They still aren’t sure what causes the disease or how to cure it. And the stakes have never been higher.
Los Angeles Times Staff Writer
There are 56 more drugs in some stage of the clinical trials regulated by the Food and Drug Administration; few people other than their creators have great hopes they will work. Sometimes, not even the creators are optimistic.
Wyeth, a New Jersey-based pharmaceutical company, has 10 candidate Alzheimer’s drugs in clinical trials. Drug companies have had such difficulty translating their research into effective neural disease treatments that Wyeth has decided to push everything it had into trials and see what, if anything, worked. Internally, Wyeth calls this the “fail faster” approach.
Neil Buckholtz, chief of the dementias of aging branch of the National Institute on Aging, said the pharmaceutical industry had little choice. “This is basically a ‘throw the spaghetti against the wall’ strategy. . . . We just have to try these various approaches. It’s very time consuming, very expensive, but it’s the only way we’ll know if things work or not.”
Spaghetti or not, after listening to scientists discussing Alzheimer’s and how to fix it, it is hard to come to any conclusion but that, at least for the moment, the Alzheimer’s endeavor is a mess.
What’s at stake
The individual devastations of Alzheimer’s disease are by now well known. It is one of several, and by far the most common, of so-called neurodegenerative diseases; literally, diseases that destroy the brain.
Alzheimer’s first afflicts the areas where new memories are encoded. Early symptoms include the incidental episodes of forgetfulness often brushed off as “senior moments.” The symptoms progress, slowly at first, to more frequent memory disruptions, to broader cognitive problems — confusion, disorganization, disorientation. Eventually, as the disease works its way through more areas of the brain, it alters personality and destroys the self, reducing the victim to little more than a warm body greatly in need of care.
An estimated 5 million Americans have Alzheimer’s. That number has lately been growing exponentially; ironically, as medical care improves and people live longer every decade, it will continue to do so.
By 2010, Alzheimer’s care will cost Medicare about $160 billion a year. By 2035, it could overtake the defense budget. One analysis has estimated that by 2050, Alzheimer’s will cost Medicare more than $1 trillion annually. Those numbers do not include privately insured and uninsured costs.
“From a social and economic view, it is about the money, the growing diversion of resources to sustain life in those increasingly unaware of their own lives,” Harry Tracy wrote recently in NeuroInvestment, his industry newsletter. “There is no greater public health issue looming in the developed world.”
While the cost of Alzheimer’s soars, federal money spent on research has flattened and is expected to decline in real terms in the future as the competition for federal money heightens. The rising costs of treating the disease coupled with reduced research funding is, to some, a foreboding combination.
Andy Grove, the former chairman of Intel Corp., spoke at this year’s Society for Neuroscience convention in San Diego. Grove, who has Parkinson’s disease, lamented the lack of a full-scale attack on neurodegenerative disorders: “We are about to experience an explosion of Alzheimer’s disease cases. . . . This situation is best compared to astronomers following a meteor hurdling toward San Diego, aimed to hit a very precisely calculated place and time. What would we do if we had such a situation? I think we would take it a little more seriously than we take the economic meteor that’s coming just as predictably our way.”
It’s been 101 years since Alzheimer’s disease was first theorized, and 30 years since the federal government began funding research on it, spending, to date, more than $8 billion. Private industry has spent billions more. What has been learned?
The answer is perplexing. There have been more than 35,000 scientific papers published on Alzheimer’s just in the last decade. They include hundreds of impressively detailed descriptions of purported disease mechanisms. But in all that wealth of information, there are some rather obvious gaps.
For example, the leading hypothesis of the cause of Alzheimer’s, called the amyloid hypothesis, is centered on the overproduction, or inadequate clearance, in the brain of a protein called beta amyloid. Fragments of the protein aggregate into clumps called plaques. These plaques were first observed more than a century ago by the man after whom the disease is named, Alois Alzheimer.
For most of the century since, scientists have believed the plaques were associated with the disease. But to date, they don’t know whether amyloid plaques are the cause of the disease or a result. They don’t know whether they are vital to the progress of the disease or incidental. They don’t even know whether their presence is indicative of the disease.
A rival idea, called the tau hypothesis, is no more definitive. Where beta amyloid generally aggregates outside brain cells, the protein tau aggregates into fibrous structures, called tangles, inside the cells.
The processes by which either amyloid or tau cause brain cells to malfunction, and in some cases die, are neither well understood nor completely coincident with observations of the disease itself.
For a long while, the Alzheimer’s field was divided between the two warring camps — the so-called (beta amyloid) Baptists and Tauists. Now, the two-front war has exploded. The lack of resolution has produced a surfeit of competing hypotheses, the most prominent of which focuses on what happens with beta amyloid before plaques form.
Beta amyloid is common in the brain and not harmful when it exists in single strands. Plaques contain thousands of strands. This new hypothesis holds that much smaller accumulations of the proteins, containing as few as half a dozen strands, are the real culprit in Alzheimer’s. These smaller accumulations, called oligomers, are, because of their small size, able to travel between neurons in a way that plaques cannot.
Researchers have discovered that oligomers can be toxic to brain cells long before plaques ever form. This would explain why some people who have been diagnosed with Alzheimer’s were not found to have plaques. The evidence that oligomers are dangerous has been so persuasive that many of the leading proponents of the amyloid hypothesis have incorporated them into their models.
Inconveniently for scientists, there are no definitive physical markers for Alzheimer’s in living patients. There is no blood test or tissue sample that can be taken and examined. It is diagnosed by the symptoms a patient exhibits, and there is no way to know definitively what is going on inside a patient’s brain.
Complicating matters are preliminary results from the first long-term studies.
David Bennett of the Rush Alzheimer’s Disease Center in Chicago persuaded more than 2,000 older people who had no signs of dementia to undergo cognitive testing, beginning in 1992. As they aged, some of the people developed cognitive difficulties. Some had mild cognitive symptoms. Some none. Some developed full-bore Alzheimer’s.
The participants agreed that after death their brains would be available for autopsy. Bennett has examined 660 of the brains. Only about a third of the people had developed symptoms of dementia. Yet Bennett found that more than 90% of the brains bore the plaque/tangle hallmarks of the disease. Some people who had the symptoms did not have the tau tangles or the beta amyloid plaques. Some who didn’t have the symptoms had the plaques or tangles; some had both.
The implications of this are confounding and frightening. Could it be that Alzheimer’s is not a specific disease, but a normal part of growing old?
Bennett recoils at the implication. Alzheimer’s might be associated with aging; that doesn’t mean it is caused by it, he said. “Alzheimer’s disease is extremely common. The estimates are probably gross underestimates. Is it statistically normal? Yes. But if you use normal to mean the same as puberty, something inevitable, no, absolutely not.”
He notes that ancient Egyptians all developed tooth decay by age 40. “But there was nothing normal about it — it was the environment,” he said.
Marcelle Morrison-Bogorad, associate director of the National Institute on Aging’s neuroscience and neuropsychology of aging program, finds Bennett’s data deeply disturbing.
She said “the distinction is getting fuzzier and fuzzier between normal aging and diseases like Alzheimer’s disease. This brings into question if these people are normal or not. I don’t think we can tell anymore who is normal.
“It worries me a lot, actually, because we’ve been trying to reassure people who are older that small lapses in memory are part of normal aging. . . . This research is suggesting, not proving, that it might be a sign of something down the road. That’s not good news.”
To say that Alzheimer’s is normal is not something anyone wants to hear. Medicine can’t stop people from getting old. And you can’t fix old age. Other than the simple arithmetic of it, no one really even knows what aging is. They know what accompanies it; they haven’t a clue what causes it.
Some people, of course, live to be 100 and never suffer dementia. But dementia is clearly associated with old age. Any individual’s probability of having Alzheimer’s is the sum total of a variety of factors.
Gary Lynch of UC Irvine summarized those factors as a combination of an individual’s genetic endowment, pre-birth conditions, life experiences, environmental conditions and health accidents. If, for example, you were born with a mutation of a particular lipid transport gene and you had banged your head on the pavement when you were 12, your chances of having Alzheimer’s would be many times greater than someone who had the right genes and wore a helmet religiously when skateboarding.
Eric Karran, chief scientific officer at pharmaceutical giant Eli Lilly & Co., states the obvious when he says his industry is “in a lot of trouble at the moment.” New drug candidates are failing trials. Old drugs are the subjects of lawsuits. The industry is accused of having insufficient concerns about the safety of its products while being urged by specific patient groups to take more risks to develop medicines for them. Patents are expiring on successful drugs, meaning revenue for many companies is about to fall off what is darkly referred to within the industry as the patent cliff.
The failure to learn what causes Alzheimer’s has made development of ways to treat it problematic, but the pharmaceutical industry has already sunk billions into Alzheimer’s programs. The disease is too tempting a financial target to ignore.
Much of the basic research of the last decade has been aimed at building an understanding of how the normal process within brain cells can break down. That process is an elaborate one, involving what biologists call cascades of events — dozens, to perhaps hundreds, of steps long. Every step represents a point of potential failure. Each also represents a point of potential intervention. Science has learned to intervene in many normal biological processes by manufacturing molecules that will disrupt one step, thus halting the cascade. That’s the theory, but it is also the biggest obstacle. The cascade wouldn’t exist if it didn’t do something useful.
Here’s an example. So far, the primary genetic contribution to normal, or late-onset, Alzheimer’s, the most common form of the disease, occurs with the mutation of a gene that makes a protein called ApoE. It might be possible to devise a way to render that protein inactive. But that causes other, potentially larger, problems. ApoE is a lipid transporter. Its main job is to carry lipids, including cholesterol, from the interior of cells to be broken down, destroyed and carried away for disposal. Think of it as taking out the garbage. A drug to attack ApoE would destroy one of the body’s natural systems of disposing of cholesterol.
Alzheimer’s has been particularly intractable, but there are optimists. Dennis Selkoe of Harvard University, one of the most prominent Alzheimer’s researchers, thinks there might be an effective therapy found within the next year or two. He thinks the disease process is now sufficiently understood. “If drugs fail, it will be because they are not potent enough,” he said, not because they don’t attack the disease process.
Buckholtz, of the National Institute on Aging, said the wide variety of proposals now in circulation reflected the vigor of the underlying science. “The therapeutics are targeted at different pathways that may be involved. I think that’s a good thing,” he said. “Although it’s frustrating they haven’t been more efficacious, I continue to be optimistic that by having all these targets available we’ll have something soon.”
More common are sentiments such as that expressed by Eli Lilly’s Karran in the talk he gave to open the San Francisco conference. After describing his notion of what the Alzheimer’s disease process was, he said: “If the pharmaceutical industry had known what this looked like, we never would have started working on it.”
A DETERMINED GROUP OF SEATTLE RESEARCHERS
AND BIOTECHNOLOGY’S POWER AND PROMISE
George Rathmann, a biotech-industry pioneer, tells this joke:
A man, having had too much to drink, has lost his car keys. The guy is pretty sure he lost the keys in the woods, but is looking for them in the parking lot.
Why don’t you look in the woods, somebody asks.
Well, he says, it’s too dark in the woods. I’m looking over here where it’s light.
“Science is done where you can make progress,” Rathmann says.
“It is not done taking on an assignment that you can’t even start to attack. It doesn’t do you any good to walk in the woods; it’s dark, you can’t do anything. Go back in the light and hope you find something.”
In the spring of 1989, Francoise Wendling, a French virologist, shone a bright light in the direction of a mysterious molecule that scientists had been hunting for decades.
Wendling was researching leukemia viruses when she noticed that a mutant gene in mice shared characteristics with a family of proteins involved in the production of human blood cells.
Scientists following Wendling’s work thought she might have stumbled on a clue to the whereabouts of the elusive molecule thrombopoietin, or TPO, which had been theorized in 1958 as a critical blood-clotting hormone but had never been found.
“It was like chasing a ghost,” one scientist said.
If it existed at all, thrombopoietin was rare, apparently rarer even than the very rare hormone responsible for creating red blood cells. That hormone was isolated almost a decade ago. Drugs based on it have been on the market for five years. Five billion dollars’ worth of them have been sold. The total volume of those drugs wouldn’t fill a 5-gallon bucket.
Those numbers – one hormone, one bucket, five years and $5 billion – are a definition of the promise of the biotechnology industry. They were a powerful incentive for scientists to search for thrombopoietin.
The Wendling research was “like a gun going off,” one biologist said. Between the appearance of her first paper in 1986 and June of this year, tens, perhaps hundreds, of millions of dollars were spent in a furious race to find the hormone. The race ran around the globe, from giant conglomerates like Kirin in Japan, to lone researchers in Tennessee, to obscure biotech firms like ZymoGenetics here in Seattle.
It was so difficult to find, one scientist involved in the chase said, because thrombopoietin is the most dilute substance ever isolated, which is an abstruse way of saying there isn’t very much of it.
In fact, thrombopoietin, when compared to any known substance, is the thing there is less of. It is, in other words, the rarest thing on earth.
Ken Kaushansky, a research hematologist at the University of Washington Medical Center, was among those following Wendling’s work.
Kaushansky’s interest was more than academic. A university research scientist leads a work life of multiple personalities. Kaushansky is foremost a researcher, a detective intent on uncovering the biology of human blood. For the last 10 years, he has been studying the hormones that make blood cells grow. He is also a teacher, staffing his laboratory with graduate and postgraduate students, often physicians who want to practice science rather than medicine. He is finally a clinician, a medical doctor with patients at the adjacent university hospital.
As a clinician, Kaushansky deals with blood disorders. Patient L was typical. A middle-aged woman with a classic, aggressive breast tumor, she had a radical mastectomy last year. She then went through the usual six-month course of chemotherapy. At the time of her surgery, physicians found 16 of her 22 lymph nodes involved with the cancer, making her a prime candidate for recurrence.
In such cases, a second, intensive round of chemotherapy is recommended. The way in which chemo or radiation therapies work is to kill cells that are actively reproducing. Cancer cells reproduce constantly – that’s what makes them so dangerous – so the therapy is effective against them. Most adult human cells do not reproduce most of the time, meaning they are unaffected.
Some, however, are affected. These include hair follicles and fingernails. More seriously, they also include blood cells, including platelets, the principal clotting agents in blood.
Without hair, people are bald. Without platelets, they are dead. The cancer therapies are often held at less-than-maximum levels to allow the blood to rebuild. This dose-limiting toxicity risks not killing the cancers. Pushing the dose risks killing the patient.
Platelets and other blood cells are replenished in time, but often slowly.
By Day Nine of the new round of therapy, Patient L required platelet transfusions, which, although expensive and sometimes ineffective, are the most frequently administered form of blood transfusion, according to the Puget Sound Blood Center.
By Day 12, Kaushansky feared Patient L’s platelets were not being replenished.
By Day 20, she was still requiring platelets.
On Day 25, Patient L had what she described as the worst headache of her life. Her brain was hemorrhaging.
By that point she had received 230 units of blood. It hadn’t worked. Patient L’s hemorrhage was discovered and her life saved, but at enormous physical cost to her and economic cost to the health-care system.
Kaushansky thought he saw in the French research a way to find the elusive platelet-producing hormone, thrombopoietin, and thereby a way to prevent Patient L’s pain, others’ deaths and the costs incurred by both.
He read with particular interest Wendling’s observation that the leukemia-inducing gene she had found was a mutation of a gene for a protein known as a receptor.
A receptor protrudes from a cell wall the way a dock juts from a sea wall. Like a dock, a receptor is designed as a berth. The boat it is designed to receive is a molecule called a ligand (meaning a thing that binds). The ligand floats through the body looking for the perfect receptor to lock onto.
Wendling’s receptor, which was called MPL, was empty. There was no boat present.
“Science sort of plods along from one conclusion to the next in a very logical way,” Kaushansky said. “Sometimes, when you’re lucky, on a good day, there’s a discovery made in one field, which has merit by itself in that field, which then can cross over to a completely unrelated field and just be the key that opens the door.”
Kaushansky noticed that the normal form of the mutated receptor Wendling described was found in a type of cell that could become either a red blood cell or a megakaryocyte, a large blood cell that breaks into platelets.
“And that’s the one and one I put together, and came up with the idea. It was my guess – and it was a guess – that this might have a role in platelet production. That was the leap of faith.”
TOWN AND GOWN
Kaushansky and Don Foster, the senior molecular biologist at ZymoGenetics, had been research fellows together a decade ago. Kaushansky had since consulted with ZymoGenetics. He went to Zymo with his belief that the MPL receptor might be used to fish for thrombopoietin.
One of the differences between academic research and that carried out in the biotech industry is illustrated by the offices Kaushansky and Foster occupy.
Foster basks in the glow of sunlight as it reflects off the water outside ZymoGenetics’ new headquarters, the smartly restored City Light steam plant on the south shore of Lake Union. In summer, the lake is dotted with kayakers and sailors. If Foster looks out on certain sunny days, he might see one of his own scientists, the lanky biochemist and consummate outdoorsman, Pieter Oort, skittering across the water on his sailboard.
On the pier Zymo built as part of the steam-plant restoration, other employees might be eating lunch or feeding the ducks.
Foster’s office itself is spartan, decorated in modern, muted grays, but spacious enough for a large desk, a small round table, new bookcases and a Macintosh computer.
Kaushansky’s UW office barely fits Kaushansky. It is a narrow shotgun shack compared to Foster’s mansion on the lake. It would make a nice closet. Its one advantage is that the similarly narrow Kaushansky can reach nearly everything in the room without getting out of his chair.
If Kaushansky looks out his window, he sees not windsurfers but other wings of the sprawling UW Medical Center, the house the late Sen. Warren Magnuson built.
The science labs at the Medical Center and hundreds of others scattered like federal crumbs across the campus are rich in many things – ideas, enthusiasm, even the occasional genius – but they are often lacking resources. Students come and go. Funding is even flightier.
The head of a university lab is its chief breadwinner. Its continued existence and thus the careers of the students in it depend on the lab chief’s ability to get money, usually in the form of government grants.
This search for funds is constant. If you ask an academic scientist what was the first thing he or she did after determining a new line of inquiry, or making a discovery, or getting up in the morning, the answer is likely to be: “I applied for a grant.”
“Your main responsibility as the head of an academic lab is as a procurer of money,” said one scientist. “It’s a myth that you have academic freedom. You can do science only if somebody will give you money to do science.”
This constraint limits the scale of academic research and is a powerful cause underlying the rise of biotechnology as a commercial enterprise.
Kaushansky has five scientists in his lab. ZymoGenetics has 200.
“Often the role of biotech companies is to fund projects that don’t get funded by the official sources,” Kaushansky said. “This (the thrombopoietin project) was my idea at the basic level but I also realized I wasn’t going to be able to carry it out. I have five other academic careers to worry about and I didn’t want to put them all into something that might not turn out.”
As big as ZymoGenetics is compared to Kaushansky’s lab, it is small to the point of obscurity among its biotech competitors. Even locally, the company is known, where it is known at all, for the mock smokestacks it was forced by historic preservationists to install atop the old steam plant.
Foster saw Kaushansky’s idea as a way to push Zymo into competition with the biotech giants known to be working in the same research area. The firms with well-known expertise in blood-growth proteins included cross-town rival Immunex as well as two of the biggest and richest biotech companies in the world – Amgen and Genentech, both in California.
There are well-worn methods for finding proteins. Typically, they require what might be characterized as brute force. Zymo wasn’t big enough to be a brute. To beat the others, Foster would have to find a way to sneak up on the discovery.
“The question is who can get there quickest. Who gets there first,” said Doug Williams of Immunex. “Because anything other than first is last.”
Si Lok, a molecular biologist at ZymoGenetics, had been involved in earlier races to clone proteins. Losing was not something he liked to contemplate.
“It’s embarrassing,” he said. “It’s like coming in second in a war.”
Biotechnology has existed for millennia. Every time a baker takes a loaf of bread from the oven, he’s looking at it. Every time a brewer turns sugar into beer, she practices it. But modern biotech differs in a fundamental respect. Its tools, living organisms like the baker’s yeast, have been altered in the lab. They are genetically engineered.
The ability to alter fundamental genetic composition began to emerge with the discovery of the structure of deoxyribonucleic acid by Francis Crick and James Watson in 1953. As every schoolchild should know, DNA is composed of strings of nucleic acids. If unraveled, a single strand of human DNA would be 7 feet long. Each strand contains 3 billion nucleic acid pairs. Sections of these strands, varying in length from a few dozen “base pairs” to several thousand, form genes. The 100,000 or so human genes make up about 10 percent of the DNA. The rest is so-called junk, perhaps a vestige of earlier evolutionary needs. The genes and junk are laid out along 23 pairs of long molecules called chromosomes. Every cell has copies of each chromosome and hence each gene.
All genes have one function – dictating the production of proteins. Different proteins in turn carry out all the work of cells, and thus the body. Certain proteins, for example, make muscle. Another makes hair.
Twenty years after Watson and Crick’s work, scientists discovered individual genes could be combined with one another by cutting-and-pasting techniques that use enzymes as scissors and glue. This ability to combine genes, and thus the activities they dictate, is fundamentally what is meant by genetic engineering, or recombinant genetics.
Much that was written about these techniques in the first few years after their discovery concentrated on the mad-scientist aspects of it. Would new, somehow dangerous life forms escape from laboratory benches? Would they poison the air? Take over the earth?
Within a decade, these fears largely receded under an onslaught of publicity that promised miracles from the new technology. Food would be abundant. Hunger would disappear. New wonder drugs would be created. A cure for cancer was just around the corner. Amidst such hype, biotech emerged in the late 1970s. It immediately began fulfilling some of its wild promise.
It had long been known that a lack of the protein insulin caused diabetes. In 1978, human insulin was isolated and inserted into yeast cells. Yeast cells reproduce every few hours. If some other substance can be inserted into a yeast cell and grown with it, you can make a lot of whatever that something else is.
When Genentech, a South San Francisco company, proved this could be done with insulin and done cheaply, everything seemed suddenly possible.
Genentech had been founded with a $1,000 investment in 1976. The company sold stock to the public in 1980, two years before it had any products whatsoever. The stock opened at $35 a share. It went to $89 in an hour. The two men who put up the original $1,000 suddenly had stock worth $66 million.
An industry was born. And its two fundamental traits – astonishing science and equally astonishing finances – were joined.
Ben Hall wasn’t present at the creation of the recombinant era, but he was close by. He had been working in the general area of DNA research for 20 years. A chemist by training, he and a student, Gustav Ammerer, had begun doing recombinant experiments at the University of Washington. In early 1980, they inserted one yeast gene into another.
“No one had done that before,” Hall recalled. “We thought, well, that second gene did not have to be a yeast gene.”
Lacking access to any human genes, Hall and Ammerer began a collaboration with Genentech, which had genes, and was looking for yeast expertise. The hot molecule of the early biotech era was interferon, touted to have potential for curing everything from cancer to infertility. Genentech wanted to produce it in yeast. Hall helped do it. Although successful, Hall gained little more than publicity from the venture. He and the company parted on less than friendly terms.
Hall had by then become chairman of the UW genetics department. By unpleasant coincidence, just as his relationship with Genentech soured, so did the prospects for his department. With Ronald Reagan marching triumphantly on Washington, D.C., and the similarly budget-minded John Spellman moving into the governor’s office in Olympia, talk of cost-cutting warmed the political air. Some of the hot air proved chilly by the time it blew into Hall’s genetics lab in the J-wing of the Med Center.
“Things were pretty grim on campus,” Hall recalled. “Deans were talking about doing away with entire programs. Things were going downward. I all of a sudden became aware of commercial interests in science.
“The joke at the time was that interferon was a substance you rubbed on stockbrokers to make them sell stock. But it seemed that we had the basis for a new biotech company.”
Hall had been working with Mike Smith, a biochemist at the University of British Columbia who had invented a method of synthesizing short strings of DNA. Because the acids that compose DNA bind molecularly to specific other acids, it is possible to use short synthetic chains as probes to search out complementary swatches in larger strings of DNA. Together, Hall and Smith used Smith’s handmade probes to isolate genes.
“Mike Smith then was one of three or four guys in North America who knew how to do this kind of chemistry,” Hall said. (This preeminence was confirmed spectacularly in 1993 when Smith won the Nobel Prize in chemistry.)
Hall called Smith.
“Around the late ‘70s and early ‘80s, all of us were getting phone calls from potential investors,” Smith said. “Most of them seemed to be coming from the eastern part of North America. Young people in dark suits, mostly from Wall Street. I was sort of interested. My whole career, or most of it, was in developing technologies that could be useful in an applied way.”
Hall also contacted Earl Davie, a UW biochemistry professor regarded as one of the fathers of modern hematology. His lab was doing groundbreaking research into the nature of blood proteins. ndependently, Smith and Davie had been talking with investors in North Carolina.
“When I told them it was possible to start a company here, they were interested,” Hall said. “It was a lot easier than flying to North Carolina all the time.”
The scientists thought they might combine Davie’s blood proteins, Smith’s chemistry and Hall’s yeast work into a commercial venture.
Intermediaries put the scientists in contact with Tom Cable, a young venture capitalist in Bellevue. Cable had been instrumental in getting several high-tech firms off the ground. Cable quickly raised half a million dollars in seed money. The money was pushed into the pot without the investors’ knowing what it would be spent on. It was invested “on the sizzle,” Cable said. “I raised all that money on the phone. Five or six phone calls. Basically, I said, `Hey, this company’s getting started with two scientific superstars at the university.’ That was it.
“We were betting on Ben Hall and Earl Davie. It was pretty basic. We hoped they would identify good ideas and good people. It was relatively typical of start-ups. The industry was really young. Nobody knew where it was going. Nobody knew how long it would take to get there. Nobody knew how much money it would take.”
Mark Murray, a young molecular biologist, was doing postdoctoral research at the Massachusetts Institute of Technology’s Center for Cancer Research when he got a call from Hall and Davie. They were starting a new company that was going to produce proteins in yeast. Was he interested?
“The company was still just an idea when they called me,” Murray recalled. “I came out. They took me to a warehouse on north Lake Union, which they hadn’t even moved into yet.”
The company was to be called Zymos, the Greek word for yeast. The name was about as much of a business plan as existed. Murray accepted a job, then returned to Cambridge to finish his research there, pack and move. By the time he got back to Seattle, another 10 scientists had been hired. A president, somebody to actually run the company, had been hired, too. And fired.
“That was a little disconcerting,” Murray said.
It also turned out to be normal. For much of its early existence, Zymos had no management. None. As it was losing presidents, the company also lost its name. Mail kept getting sent to an electronics company called XMOS, so the word Genetics was tacked on.
“It’s not like this was done on purpose,” Murray said. “This was a series of screw-ups. Earl and Ben saw this simply as a way to do more science. They had no clue about how to build a business. They weren’t even thinking of that. It was just a group of guys in the clubhouse.”
Donna Prunkard, another of the early hires, remembers: “In the first few years we didn’t even have a structure. We had a president and we had us. And some of the time we didn’t even have a president.”
The science was entirely driven by the scientists. At the time, the bacterium E. coli was the industry-standard host cell for producing recombinant proteins. Unfortunately, E. coli did not do a very good job of making complex human molecules. The scientific basis for Zymo was to replace E. coli with yeast. The test case was a protein from Earl Davie’s UW lab called Factor IX. It didn’t work. The yeast couldn’t produce it.
“Right off the bat,” Murray said, “the whole basis for the company was blown out of the water.”
The company lived hand-to-mouth doing contract research, most of it for pharmaceutical companies, known within biotech as Big Pharma. Hall worried. He and Davie argued over direction.
Hall provoked a showdown. He and Davie each had a candidate for president. Hall called a meeting of the staff and insisted the scientists decide. Many felt backed into a corner and resented Hall for pushing them there.
“Ben forced us to choose,” Murray said. “Brought us all in there and made us vote. We resented even being put in that position. So we voted for Earl’s guy.”
Hall, the principal force behind its creation, quit the company. Within two years of its founding, Zymo had lost its founder, two presidents, its name and much of its reason for being. The company continued to struggle financially after Hall left.
Biotech financing rolls in and out every year or so with great waves of investor confidence. Zymo missed every wave. The company did develop some promising product candidates. One of its contract jobs – inventing a yeast-production system for insulin – grew from an idea sketched out over a restaurant dinner into a long-term relationship with Novo Nordisk, a large Danish pharmaceutical company.
In 1988, Zymo was still floundering financially; the previous autumn’s stock-market crash had wiped out a plan to sell stock to the public. The Novo contract called for royalty payments to Zymo if it hit specified targets. A big payment was due in that year – big enough, Mike Smith said, that it became cheaper for Novo to buy the whole company. Zymo was willing.
Smith, Davie and the other original investors sold for $23 million. Zymo has since evolved into a principal Novo research center.
For most of human history, the function of the human circulatory system was a mystery. The predominant view held that blood’s main function was to keep the body warm. William Harvey discovered in the 17th century that blood serves mainly as a transportation system of considerable complexity. The bloodstream might be imagined as a particularly crowded highway: Interstate 5, say, at rush hour on a rainy winter night.
A single drop of blood contains more than a quarter of a billion individual cells. Almost half of those cells are blood cells: red, oxygen-bearing cells; white, immune-system cells; and the tiny platelets that cause clots to form at the site of injuries.
The rest of blood is a swamp of vitamins, sugars, salts – almost everything the body needs, including the class of molecules called hormones.
The general role of hormones is to control other cells or systems in the body. They are related to one another more by function than composition. They might be proteins, amino acids or cholesterol derivatives, such as steroids. Typically, they are produced in one part of the body and travel through the blood to the cells they are designed to control.
The blood is full of these hormones and other proteins commuting to work at various job sites throughout the body. Being of often great potency, hormones make inviting targets for research. They have been a principal focus of the biotech industry since its inception.
A small, especially powerful subclass of hormones called cytokines began to emerge as particular objects of interest in the 1980s. Cytokines typically do not travel through the blood in great numbers. Most of them are made in a particular area – the bone marrow, for example – and travel only to neighboring cells to do whatever they do. Think of them as hormones that walk to work. Because they do not move around much, cytokines are hard to find if you don’t happen to know where they’re made.
Red and white blood cells and platelets all derive from identical so-called stem cells. A stem cell will become red, white or platelet depending on what hormones hit it. Over time, scientists had discovered, isolated and turned into drugs the hormones, or cytokines, that make stem cells become red cells and white cells. They had not found thrombopoietin, the hormone that was supposed to make platelets. Different people around the world looked for it for so long, in so many different ways, that many leaders in the field had concluded it didn’t exist. Thrombopoietin came to assume a kind of comic-mythic status.
No one looked longer or harder than Ted McDonald, a biochemist at the University of Tennessee. McDonald has published more than 300 papers in an academic career that dates to 1958. All but three of them concerned TPO.
“People laughed at me,” McDonald said. “We ran out of money. I couldn’t get enough, ever. I lost my grants. I couldn’t even get a postdoc to work with me. People would tell me, if this doesn’t work, you’ve shot your whole career.”
McDonald is now 64. The search, in fact, did consume his career, or, as he said recently, “99.9 percent of it.” After a moment’s pause, McDonald, thinking back on those 35 years, added:
“The other tenth of a percent was breathing.”
Kaushansky, the UW hematologist, knew the difficulties other researchers had encountered. He knew he was asking ZymoGenetics to take a gamble when he showed up with a new plan to find TPO.
As it happened, the company already had a search under way. One of Kaushansky’s UW colleagues, Gerry Roth, had been a constant source of new ways to look for TPO. He himself had been searching since 1987.
“We thought of maybe a hundred different ways to fail,” Roth said.
A small group met every couple of weeks to talk about TPO. “I used to laugh, saying I was going to my TPO meeting. It was kind of an embarrassment,” Roth said.
The best way to find a hormone is to know where it’s made. Erythropoietin, the red-blood-cell hormone, is made in the kidney. This knowledge helped give scientists a place to look for it: urine. Amgen, George Rathmann’s old company, purified and cloned EPO in the mid-1980s. The project established the company and has paid for a sprawling campus of labs, offices and production facilities in suburban Los Angeles.
Finding it, however, was as much luck as it was scientific brilliance, said Fu Kuen Lin, the molecular biologist who discovered it. When Lin joined Amgen in 1981, the company had a single lab bench and a list of potential projects ranging from EPO to indigo dye for blue jeans.
Lin chose EPO. Who knows what blue jeans might be like today if he had picked indigo. Molecular biology was still in its infancy then, and Lin was making up much of what he did as he went along.
“Management tried to help,” Lin said. “They were running all over the world trying to line up a source of EPO. At one point Dow Chemical came to us. They said they had this urine source – the Italian army. They were collecting all the Italian army urine and they were concentrated on purifying EPO out of it.”
As Kaushansky says, “Not a pleasant task, but simpler than blood.”
Protein-purification experts regard blood as a singularly bad starting material. “There’s a lot of stuff you have to get rid of,” said Roth.
In any chemical purification process, half of the material that is the object of the purification is lost in each step, and successful purification often takes a dozen steps. This was, nonetheless, the main path by which people looked for TPO.
Zymo was working on purification when the crucial Wendling papers were published. When Kaushansky made Zymo aware of the new receptor research, Foster decided it was worth a renewed effort.
“The meetings started with two or three people,” Roth said.
“Then they increased to four or five. Then after a while I didn’t even recognize half the people walking into the room.”
The expertise in Foster’s lab is molecular biology, not protein chemistry. Foster adopted a search suited to the talents at hand. Zymo would try to find TPO not by purifying blood, as Foster suspected Amgen and Genentech would, but by a method called expression cloning. Rather than trying to isolate the material and see if it would cause the activity, Zymo would look for the activity, then try to isolate the material.
It is as if you were trying to find what kind of people scream when they hear Eddie Vedder sing. Say you suspected that teenagers wearing socks with very subtle polka dots and living in Tukwila were the only people who did this. If you were a protein chemist you would round up all the people in Tukwila and sort them, first getting rid of all the adults, then the children, then those not wearing socks, then those wearing solid-color socks, and so on until you found a 14-year-old wearing what looked like polka-dot socks. Then you’d play a Pearl Jam song and see what happened.
This could take a lot of people a very long time, and the kid might not scream. Maybe the socks were just dirty and not polka dot after all.
“With protein chemistry, if it works it always requires brute force,” Foster said. “The beauty of the molecular biological approach is if it works it doesn’t ever require brute force.”
If you were a molecular biologist, you would get in your car, pop a Pearl Jam tape into the cassette player and drive around Tukwila high schools with the stereo cranked up as high as it goes. If somebody screamed, you’d stop and see what color socks he had on.
Andrzej Sledziewski, Zymo’s vice president for bio-pharmaceutics, subscribes to a description of the company derived from “One Flew Over the Cuckoo’s Nest.” It is called The Theory of the Staff and the Patients.
“No one knows who is which,” he said.
“Him. See him,” he said one day this fall, pointing to one of his top scientists. “He thinks he’s staff.”
Sledziewski shook his head. “Uh-uh. He’s a patient.”
When Foster set out to build his TPO team, he went straight for the patients. The first person was Si Lok, a cloning expert who had recently joined the lab. Lok is by all accounts the quirkiest scientist in the Zymo asylum. He cultivates some of this image, wearing what are alleged to be different, specified pairs of jeans for each day of the week. He has never been seen in an unwrinkled shirt.
According to company legend, when Lok first arrived at Zymo, he didn’t own a car or know how to drive one. But after a problem on the bus one night, he went out the next morning, bought a car and taught himself to drive it on the way to work. It took 45 minutes to cover a couple of miles, largely because he searched diligently for a route that included no hills or left turns.
Lok is the only Zymo scientist not tied into the company’s electronic-mail system.
“If something is important enough, they’ll come and tell me. If it’s not, I don’t want to hear about it anyway,” he said.
This self-confidence comes across as charming, not off-putting. Another scientist has labeled a project folder in his computer “IwannabelikeSi.” People happily put up with Lok’s idiosyncrasies because he is very good at what he does.
“When we got the information on the (Wendling) receptor, we asked Si to clone it, just to position us in case we wanted to try something with it,” Foster said.
As Zymo scientists began investigating TPO, they found more and more dead ends.
“Everybody worked in the lab,” Foster said. “We would meet weekly and go through our data. Discuss it. We were just getting together and sharing results, which were all bad.”
Foster is not apt to pursue ill-fated ventures simply because he starts them. His steadfast goal from the time he was a child was to become a physician. After receiving his undergraduate degree, he enrolled in medical school. He hated it, immediately and passionately.
“I woke up every morning and didn’t want the day to be,” he said. He quit school after a month.
This same willingness to make decisions, to go straight to the heart of a problem, is one of Foster’s best qualities as a scientist, according to John Forstrom, his boss.
“Essentially, I decided – with some support and some opposition – that if the other things weren’t working and if the MPL receptor was the right thing, other companies would be working on it. If this is the right thing, we better put a massive effort into it,” Foster said.
All other TPO projects were shut down. Eventually, all other molecular biology projects were shut down.
Once Lok and Joe Kuijper cloned the MPL receptor, Pieter Oort spliced it into a line of cells whose chief quality was that they thrived when fed blood-cell growth hormones; they died without the hormones. If all other hormones were taken away, only those cells that were receiving TPO would stay alive. It was a classic biological solution: The cells would select for life.
This gave Zymo a quick lab test, called an assay, for the existence of TPO. It would work like this:
The ligand half of a receptor-ligand pair is often a hormone. The receptor is on the cell surface and acts as a communication link between the inside of the cell and its surroundings. When the hormone bumps into its receptor, it adheres “like hair sticking to a comb,” Kaushansky said. This initiates some prescribed action inside the cell on which the receptor sits: for example, making another protein, or dividing, or growing; doing, in short, any of the things cells do. Nobody knows why this happens. It’s what cells do, “a black box,” Foster said.
Zymo had the receptor. The question was where to find the hormone that would bind to it and stimulate the cell. Where might TPO be made? What tissue sources should the assay be exposed to?
Blood is a homostatic system; it’s self-balancing. When it has too much of something, it sheds it. When it has too little, it makes more.
When platelets, for example, are low, hormones are called forth to make more. Theoretically, then, killing platelets should stimulate the production of TPO, which would go to work replacing the platelets. Laboratory mice were injected with platelet antibodies, killing their platelets and presumably causing TPO to go to work. The mice were then killed – sacrificed, in the industry vernacular – and from each mouse four organs were “harvested.” There was some reason to suspect any of the four organs – the kidney, liver, spleen and bone marrow – might be the place TPO was made. There was also reason to suspect none of them was the place.
Lok and Kuijper built what are called libraries of DNA samples from the four different mice organs.
The basic plan was to extract the DNA from the library samples, then combine it, one bit at a time, with the receptor cells. Theoretically, if any of the DNA samples contained the TPO gene, the gene would make the hormone, the hormone would bind to the receptor and the receptor cells would live. Otherwise they would die.
The logic of the approach was probabilistic. If you had enough DNA samples of each tissue, you would have at least one copy of every gene in the tissue. If you took enough samples, in fact, you couldn’t miss.
The literature contained numerous examples of similar approaches being used for other discovery efforts. Because TPO was thought to be especially rare, Zymo made more samples than anyone thought would be necessary – more, they thought, than anyone in history had ever made, enough samples that if one in 100,000 molecules was TPO, they would find it.
As Lok said, “It was a lottery. The more tickets you bought, the better chance you had.”
Molecular biology is the chemistry of the very small. Many of its tools are those a 19th-century chemist might recognize. The most ubiquitous device in a modern DNA lab is nothing as sophisticated as, say, an electron microscope. It’s a long suction needle called a pipette.
Even many of the most powerful devices are not technologically complicated. Machines called polymerase chain reactors are capable of multiplying – or amplifying, as it’s called – DNA from a single molecule to more than a billion identical copies in a day. Yet a PCR machine is little more than a heat block.
Most lab work is craft, not genius. “It’s not so complicated,” Sledziewski said. “You get some of this stuff and put it together with some of that stuff and see what happens.”
“No one enjoys working on a bench,” Lok said. “Anyone who tells you they do is either lying or they mean something else. Surely, no one can actually enjoy pipetting.”
Chimp work, Anne Bell calls it. Bell led Zymo’s massive effort to prepare the TPO DNA samples, which are called “mini-preps” because a small amount of DNA is extracted from each sample. It’s a time-consuming but necessarily exacting task. Like much DNA lab work, mini-preps require precise repetition of mundane tasks: combining, then separating various compounds.
Bell, Foster, Lok and almost everyone else involved in the TPO project belong to a generation of scientists who were in college during the 1970s and were seduced by the promise of biotech, which was just then being born.
Everybody in the industry, Foster said, is “within one or two standard deviations of 40.”
Bell had planned on being a physical therapist.
“I loved the course work, but I hated the idea of helping little old ladies up and down the hall,” she said. In her junior year at Syracuse University, she took a class on restriction enzymes. It was brand-new science, “really cool,” she recalled. The thought that you could “take a cell from a frog’s toe and turn it into a frog” changed her life.
She took a job in an academic lab and eventually made her way west. She arrived in Seattle on a typically depressing December day in 1984.
“It was cool, dark, raining. I said, `Wow. This is great.’ “ She’s been at Zymo since.
Biologists tend to divide along the lines of the cells they work with. It will be said of someone that she is a bacteria person. Or a mammalian. Bell is a yeast person. “They’ll do amazing things for you,” she said.
Bell rolled her eyes when it was suggested that Foster thought she had “volunteered” to lead the mini-prep effort.
Given the competition Zymo thought it was racing against, speed was a paramount consideration in the TPO project and the DNA prep work was the biggest roadblock.
“We were all trying to duck it. It sounded like your worst nightmare come true,” she said. “Preps are one of the first things you learn in the lab. It’s difficult to be motivated to do a lot of them. It is not creative at all. The goal was to do 5,000 of them, which everybody regarded as crazy. A crazy mini-prep day was 50. At one point on this project we did 824.”
In part because of the effort involved, in part because of Bell’s personality – she wears her emotions on her sleeve; some days the sleeve gets a pretty good workout – the mini-prepping became the visible symbol of the project within the company. People passing in the hall would be pulled in to help with the most mundane tasks.
The basic process involved separating the DNA from the source tissues and inserting it into E. coli bacterium cells. The cells, each containing a single inserted gene, were grown, producing at least 600,000 copies, or clones, of the DNA from each of the four mouse tissues.
Then the clones were grown in groups of approximately 250 colonies each. The colonies were scraped off and a series of chemical treatments was used to break up the cells and release the DNA. A centrifuge removed the cell debris. The DNA was then bound to a silica-type material to extract it from the liquids. Then the silica was washed and treated, freeing the naked DNA.
“The pace was feverish,” Bell said. “I’ve never been so tired in my life. . . . As soon as we reached one goal, there’d be another.”
As if she needed further motivation, as Bell got deeper into the TPO project, her father became ill. His blood had quit making platelets. He was dying.
IN THE DARK
Different cells have different properties that make them easier or harder to deal with in different circumstances. Thousands of different cell lines are available commercially. They’re advertised in thick catalogs and range from tongue, bullfrog, to lung, buffalo.
After the naked DNA was extracted from the E. coli cells, it was inserted into hamster kidney cells, which are especially hospitable for growing foreign proteins. Proteins grown this way are secreted from the cells into the liquid medium the cells are in.
If the cells were producing TPO, it would be in the liquid.
That liquid was combined with the receptor cells and tested. Almost all of the tests, or assays, were done by one person, Pieter Oort.
Oort was born to science. His grandfather discovered the Oort asteroid belt. His father was a research meteorologist.
“He would come home, have dinner, then go to his study and work until late at night. On Saturdays, he’d go into the office. On Sundays, he’d work at home,” Oort said.
By his nature, Oort is a loner, almost an outsider in the lab.
This was emphasized during the TPO project by the physical layout of the work. While most of the rest of the molecular biology group was making the libraries and doing mini-preps in the main lab, Oort worked by himself in a separate tissue-culture lab.
Tissue culture, as its name implies, involves the growing of living cells. Because of the temperamental nature of most live things, culture work requires persistent attention. There is a care-giving quality to it. Mini-prepping is cooking. Tissue culture is baby-sitting. The cells can’t be left alone.
As the TPO project progressed, Oort began to take on his father’s work habits. Hardly a day went by that he stayed away from the lab. More precisely, hardly a night went by. Oort became nocturnal. He was seldom seen during the day; almost never out of the lab at night.
The mini-prepping was the most labor-intensive work and as such governed the pace of the project. The assay was the very end. It was where you would find, or not find, what you were looking for. It was where the pressure built.
There is in the lobby of Zymo’s offices a mixed-media piece of art called “The Ambiguity of Negation.” The scientists, who are largely pragmatic people not much into what Zymo chemist John Forstrom calls “brain-farting,” do not care much for this piece, or for any of the other abstractions collected by the company’s president, Bruce Carter, and scattered through their building.
But ambiguity and negation are woven into their work. Much of science is finding things that aren’t, doing what are called null experiments. You don’t win Nobel Prizes doing null experiments, but you learn from them. The problem is, you can never be certain exactly what.
“The good thing about this job is you’re always learning,” Bell said. “That keeps it exciting. It also makes it heartbreaking. Most of the excitement is over failure. Most things don’t work.”
Oort’s solitary habits, combined with what he was finding, which is to say, nothing, put enormous pressure on him. Nobody blamed Oort outright – he was doing what he was asked to do – but the failure to get results led some people to wonder about the quality of the assay. Oort was confident the assay worked, but without the thing it was meant to test, TPO, there was no way to test the assay itself.
The assays were read by computer. The results were data plots. Negative results would have one general shape. Positive results supposedly another. People began to wonder how much difference there would be between them. The least variation in the data was scrutinized over and over, trying to make something pop out of the background. This went on and on and yielded nothing.
Different twists were attempted. New targets were set for the mini-prep group, buying more tickets in the lottery. A total of more than 12,000 were done. At one point, the manufacturer of one of the chemicals used in the lab changed its formula unannounced. More than 4,000 preps had to be thrown out.
Zymo scientists assumed they were playing in a bigger league than they were used to. If we were smart enough to see the Wendling stuff, so were the big guys, is the way several people put it. But beyond assumption, rumor, and hints, there was nothing anyone could do to find out.
Foster is usually upbeat. When some project or another is described to him, his typical response is to say something the equivalent of, “No problem.”
As in: “Don, we’d like your people to find a cure for cancer.”
“Piece of cake,” he’ll say. “Do it in a day.”
Some of the scientists in his lab call such Pollyanna-ish appraisals Fosterisms. As it happens, they have the wholly unanticipated effect of making some people work very hard to make them come true.
TPO was at the other end of scientific feasibility from a piece of cake. The project, Foster said, began as a gamble and sank into a “long trough of discouragement.”
Most people in science would not be there, however, if they were pessimists. Every time the lab embarked on a new tissue source, optimism would rise. One night, Oort got what looked like a positive result on one of the assays. But when he looked closer at the culture dish, he realized it had been contaminated. The contamination was the cause of the spike. He left the data on his desk and when people noticed it the next morning, they started celebrating.
“By the time I came in they were all jumping up and down,” he said.
The frustration went on for weeks, until one night they hit a spike in the data that couldn’t be explained away. They had it.
No, they didn’t. The spike was caused by a growth hormone, but not the one they were looking for. This one, interleukin-3, had been discovered years earlier.
They discovered IL-3 several more times in the course of not discovering TPO. They came to think of it as a weed. People by this point were not inclined to find humor in their annoyance at repeated discovery of something that would have set off rockets a decade before.
Lok claims never to have lost confidence.
“You have to think the thing will work,” he said. “I just accept that as a foregone conclusion.”
One of the scientists involved early in the TPO project was Rick Holly. Holly is unusual in the industry in that he has risen to a senior scientific position without a doctoral degree, which at many companies is a requirement. Foster said Holly succeeds on sheer brilliance. He consistently has insights others regard as strokes of genius.
Holly isn’t so sure. He once wrote in his annual performance review that he was lazy and ignorant. As a consequence of these failings, he said, he tried to take shortcuts. Sometimes they worked.
Foster had asked Holly to perform a routine chore in the TPO project. He, Mark Heipel and Steve Burkhead were responsible for injecting the DNA clones into the hamster cells before the assay process.
It’s “drudgery,” Foster said. As was his habit, Holly began fooling around.
He saw two obvious ways the project could fail: One, the receptor might not be what they thought it was and so wouldn’t bind to the ligand they were looking for; or, two, they might be looking in the wrong place for the ligand.
“We had no way of knowing where it was going to be. We didn’t know which tissue to use. I started working on that aspect of it, trying to find a way around it.”
Holly decided if he couldn’t figure out where the ligand was made, he would try to make it somewhere.
All cells have copies of all genes. What a cell does depends on which genes are turned on. TPO would be made only in the cells with TPO genes activated.
One of the things that happen when cells are mutated is different sets of genes are switched on and off. The classic causes of mutations include viruses and chemicals. Holly began experimenting with chemicals.
“He does this all the time,” Foster said. “Every project he’s on. He goes off and plays.”
With Burkhead, Holly exposed some cells to a chemical that causes random mutations. If you exposed enough cells to the mutating agent, some of them might have their TPO genes turned on, he thought.
“It seemed theoretically this should work,” Holly said. “It was sort of like applying the most basic genetic idea.”
Holly and Burkhead played with the idea. Once it seemed like it should work, Holly told Foster. A new experiment was approved. Ten million cells were doused with the chemical mutagen. Cells in 24 of the pools stayed alive.
Nineteen pools produced something. Fourteen produced a hormone. One produced a hormone they couldn’t identify.
“Almost everything we do all day is working with apparently empty test tubes,” Foster said. When the cells started producing the unidentified hormone, Holly said, “within an hour you could see the cells. You could see them stretching and breaking.”
After that, isolating the gene for the hormone was straightforward. A new library of all the DNA in the pool producing the unidentified hormone was prepared. The DNA clones were again broken into 2,000 groups of 250, inserted into the hamster cells and assayed. The ligand hit twice. It had come home and Zymo had it.
They had TPO.
The stakes in biotechnology are high. Said the UW’s Roth: “This stuff works. It actually helps people. It’s not just a game to see who can find it first.”
A U.S. government report recently concluded: “Genetic engineering is to modern humans what the discovery of fire was to early cave-dwellers.”
Perhaps, but biotech at this point is setting fire to itself as often as it is being warmed by the flames. The key index in most commercial undertakings is revenue. Sales, in other words. In biotech, the key index is called the burn rate, which is a measure of how quickly money is spent. That it is said to “burn” is an indication of just how fast that can be.
There are now more than 1,300 U.S. biotech companies. There are more than 100 in Washington state alone. An overwhelming majority of the 1,300 have no products. They have not been able – yet – to find or make or sell whatever it is they set out to find or make or sell. Some of them have worked for a decade without making a product.
The majority of biotech companies try to identify naturally occurring, medically useful human molecules, isolate and reproduce them, a process called cloning, then develop them into drugs. This is a time- and money-consuming enterprise. The great promise of biotech was it would nonetheless be much faster at this than traditional pharmaceutical companies.
Big Pharma was scorned by biotech pioneers as slow and clumsy.
Its traditional way of finding new drugs is to collect samples of microbes, sprinkle them on tissues and see what happens. The lack of elegance, the sheer randomness in this, compared to rationally isolating genes in a lab and reproducing them, led many people to think that biotech would somehow be easy.
That it is not has been a surprise, often an unpleasant one, especially to the people who invest in the industry.
The reasons for this are many, but in most cases boil down to two simple facts:
The human body is complex and little understood. Biotechnology has developed a set of techniques that make finding genetic sources of action in the body, if not exactly easy, then doable. Understanding the action is altogether another matter.
The case of TPO is unusual in that its biology was suspected to begin with. More typically, scientists will discover a gene and then try to figure out what it does. The only way to definitively do that is to remove the gene and see what the organism does differently.
Lee Hartwell, a UW geneticist, likens this to examining a factory with 70,000 employees, and – solely by looking at the factory’s output – trying to figure out who didn’t come to work that day.
THE NEXT ROUND
Patrick O’Hara, the head of Zymo’s computational biology lab, said later of Rick Holly’s experiment, “It was one of the most brilliant things I’ve seen here at Zymo.”
That was the predominant view within the company. Outside, some people thought Zymo had gotten really lucky. After all, one cell out of 10 million? Couldn’t they have as easily missed it?
“We could do 10 million cells a week. We would have just kept going,” Foster said. Nobody disagreed there was luck involved. Lok called it “truth, beauty and chance.” Kuijper called it “serendipity.”
Whatever the reason, Zymo had found the hormone and now had to confirm it did, indeed, create platelets.
Once a substance is isolated, it is relatively easy to grow more of it. Since the discovery, Zymo has made more TPO than had existed in nature in all of human history.
After the first small amount of it had been made, Zymo injected it into mice. Within seven days, their platelet counts quadrupled. TPO worked.
“Usually, with the initial results you sort of scratch your head, `What’s this mean?’ This was not subtle,” said Kaushansky.
ZymoGenetics published news of its discovery last June in the prestigious journal Nature. The same issue carried a paper by Genentech scientists announcing they, too, had found TPO. Shortly thereafter, Amgen and the Japanese company Kirin announced similar discoveries.
Amgen and Genentech had used Wendling’s receptor to help purify the hormone from blood. They had glued the receptor chemically to inert material in a glass column, then poured blood – lots of blood, from rats and dogs – through the column. Eventually, a bit of the hormone stuck to the receptor.
Kirin, to everyone’s utter astonishment, found the hormone by traditional chemical purification.
No one knows who was first. They have all filed patent claims and are racing to develop the hormone into a drug. The stakes are large. Often after a discovery, a company will ensure it has a secure patent before spending money on development. The TPO competition has undone the process. The company that gets a drug to market first could make billions whether a patent has been issued or not. Asked about the sequence of development and patenting, Foster said:
“There is no sequence. The race is so intense nobody’s willing to back off to see what the resolution of the patent fight is. We’re just plowing ahead.”
Decisions have been made. More millions of dollars are being spent. Some people expect the development to go much quicker than usual and clinical tests to begin sometime next year. Others aren’t so sure. By some counts, 99 percent of biotech discoveries never make it to market. Doug Williams of Immunex cautions that “everything looks good and sounds good when it gets cloned,” but most clones don’t become human drugs.
George Rathmann, the Amgen founder now running Bothell-based Icos, with no more effort than peeling playing cards off a deck, can list dozens of ways a drug-development effort can fail.
Zymo isn’t yet halfway through the deck.
Los Angeles Times
Saturday September 11, 1999
ROCKETS: A Love Story
By Terry McDermott
Los Angeles Times Staff Writer
Shortly after nine o’clock on a Friday night in May, George Whittinghill realized he didn’t have enough three-eighths-inch cap screws. At the time, he was sitting at his kitchen table in his house in Camarillo. This is not the time or place most men choose to think about cap screws, but George Whittinghill in many ways is not like most men.
He got up from the table, got in his car and drove down to B&B Hardware, which was closing for the night. George told the night clerk he needed cap screws.
Come back in the morning, the clerk said.
But I need them now, said George.
What for? asked the clerk.
You don’t want to know what for, George said. You wouldn’t understand.
The night clerk stared.
Really, you don’t want to know, George said.
It’s hard to imagine George Whittinghill intimidating someone. He’s boyish, almost winsome, Tom Sawyer with straw-colored hair, crinkly eyes, and a self-deprecating tilt when he talks. Night clerks, on the other hand, can be hard-hearted people, the kind who would lock doors in the faces of handicapped people seeking canes.
But for mysterious reasons–who knows? Perhaps he was human, perhaps he saw something deep in George’s eyes that made him understand a man’s Friday night need for three-eighths-inch cap screws; whatever–this night clerk relented and let George in to buy his screws, which George then took back to the car, to the house, and to the kitchen table where he used them to bolt together a rocket motor. George once bolted together his rocket motors in the garage, but he missed his family and they missed him, so he moved to the kitchen.
The next morning he put the rocket motor in his Plymouth Voyager minivan, in the back next to the Toll House Cookie box that held the electronic assembly. Then he drove the whole works out to the Mojave Desert, where he was joined by mechanical engineer Al Cebriain, guidance and control specialist Joe Lichatowich, and computer programmer Brent Lytle.
This crew of specialists–think Mission Impossible team with bad wardrobe advice–spent the rest of the day attaching George’s rocket motor to oxygen lines, pressure transducers, computer leads and an Interstate car battery (sale tag attached, price: $79.95).
Except for the battery, it is what rocket crews have always done, the testing, checking, double-checking and securing that, back in moonshot days, would keep an entire nation in its grip, tension building and breath shortening with every pause by Walter Cronkite.
The Whittinghill team isn’t going to the moon. This was just a test to determine what material to use in a valve that had failed spectacularly the last time out. The long-range goal is to incorporate the new valve into Whittinghill’s 401K rocket, named for its source of financing: his retirement account.
The 401K looks nothing like a regular rocket. The 401K is, by most accounts, one of the most sophisticated rocket motor designs in the world, packing enormous power into a very small space. Its engine is a short, squat steel cylinder about the size of a small wastebasket.
It burns solid Plexiglas plates as fuel. The 401K is Whittinghill’s entry in what might be thought of as a new space race, a contest not between governments of superpowers, but among a ragtag group of entrepreneurs, freelance rocket scientists and dreamers trying to reinvent rocketry and, with it, space exploration, as a business.
There are some truly nutty ideas in play, from nuclear bomb-propelled spaceships to IPO-financed gold mines in the asteroid belt. But there are reasons to pay attention, too. California has a significant history in both the business of dreams and the business of space.
In rocket country today, people put it this way: As the United States fills up, the more adventurous spirits still head West. When they arrive in California, they discover they’ve gone as far as they can get. They have no choice, they say. There is no place to go but up.
From Weapons to Tools of Science
A rocket is a pressurized vessel containing combustible fuel. When ignited, the fuel burns. As it burns, pressure increases inside the vessel. When it becomes strong enough, the pressure escapes through a valve. As it escapes, the container, acting according to Newton’s Third Law of Motion–that for every action there is an equal and opposite reaction–is propelled away from the escaping gas. If the pressure, which in the case of a rocket is called thrust, escapes toward the ground, the container flies toward the sky.
The first machines to do this were invented more than a thousand years ago by the Chinese. They were simple devices: bamboo sticks stuffed with gunpowder. Aim the stick, light the fuse: Boom!
Rockets were used exclusively as weapons–and crude ones at that–until the 20th century. Around the turn of the century, a Russian schoolteacher, Konstantin Tsiolkovsky, proposed building rockets fueled by liquid propellants, which would create greater pressures and thus greater thrust than the solid propellants then in use.
An American, Robert Goddard, independently arrived at the same conclusion and explained how such a rocket might reach extraordinary altitudes, perhaps escaping Earth’s gravity entirely. This was greeted with derision, but Goddard in 1926 built a liquid fuel rocket that actually flew. It rose to about the height of a house and landed 2 1/2 seconds later in a cabbage patch.
Thus began the Space Age.
Within a decade of Goddard’s invention, German scientists under the direction of Wernher von Braun developed liquid fuel rockets with ranges of more than 100 miles. These V-2s, their nosecones stuffed with explosives, were fired at Great Britain during the closing months of World War II.
As the war ended, Von Braun delivered himself and his scientists to the invading U.S. Army. They formed the basis of the U.S. rocket program, pioneering V-2s as transport for scientific instruments rather than explosives, then expanding their designs to build the family of Redstone rockets that launched America’s first astronauts.
The Army and Von Braun tightly controlled design and production. They were reluctant to contract out anything to private industry and, when they did, they usually went to traditional suppliers: Midwestern car makers. This continued after Von Braun’s group was transferred to the newly created National Aeronautics and Space Administration in 1958.
The Air Force had gained autonomy from the Army in 1947. Lacking an in-house production bureaucracy, it subcontracted almost everything to private industry. So when the Air Force was assigned to develop an intercontinental ballistic missile program, it established its administrative center where its main aerospace contractors were: Los Angeles.
Several early commercial aviation pioneers–Donald Douglas, Jack Northrop, the Lockheed brothers–had previously made L.A. the Detroit of the aircraft industry. The huge industrial expansion of World War II solidified that role. At peak production in 1944, according to census data, half of all civilian employees in Los Angeles County worked for aerospace firms.
The business fell sharply after the war, but rebuilt around the new Air Force missile programs. Companies few had ever heard of–TRW, Aerojet, Rocketdyne and Litton–joined earlier regional aircraft stalwarts to make Southern California the aerospace capital of the world. By the 1970s, half of all space-related jobs in the United States were in Southern California. The post-Cold War recession crippled aerospace, but left fertile ground–not to mention infrastructure and a healthy supply of engineers–out of which a new Space Age could grow.
Space Flight Becomes a Passion
If human beings were laws of physics, George and Judith Whittinghill would be Newton’s equal and opposite action and reaction.
George came from back East, son of a cosmopolitan family of world travelers. His father held advanced degrees from the Ivy League and worked all over the world. George attended Eastern prep schools and lived abroad for various periods. It was during one of those overseas stints, in Ivory Coast in Africa, that America launched the Gemini astronauts into space. George was stricken, as helplessly in love as a schoolgirl.
Spaceflight became his life’s dream. He went to the Massachusetts Institute of Technology and majored in propulsion. He dreamed of settling down in a sunny subdivision in Southern California, a place where, before heading out for a day of rocket work, he could walk out for the morning newspaper, look up and down the street and see a dozen other dads doing the same thing. He wished to be rooted, he says, and California seemed the place.
Judith, meanwhile, was growing up in those very same subdivisions in and around Los Angeles, but she was hardly rooted. Her family lived in 22 houses before her mother, the family breadwinner, finally settled everybody in Irvine. Judith attended a small teachers college, studying mainly the humanities.
Degree in hand, she took a teaching job in Guam as the first waves of postwar Vietnamese refugees arrived. It was an epiphany, opening Judith’s eyes to a wider world. She went back to school to bring her and that world closer together.
So, she ended up in the summer of 1976 studying Mandarin Chinese at Harvard. On the third day of class in walked Holden Caulfield. Or so Judith thought. It was George, well-mannered, preppy, proper, diffident George, who had missed the first two days of school because he’d gotten lost in the Sahara.
They dated that summer at a cautious emotional distance. The problem, such as it was, Judith says, was that everything was almost too perfect. “Anyone could fall in love at Harvard. I wanted to be sure.”
She returned to Irvine and George followed, courtesy of Northrop Aviation, which hired him for a work-study program at its Hawthorne plant. George told Judith about his California dream, about the little subdivision and cruising Van Nuys Boulevard in a big-block Ford. It was a magical time. George remembers evenings driving south through the industrial swath of south Los Angeles to arrive in the blossoming Orange County orchards.
“Orange County at the time was a very charming place to fall in love,” George says.
Within a year, George and Judith made plans to marry. George returned to Cambridge to finish school. When Judith went back for his graduation, she and George’s mother offered to help pack his things. This was MIT, remember; George and all his friends were engineers, clever engineers. Their whole house was wired in weird ways.
Everything had purposes that their makers never envisioned. Blinds were connected to light switches; the phone could tell you if a clothes dryer in the basement was in use. Judith and George’s mother walked into this den of gadgetry and stared. After a moment’s wonderment, George’s mother turned to Judith.
“I’ll do motors,” she said. “You do power cords.”
When they finally got everything packed into George’s Mustang, the car sank to its axles under the weight. Judith was properly chagrined, George and his roommates thrilled.
Judith recalls: “His friends looked at it and said, ‘Oh great! A trip to Sears!’ ”
They bought heavy duty air shocks, jacked up the car and installed them. When that was insufficient, they finally installed the shocks upside down to make them stiffer. This worked, to a point. The car drove like a rock. It didn’t matter.
“They were as happy as could be,” Judith says.
Judith and George married that summer on Lido Peninsula and set up house in Corona del Mar. George took a job at McDonnell Douglas, Judith at the Bowers Museum.
Then George was transferred to the Marshall Islands in the Pacific, where McDonnell Douglas was conducting tests on an early version of a system to identify and destroy missiles in flight. The Marshalls were at the tail end of the U.S. ICBM test range. Watching the missiles come over the eastern horizon, George says, was enchanting, “like miniature suns coming across the sky, moving very fast and very quiet.”
By then, Judith understood George’s love of space and even shared some of it, but much else remained a mystery.
“At one point, before we had children, we were living in a studio apartment. Just the two of us and, I think, we had three camshafts and at least as many carburetors there in the apartment with us. It finally occurred to me to wonder just how many camshafts does a person want to have.”
There is, of course, no easy answer to this. Judith, for one, had no need for camshafts whatsoever. George’s needs were large, perhaps infinite. At the time, he was regularly running his ’69 Mustang at the neighborhood drag strip. The apartment doubled as his spare parts warehouse. He was, noted Judith, the only drag racer wearing penny loafers.
The question about the camshafts led directly to another question that must eventually be asked by everyone in a serious relationship: Who is this person?
Judith eventually came to realize that she and the engineers were like Pygmies and Bantus, members of tribes sharing land but living in different worlds. These people liked problems, she realized, even problems they could not solve.
“Science is cruel to somebody out of the humanities, someone who knows how to define success and achieve it,” she says. “It’s cruel to put them in the sciences where you suddenly realize that the whole history of human existence has been built on failure. Scientists understand this because almost all of what they do fails.”
This didn’t become clear to Judith until years later, after they had come back from the Marshalls, after graduate school, after George worked at NASA and, finally, in 1989 came to California to work for a fledgling firm called American Rocket Co.
“I should have known better,” says Judith, “American Rocket Co.? It sounds like something out of the Road Runner.”
A Need for Better, Smaller Satellites
In rocket country, men say things like: “Those big liquids are fun.”
In rocket country, this does not mean the man enjoyed his 32-ounce Big Gulp from the corner store. In rocket country, a big liquid is a 100-foot-tall steel container filled with highly combustible materials that ignite, one hopes, only when asked to send the container skyward.
Big liquids are what made space flight possible.
The bigger something is, the bigger the rocket needed to get it into space. But the bigger the rocket, the more it costs, as much as $50 million to put a large satellite into orbit. For decades, almost everything anybody wanted to put into space was big, expensive and paid for by the government: satellites, nuclear warheads or capsules carrying people. Now, however, the old rockets are too big and too expensive.
The same technological forces that created the microcomputer and home electronics industries are revolutionizing the satellite business. What once might have weighed 10 tons is now 200 pounds. You don’t need mega-rockets like Titans or Saturn-class behemoths to put these new satellites into orbit. But there aren’t enough smaller rockets.
There are now about 2,200 satellites in Earth orbit. That is the net result of four decades of launches. In the next seven years, industry analysts see a demand for 1,200 more launches. A single company, Teledesic, wants to launch 288 satellites all by itself.
Lift capacity, as it’s called in the business, is insufficient to meet this huge demand. In part, this is because of a former congressional mandate that all U.S. government missions fly on the space shuttles. Commercial rocketry, always an improbable business because of high costs, was a dead end so long as the government, the biggest customer, wasn’t buying.
That policy ended abruptly Jan. 28, 1986, with the explosion of the Challenger shuttle. The disaster grounded the shuttle program for two years. NASA was forced to look for other means to put missions aloft and found the options limited. Out of the ashes of that disaster, the commercial space launch business was born.
This new business is two-tiered. There are old-line aerospace contractors such as Boeing and Lockheed Martin, concentrating on proven technology and using government contracts for any experimental work.
The second-tier companies are far smaller, far poorer and tend toward innovative, sometimes fanciful, design. Almost all of them are trying to develop smaller, cheaper, reusable rockets aimed specifically at the surging telecommunication satellite business. In effect, we’re living in the age of the Stanley Steamer, waiting for Henry Ford.
American Rocket Co., AMROC as it was called, was among the first and most promising of these new firms. It was formed in 1985 to develop a novel form of rocket engine, one that would combine liquid fuels and solids, such as Plexiglas or plastics, in the same chamber. Hybrids theoretically would be cheaper to build and safer to operate.
Liquid rockets, whatever else they are, are large canisters filled with volatile materials. They sometimes blow up. “When they go, they go spectacularly,” Whittinghill says.
This could never happen with a hybrid. If a liquid rocket is a Molotov cocktail waiting to be ignited, a hybrid rocket is a charcoal fire waiting for someone to blow on the coals.
When Whittinghill went to work for AMROC, in a way, it was like going back to MIT. It was day after day of putting the air shocks on upside down, trying to figure out what worked. At one point Judith contracted acute pneumonia. George’s colleagues came to visit. They inquired after her health and prognosis, then sat down on the foot of her bed and argued about redesigning a rocket.
“That was a life-changing moment for me,” Judith says. “They were excited. As excited about the failure of their last test as other people might have been by success.”
Dealing With Lots of Disappointment
To read a catalog of rocket failures is to hear a droll litany of understated misery:
Vehicle terminated on launch.
Second stage failure, vehicle destroyed by range safety.
Inadvertent launch control command, vehicle terminated on pad.
Anomalous underperformance of booster.
Vehicle exploded 100 seconds after liftoff due to water line blockage.
Vehicle exploded after .75 seconds.
Stage failed to ignite, vehicle fell into Pacific.
“Ultimately, you’re building something that has to work perfectly,” says Al Cebriain, one of Whittinghill’s engineers. Often, it doesn’t. One in every seven rocket launches fails.
Just this past April, three consecutive Air Force Titan launches failed at a cost to taxpayers of more than $1 billion. That’s more money than the entire capitalizations of all of the new commercial space companies.
The new space race is a search for scientific solutions, yes, but at the outset, it is a search for deep pockets. Most companies fail not because their science is bad, but because their wallets are thin.
AMROC spent millions of private investors’ dollars over 10 years and, many people thought, proved the viability of its hybrid technology. Its conclusive experimental launch was held at Vandenberg Air Force Base in 1989. More than money was at stake. This was to be the next great stage in making access to space affordable, in a sense, democratizing it. People flew in from around the world to watch.
“All systems were up, the countdown went, we hit fire,” Whittinghill says. “The motor developed only 30% of thrust. It sits there on the pad. Now we have a torrential fire under the rocket. That’s fine as long as you have thrust. We never did.
“AMROC was a $20-million company sitting there on the launch pad and it failed because of a little piece of ice on the back of a valve somewhere. It’s very frustrating,” he says. The rocket continued to burn. Eventually, “it fell over, ingloriously, on its side and lay there smoking and burning like a pile of tires.”
The scientists assumed they would come back out and do it again as soon as they could refurbish the motor. They never did. The money ran out. AMROC went under.
Whittinghill took a job in 1996 with a small software company that has almost nothing to do with rocketry. He couldn’t just stop cold, however. As Judith says, “George designs rockets like Van Gogh paints. He has no choice.”
Plus, their now 14-year-old son, Ian, was already a budding rocket scientist himself. George had to have something for Ian to work on. So he started building the 401K in his garage. It incorporates some of the same technology that AMROC used and goes beyond it. It also goes beyond a hobby. George and Judith, now in their 40s, have sunk more than $50,000 into the project, an amount that has begun to seem even larger now that George’s software job has disappeared.
Every month or so George takes the motor out to Edwards Air Force Base, where developmental tests are permitted. The test range is dotted with cracked and grassy concrete launch pads, equipped with five-ton gantry cranes, industrial-size iron skids and concrete revetments, all of it vestiges of the Space Age.
George’s little motor looks almost silly hooked up to the huge crane, but its small size is a good part of its value. “Weight is the enemy of every rocket,” he says. His won’t weigh much.
In the Space Age, this range was a busy place; the air buzzed with importance. The Space Age, or at least its glorious early decades, ended, as more and more things seem to lately, in the ignominy of boredom and bad TV ratings.
Today, the only buzz at the test range comes off the empty wind whistling through the scrub, broken by the slow, quiet murmurs of a ragtag collection of freelance rocket scientists.
Given the difficulties, it’s easy to wonder what motivates these people to keep at it. You either work for a huge, bureaucratic corporation doing less than cutting-edge science or suffer at an underfunded start-up.
“Whattya think? Why do we do this?” Al Cebriain asked, setting his beer on the table. It was the end of a long, hot day in the desert spent in slow-motion tinkering with valves and seals, testing the new valve, a long day that produced a single test-firing: a brilliant flash of blue-green light and heat. It lasted almost a second.
Cebriain laughed and motioned to the rocket men around the table. “I don’t know about everybody else, but by the time I was 10 years old, I was the fireworks dealer for my whole neighborhood. I just like to watch things blow up.”
This isn’t an isolated appreciation. Almost everybody who has spent any amount of time around rockets talks about the sheer, brute physicality of it, something approaching sensuousness.
“If you’ve ever stood next to an old piston-driven airplane or a jet engine under full power, it’s just so much energy getting released so fast. It’s very exciting, very scary, but it goes beyond that,” George says. “I feel space is man’s ultimate destiny. It’s pushing back the barrier and I want to be a part of it. It’s really out of love. I feel it passionately.”
Like Father, Like Son and Daughter
Judith Whittinghill, speaking of George, their daughter, Catherine, and son, Ian, says:
“The children have grown up the same way, willing risk-takers who keep plunging forward no matter how often they ought to stop. I have died a thousand deaths being associated with these three people.”
Judith and eighth-grader Catherine, whose risk of choice is horseback riding, are at the kitchen table talking about life among rocket men. They’ve just moved into the first house the family has ever owned. Judith has set ground rules, one being that George and Ian may not snake their power cords from room to room. Tripping was a genuine hazard in the last house.
“They’re hard people to dust around,” Judith says.
“Yeah,” says Catherine, pointing to a pile of transistors on the dining table, “the vacuum cleaner is always getting plugged with this stuff.”
The stuff causes a recurring problem at dinner time, too. In many households, people ask: “When’s dinner?” At the Whittinghill home, the question is not when but where, a reflection of how hard it can be to find horizontal surfaces not covered with rocket stuff, which Judith says arrives in a steady stream via UPS. “The man comes every other day and it’s never, ever things, things . . .”
Her voice trails off.
“. . . things we need,” volunteers Catherine.
“It’s flanges,” says Judith. “Flanges. We have many flanges.”
Then Judith smiles. It’s a satisfied smile that softens the angular lines of a long, lean face.
The Whittinghills are in fact rich in flanges. And much else as well.
Judith didn’t know this then, back when the camshafts began collecting in her little studio apartment, but whenever a camshaft breaks, George is going to replace it. He might even try to redesign it, but rest assured, he will continue to replace camshafts.
Judith didn’t know this then, but she has come to understand that to be married to a dream or a dreamer is to be wed to some extent to failure. There is always going to be a camshaft breaking, a rocket failing.
To be wed happily and with understanding to a dream or a dreamer, one must not disparage the failure, but embrace it. Judith didn’t know this then, but she has come to understand that the embrace of failure is, in its way, what love is.
Darwinian Medicine — It’s A War Out There And Margie Profet, A Leading Theorist In A New Science, Thinks The Human Body Does Some Pretty Weird Things To Survive
Pacific Magazine, 1994
By Terry McDermott
BEFORE WE LIVED AS we live today, which is to say before we were organized, stratified, classified, specialized and sorted square pegs into square holes, round into round and polygonal into polygonal, human societies tended toward generalization. So did the humans in them.
Leonardo da Vinci, undoubtedly a genius in any age, was more apt to become a Renaissance man because he lived during the Renaissance. That is, generalists were common, specialists rare.
Today, if a person wants to be a scientist she becomes a particular kind of scientist, a physicist, for example; and not just a physicist, but a still more specific type; say, a particle physicist. To do this, the would-be scientist will spend 20 years in increasingly specialized education.
Twenty years, in Margie Profet’s mind, in jail.
A decade ago, Profet, having just received her second undergraduate degree, this one in physics from the University of California at Berkeley, decided, unaccountably, to become a biologist.
She also decided she hated school. So she went out and bought a good basic biology textbook, took it home to her cramped San Francisco apartment and began reading and thinking.
To succeed as a self-made scientist is to overcome almost impossible odds. Yet today Profet has a growing reputation among evolutionary biologists and is recognized for pioneering work in a nascent field known as Darwinian medicine. She has published three significant, in some ways revolutionary, papers. She is finishing work on a book on early pregnancy to be published worldwide. She is the recipient of a quarter-million-dollar MacArthur fellowship, the so-called genius grants that allow people to work unencumbered by jobs. With it, she has escaped California and moved to Seattle where she is affiliated with the University of Washington’s Department of Molecular Biotechnology. At 35, she has rented her first house and bought her first car.
She has yet to take her first college biology class.
MARGIE PROFET IS, almost without doubt, the only working biologist in the world today whose work, while published in specialized academic journals, also has been featured in general publications such as Time, Newsweek and People magazine, the one with Shannen Doherty’s “secret wedding” on the cover, and in a whole slew of fashion magazines, including an issue of Elle whose cover story was “Good Hair Days.”
This is not normal company for biologists, people more accustomed to seeing their work buried in library stacks than displayed at checkout stands. Most biologists don’t get asked, as Profet was by Harper’s Bazaar, if she had her own hair and make-up artists, or should they send someone out to help her prepare for a photo shoot?
Profet, by every account including her own, is not a normal scientist. She is odd in almost every important way, from her background to her research methods, which on a typical day might amount to puttering around the house or listening to Pink Floyd and chatting amiably with the neighborhood cat, or heading for the library with no particular goal in mind.
“I’d go to the library and just say, `What do I want to search for today? … Something about the eye, about the heart, anything. My family’s life, somebody’s fever, thymus evolution? I’d pick a topic that intrigued me for some reason … and follow it down little trails and tangents.”
One of these tangents is responsible for landing Profet in People and Glamour, amid the gossip and the celebrities and the cosmetics ads. It had to do with something that had been bugging Profet for 20 years.
“I first learned about the phenomenon of menstrual bleeding when I was 7 years old,” she says. “I found a tampon applicator, and I wanted to go play spy with it.”
Her mother told her what the applicator was.
“When she told me I’m going to do this, you know, every month I’m going to bleed, it made no sense. I mean, it was, `God hates us.’ It was like the lamest thing I had ever heard in my life. And I grew up Catholic, so I heard a lot of lame things.
“I never thought it was something I was going to spend years of my life working on. But I’m very opportunistic and if I think of a neat idea, I work on it.”
Profet’s neat idea came to her decades later in a dream. The dream, animated in the style of the grade-school filmstrip that tried to explain menstruation with cartoons, featured little creatures swimming valiantly upstream, carrying some dark, indefinite cargo with them. When Profet awoke, she knew exactly what those creatures were, what their cargo was, and where they were headed. They were sperm en route to the uterus carrying bad news, germs.
Eventually, she summarized the dream and the five years of research it inspired in a single sentence:
“Sperm are vectors of disease.”
You do not expect and usually don’t find sentences of such economy and weight in the scientific literature.
When published in the Quarterly Review of Biology last fall as the lead of Profet’s article proposing a new theory of menstruation, this was a high-volume grunge-rock power chord in the sleepy halls of academe. The conventional wisdom holds that menstruation occurs because of an accident of evolutionary history. It is usually described as an unnecessary and inconvenient by-product of the female reproductive cycle.
Profet declared this scientific nonsense, useless at best, harmful at worst. If menstruation was unneeded, it would have been eliminated ages ago, she said, because it inflicts such a heavy cost on women. It is not just an inconvenience, it diverts resources the body could use profitably for other purposes.
Some evolutionary theorists see evolution as improvisational, proceeding almost haphazardly. Others, like Profet, see it as more disciplined, as a careful weighing of costs and benefits. If some significant feature of life evolves in a certain way, there must be a reason for it.
Profet says menstruation is just such an adaptation. It evolved to help women fight disease. “I propose,” she wrote, “that menstruation functions to protect the uterus and oviducts from colonization by pathogens.” The most likely means by which those pathogens would reach the uterus would be to hitch a ride on sperm headed that way for other purposes.
Profet was hardly unaware that in the war between men and women, in which she insists she is not engaged, will not enlist and will not be drafted, those words carried powerful political content. But Profet wasn’t aiming at men; she was opening another front in her continuing war with business-as-usual biology.
THERE IS IN ANY POPULATION variation among its members. With human beings, for example, some are tall, some short, some of medium height. A statistician wanting to describe how tall a person was relative to other people might plot the distribution of heights on a graph. When plotted, heights describe a bell-shaped curve. A very few, very tall people are at one edge of the bell; a very few, very short people are at the other. Most people fall somewhere in between, bulging along the middle of the graph, the so-called norm. One common measure of distance from this norm is called a sigma after the Greek letter that is used to represent its formula.
So if the average height of American women was 5 feet 4 inches, someone who was 5 feet 7 might be one sigma away from the norm. A 6-foot woman might be three sigmas, a 7-footer five sigmas.
Margie Profet’s father, Bob Profet, an admirer of hers, once said jokingly that Margie was a 10 sigma. Off the chart for weirdness. A 9-foot giant. He was exaggerating, of course. She’s more like a six or seven.
Bob and Karen Profet are both physicists, employed by California aerospace companies. They raised four children in the glow of eternal summer on the suburban beachfronts south of Los Angeles. All the children were bright, Margie especially so.
“In first and second grade, she would get up early, sit on the heat register and study by herself before school,” Bob Profet says.
Margie recalls being bored with school from the age of 7. She nonetheless vowed to herself she would make an effort in school, so she didn’t foreclose future choices. She was precocious in math and by the sixth grade was taking high-school algebra exams.
“I just knew I didn’t want a suburban little life,” she says now. “I didn’t know what I wanted in life; I just knew I wanted to do something stimulating, and I hadn’t a clue what that would be.”
She was accepted at both Harvard and Cal Poly, San Luis Obispo. Choosing Harvard was intended as a conscious move away from science.
Profet majored in political philosophy. Her faculty adviser was Harvey C. Mansfield, a philosophy professor so renowned for toughness that his nickname was C-minus. Profet had the same effect on Mansfield she would have on a succession of mentors.
She “looked like she just came in from the beach even in mid-winter,” Mansfield says.
When she wanted to, Profet was an exceptional student, he says, who “somehow transcended the usual distinction between ordinary and weird.”
Writing her senior thesis on the German philosopher Nietzsche was a defining experience. She discovered she was actually capable of doing what she had always wanted – original thought.
She did not, however, discover what she would do with her life.
“It came time to graduate. I didn’t have a clue what I was going to do.”
A younger sister who came east for the graduation ceremony took one look around and summarized things nicely. “She said, `Margie, everybody here has a plan about what they’re going to do, and all you know is that you’re going to Maine for the weekend.’ ”
Profet had a plan that extended somewhat beyond the weekend. She had learned to think. She had learned she liked it. She had also learned that many of the questions that absorbed her – what she calls “why questions” – might be answered by science. After a period of bumming around Europe, working as a computer programmer in Germany, trekking in Nepal, climbing mountains in Africa, she returned to California and enrolled at Berkeley as an undergraduate physics student.
If her first stretch in college had been liberating, this second was imprisoning. She struggled, getting a second degree but hating the regimentation of it. She knew further schooling was out of the question, but she also knew she wanted to continue to work in science.
“For some people going to grad school is a very wonderful experience,” Profet says. “I mean for some people. And they learn a lot. But so much of it is so regimented and it can be so long before you’re doing anything on your own.”
PROFET BEGAN HER independent education in biology and evolutionary theory. She took odd jobs to support herself and spent almost every spare minute thinking and reading. Even when her boyfriend came to visit, they would sit on opposite sides of her tiny dining-room table and read.
In 1986 she had her first real insight. Several relatives were pregnant at about the same time and, talking to them, Profet began to think about what was called morning sickness. She wondered what function it served.
“I went on a detective hunt,” she says. “I discovered the Berkeley biology library. I’d never been in it. I had this phobia of libraries. They were dusty and old, and I was afraid of going to the stacks and finding some old 18th-century scholar rotting there. Now I love them. They’re like my sanctuaries.”
Profet eventually concluded morning sickness didn’t necessarily occur in the morning, and its purpose was to shield the human embryo from plant toxins eaten by the mother. It had evolved as a defense mechanism designed to protect a pregnancy at its most vulnerable point, in the first three months before the embryo grows into a fetus and develops resources to defend itself.
It took a year to develop the theory, and publication was delayed beyond that for a variety of other reasons. By then she was off on another library adventure. This one also started in bed.
“I’m allergic to a lot of things, mostly detergents and things like that,” she says. “One night, when I didn’t know exactly what I was allergic to yet, I’m in bed scratching and I just remember thinking: `What is this for?’
“I knew because I had studied some immunology that there was this whole class of antibodies that does nothing but cause allergies. And I thought, `What on earth could it be there for?’ I thought, `What are the symptoms of allergy?’
“It’s immediate. It’s unlike a viral illness or a bacteria, which are delayed, and might be days before you get any noticeable reaction. With allergies, it’s immediate, within minutes. You’re scratching it off, you’re tearing, you’re sneezing, you have diarrhea, or you vomit and you drop your blood pressure. All of these are ways to immediately expel something.
“I thought, `What could cause this? What could kill you within minutes? Viruses don’t work that fast. Bacteria don’t. Toxins do.’ ”
Profet had no idea at the time what the conventional analyses of allergy were. When she found out that most scientists believed it was either, one, a mistake, or two, a reaction to the potential presence of parasitic helminth worms in the digestive track, she was appalled.
“When I came across the helminth worm theory, I thought, `NO, they couldn’t be taking this seriously. Maybe one or two immunologists think this is the reason, but this is beyond silliness.’
“It doesn’t make sense from an adaptationist viewpoint because there’s not a fit between the mechanisms of allergy and the problem of worm expulsion,” she says. “Worms are a chronic problem, and allergies were designed for something acute.”
All the while Profet was working on her pregnancy-sickness and allergy research, she was unable to get decent part-time jobs. She faced the daily problem of being poor.
“I was constantly applying for jobs, looking at the want ads,” she says. “One of my versions of hell is a world populated solely by personnel directors.”
Finally, she met toxicologist Bruce Ames, who ran a research lab at UC-Berkeley and outfitted it with scientific oddballs.
Ames recalls his first encounter with Profet. He was giving a seminar to physics students on current research in toxicology. Profet, who was long out of school, somehow got into the seminar, and began asking unusually insightful questions. After the class ended, Profet trailed Ames back to his office, “peppering me with some more really good questions. Finally, I said, `Hey, who are you, anyway?’
“She said she was a waitress or something like that.
“I said, `What do you mean, a waitress?’ ”
She told Ames that’s what she did to make a living, and in her spare time she was a biologist.
Ames hired her to work half-time in his lab, where her job was intended to be clerical. She proved to be “a major contributor,” Ames says, and was soon editing much of the research the lab published. She became a principal editor of Ames’ own published works.
“She’s a fanatic on getting every sentence right,” Ames said. “There was a paper she contributed to, and I said I was going to list her as a co-author. She said no, she felt the paper wasn’t up to her standards and she didn’t want her name on it.”
“She’s a person who goes her own way in life.”
By this time Profet’s pregnancy-sickness paper had been published by a small journal and her allergy research, after surviving significant criticism during its peer review, was accepted by the Quarterly Review of Biology. George Williams, the Quarterly’s editor and a highly regarded evolutionary biologist, thinks Profet is helping to form what amounts to a new science, uniting biology and medicine in a way that hadn’t been done.
For reasons neither Williams nor Profet can fathom, physicians and biologists, who, after all, share the human body as a subject, seldom were aware of one another’s work.
Profet says, “Physicians don’t look at function. Physicians seem to think if you ask what’s the function of something, it’s teleological. It’s an intellectual theory, and there’s no practical utility.
“It’s not important? It’s the basis, it’s the foundation for understanding physiology. And physiology is the basis for understanding medicine. Imagine if we didn’t understand the function of the heart. How could you recognize heart disease? How could you define heart health? How could you do anything? How could you perform heart surgery? How would you know when to do it? What to do?”
“Say we have two theories about the function of the heart. One is that it pumps blood. The second theory is that it’s there to give us love and heartbreak.
“In the second case it’s removable. You had a bad loveship, take out your heart.
“These things have major implications. With pregnancy sickness, they did awful things to women. Not only did they think it was not a function, they thought it was dysfunctional, especially if you had severe pregnancy sickness.
“Of course, with the Freudian revolution a lot of people thought this was just in people’s heads; they’re just neurotic. So a woman with a lot of pregnancy sickness is super-neurotic. They would tell her, `This is an attempt at oral abortion. It’s a loathing of femininity. A loathing of your husband.’ “No matter what aspect of physiology you look at, the core question is: What’s it there for? Maybe it is just a fluke or a by-product. But maybe it has a function. You have to know that. Otherwise you’re doing blind medical intervention.”
The reactions in the medical community to Profet’s theories have ranged from the cool to the hostile. One criticism to her allergy theory complained that a new explanation of allergy wasn’t needed. They already had one.
“Science isn’t a democracy,” Profet says. “Voting is not the basis for truth. You don’t go to some allergist and say, can I have a show of hands? That’s not how you demonstrate science. I find things like that mind-boggling.
“You know, you tell any lay person, `Guess what the immunologists think that allergy is designed for.’
“They say, `What?’
“And you say, `Little worms.’
“And they go, `Huh?’ ”
It is this intuitive grasp of the apparent failure of existing theory that is the basis for all of Profet’s work. Her three major ideas – on pregnancy sickness, allergy and menstruation – all subject anomalous human behavior to an adaptationist critique. Why does this happen? What does it cost? What is the resulting benefit? The fundamental supposition of evolution, that all organisms are engaged in an evolutionary race for survival, is the main motivation of all of her explorations.
IT IS HARD TO IMAGINE someone of Profet’s physical demeanor succeeding at any pursuit as sedentary as thinking. She is a small, preening rabbit of a woman, with a skittish hyperactivity that prompted me to ask her, not facetiously, how often she ran into walls.
She considered it a legitimate question.
She has developed the odd habits of the solitary, talking to herself, to animals, to people who aren’t there. She hasn’t enough patience to eat normal meals. She grazes at her desk, consuming low-calorie animal crackers, fruit, bread, milk and diet colas. “I don’t like to cook,” she says. “When I’m hungry I want to eat now. I don’t want to eat in an hour.”
When she went shopping for her first car this year, she decided that for the good of the public order it had to have a manual transmission. The need for constant shifting, she thought, would keep her attention focused on driving. Otherwise, it was hard telling where her mind, and the car, might wander.
True to her beachfront roots, she wears T-shirts and running shorts year round, changing the length of the shorts in carefully calibrated accord with the temperature.
George Williams, the biologist, asked recently to evaluate Profet’s history and habits, concluded, “People don’t always get born when they should.”
Profet acts much more like a medieval hermit monk than a modern scientist. Her big social event of the week is going to the library. Her major expense last year was photocopying. Given her work habits and highly unconventional training, she would seem more in sync somewhere in the late Renaissance. In some fundamental way, Profet might belong to an even earlier era.
Most modern scientists are grown in much the same way as today’s crops. They are lined up all in a row, standardized, carefully fertilized and watered, grown to uniform size. They have been domesticated. Profet is a throwback to the days before domestication. She is a precursor, foraging through the fields of human knowledge, searching for some things, happening upon others.
In her own evolutionary race, she seems to have outlasted her natural enemies. The hunter-gatherer has come back.