a protein that temporarily stops the growth of cells that create components of the blood system. It is now being tested under the name MPIF as an aid to people undergoing chemotherapy. Because chemotherapy kills cells that grow rapidly, a temporary halt in blood cell growth could protect a patient’s blood system and ease recovery after the cancer treatment.
Haseltine became excited as he talked. “This is unbelievable,” he said of his database. “This speeds up biological discovery a hundredfold, easily. Easily.” The result, he said, is a virtually limitless supply of good candidates for the development of drugs.
Haseltine’s method has competitors and limits. Other companies are also using automated methods to compile lists of genes and to glean information about how genes might cure illnesses. “We have a lot in common with what Henry Ford did” in creating the assembly line, said Rothberg, the CuraGen chief. “Now that we have the whole genome, let’s march through it to see which genes have a role in disease.”
Haseltine’s drugs might have a limited appeal to patients, since proteins cannot be made into pills and are generally delivered intravenously. Some competitors, such as Millennium Pharmaceuticals Inc. of Boston say that they have made big advances in using genes to create drugs in convenient pill form.
Haseltine’s method is designed to find one set of possible drugs, but it does not cast its net for many others. His database probably does not include the sections of human DNA that turn genes on and off, said Dr. Joseph G. Sodroski of the Dana-Farber Cancer Institute in Boston, a former student of Haseltine’s. Understanding those instructions could lead to elegant ways to shut down overactive genes that are causing disease.
And Dr. Robert C. Gallo, the famed AIDS researcher, said that HGS would not likely turn up a fragment that splits from a protein, which might be a good drug candidate in its own right. “I don’t want to come across as being negative about Bill’s company. . . . But I want to make sure we don’t all go blindly that way” into automated drug discovery, Gallo said.
Impulse to Develop Drugs
Haseltine’s impulse to develop drugs came from the sickness he saw around him as a child.
As a 10-year-old, he developed inflammation of the heart lining, which required him to stay in bed for months. His mother, Jean, suffered from a variety of ailments, including a skin disease that led to infections. Haseltine remembers the red, infectious streaks spreading up her arms.
She also fought the demons of mental illness, said Haseltine’s sister Florence, who at age 13 found her mother after a suicide attempt. Jean Haseltine finally took her life in 1981 at age 64.
Haseltine believes that he already has earned a place in the history of medicine, but he thinks his entry will credit him with more than just speeding up the drug discovery process. Without disease, he believes, humans would live 120 years. His work is making a disease-free life more likely, he said.
Just as some genes in his database prompt skin and blood vessels to grow, Haseltine believes that he can find genes that trigger all kinds of cells to replace themselves, in essence rebuilding the body’s tissues and organs. Finding them will lead to a new era of “regenerative medicine,” in which drugs keep us eternally young by remaking our bodies.
It is a huge ambition, matched to a big personality. “Cellular replacement may keep us young and healthy forever,” he said. “The fountain of youth is likely to be found in our own genes.”
