Closing In on Cancer : In Search of a Cure, a La Jolla Research Center Reaches Into the Outer Limits

Kathryn Phillips is a Pasadena writer .

It seemed so simple in 1971.

President Richard Nixon declared war on cancer with the promise of new funding that politicians and physicians claimed would lead to a cure before the end of the decade.

But 18 years later, there's still no cure, no magic bullet for cancer. And the strategy of waging a short-term, one-front war on the disease has died as policy-makers, physicians and scientists have come to realize just how complex cancer really is.

For cancer is not just one disease; it's more than a hundred. Treatments that work on one variety will not necessarily work on another. But more important, researchers realize that they need to focus their work on a more fundamental level--how normal cells and cancer cells work. They know that the conventional treatments--surgery, drugs and radiation--simply kill or remove cancer cells and aren't effective enough. The goal now is to find treatments that will change cell behavior and then force cancer cells to stop acting like cancer cells.

Not that conventional treatments haven't helped. They have. According to the National Cancer Institute, the overall odds of surviving cancer have risen from 39% in 1950 to 50% in 1985, the latest year for which statistics are available. And for certain types of cancer, the chances of being alive five years after treatment and not showing new signs of disease are much higher. For instance, in 1960, a person found to have Hodgkin's disease had a 40% chance of surviving. By 1984, a person with Hodgkin's disease had a 74% chance.

Still, the number of deaths is discouraging. In 1988, the American Cancer Society estimates, about 1 million Americans were found to have some form of cancer and about 500,000 died--10 times the number of people who have died of AIDS in the past decade.

So, the question remains: Will there ever be a cure for cancer?

Last year, experts in Japan predicted that by 2002 their country's scientists will have developed a way to prevent the spread of cancer in the human body. By 2005, they said, they will be able to correct the abnormal proliferation of cancer cells and change them back into normal cells.

American scientists are not as optimistic.

In 1987, Louis Harris & Associates interviewed 227 prominent American researchers. The polling firm found that cancer scientists expect the cure rate to rise from about 50% today to 67% by the year 2000. The survey also showed that most cancer scientists believe that significant progress against cancer "will be made slowly, in a piecemeal fashion on a disease-by-disease basis, rather than as a result of one central insight that helps control a number of different cancers."

The common ground between the American researchers and the Japanese predictions seems to be that to achieve any major breakthrough, scientists must answer the fundamental question: What transforms a normal cell into a cancer cell?

In a large and growing complex at the north end of San Diego, scientists on the leading edge of biological research are trying to answer that question and others.

ON THE BRINK OF DISCOVERY

Nuclear scientists use the term critical mass to describe the amount of material it takes to create the chain reaction that causes a nuclear explosion. Biologists in La Jolla believe that something like a scientific critical mass has been reached in the research labs overlooking the Pacific Ocean, among the eucalyptus groves and Torrey pines on the northern edge of San Diego. La Jolla, once better known for its beaches than its brains, has evolved into a thriving generator of landmark biological discovery. Three major research organizations--the University of California at San Diego, the Salk Institute for Biological Studies and the Scripps Clinic and Research Foundation--came first and formed the nucleus of what was to follow. From the beginning, they have drawn world-class research scientists. But the intellectual explosion has occurred only within the past decade.

Today, La Jolla is often compared to the Boston area, where a collection of prestigious older academic institutions and new high-tech companies have created one of the country's most important biomedical research centers. Scientists occasionally even talk about a Boston-La Jolla axis. Some refer to the La Jolla scientific community as "Boston West." Ralph Reisfeld, a widely known cancer researcher who came to Scripps Clinic and Research Foundation from the National Institutes of Health in Washington in 1970, notes that he no longer has to spell La Jolla to colleagues when he attends out-of-town scientific meetings.

There are, of course, other important research sites in California. Caltech in Pasadena, City of Hope National Medical Center in Duarte and UCLA all have outstanding research reputations. But La Jolla is unusual in that it has, in just a few square miles, so many prestigious institutions that have come of age in the last 10 years.

"There is a feeling across the country that this upstart--and compared to Yale and Johns Hopkins and Harvard, (the La Jolla scientific complex) is an upstart--has really jump-started, that major science is going on here," says Gerard Burrow, who became dean of the medical school at UC San Diego, which is in La Jolla, last year after a career at Yale and Toronto universities.

Within this scientific environment, biology is the dominant science and cancer is a prime target.

Some of the most fundamental and important cancer cell research is being done at a relative newcomer to the area, the La Jolla Cancer Research Foundation. Founded in 1976, it is 16 years younger than the larger and more famous Salk Institute for Biological Studies, which sits less than a five-minute drive away. And it is 15 years younger than the Scripps Clinic and Research Foundation.

Yet, within cell biology circles, the La Jolla Cancer Research Foundation is becoming known for having discovered some of the mechanisms that make normal cells and cancer cells behave as they do. Since 1981, it has been one of only three labs in California, and one of 15 nationwide, designated as a basic research lab by the National Cancer Institute, the federal agency that funds cancer research. The designation, which comes with grant money, is given only to institutions able to prove that they have high-quality cancer research programs and continue to conduct top-flight research.

Much of the La Jolla Cancer Research Foundation's reputation has been built in Erkki Ruoslahti's lab. Ruoslahti is a cell biologist who is both typical and atypical of the scientists who have built the area into an important research center. In March, he will succeed its founder as president and chief executive officer of the institution, where he has been scientific director since 1979.

Ruoslahti has done pioneering work on how cancer cells and normal cells adhere to other cells and to a fine protein meshwork called the extracellular matrix. The type of science he is involved with is rarely discussed in newspapers or on television. It's not sexy. It's complicated and delicate and tends to provide only pieces of a puzzle instead of whole, easy-to-grasp parts. But it's the stuff that causes curious scientists to chart new territory and ultimately may lead to better ways of treating disease.

There are other equally talented scientists in La Jolla. But only a few have been in a position to lead a young institution from obscurity to prominence while determining the direction of research locally and internationally. Roger Revelle and a few others did so with UC San Diego. So did Jonas Salk with his namesake institution. And Frank Dixon led Scripps to its star status. At La Jolla Cancer Research Foundation, Ruoslahti is getting his chance to match the achievements of the others.

THE SCIENTIST /EXECUTIVE

There are strong reminders of Erkki Ruoslahti's Finnish homeland in his La Jolla office. The furniture is contemporary Finnish--blond wood, leather cushions, sleek lines. A black-and-white photograph of his childhood home, a large house surrounded by snowdrifts, hangs on one wall. It was once a summer place for a Russian nobleman, later the home for an engineer-turned-paper-company-executive and his wife and four children. Ruoslahti, the third of those children, became a scientist to avoid following in his father's footsteps. Now, though, he finds himself with an executive title of his own, trying to balance his passion for science with his drive to build an institution.

The door to his office is almost always open, but Ruoslahti is almost never in. He prefers to work down the hall, his lanky 6-foot-4 frame squeezed into a desk chair at his lab bench. There, he takes phone calls, drafts fund-raising letters, reads scientific papers and meets with the dozen or so young scientists conducting the experiments he helps conceive. He is surrounded by the laboratory tools that he now rarely gets to touch but that he knows are the foundation of his success.

"All these titles, being an executive and all that, don't mean that much," he says, speaking deliberately and with a mild Scandinavian accent. "(Such) things will change. But good science will always endure." Then, after a moment, he smiles shyly and adds in an uncharacteristic lapse of confidence, "I hope that doesn't sound too corny."

Ruoslahti has a reputation among other scientists for being honest, fair and extremely competitive. At 49, he plays serve-and-volley tennis on his backyard court at an age when most men are retiring to a base-line game. He is a self-described feminist whose rare leisure reading includes novels by Margaret Atwood. He has a knack for business and likes to "wheel and deal a little bit." He thinks science is fun and loves finding something that nobody else has. His goal in all things is fairly simple: He wants to excel.

At the foundation, he wants growth without bureaucracy. He wants to preserve a place where good scientists can perform good science without the hassles of paper work and budget constraints.

In his lab, he wants to dazzle competitors with new findings without forgetting the practical benefits of research. He wants to see those discoveries transformed into treatments for disease.

To do any one of these things would be an achievement. To do them all would be remarkable.

THE FIRST PIECE OF THE PUZZLE

It is 10 a.m. on a Monday, and Ruoslahti politely cuts off an interview in his office to join his research team at its morning meeting over coffee and pastries. He has been up since dawn. Typically, he spends about an hour reading scientific journals and other papers before driving the 25 minutes from his house in Rancho Santa Fe to arrive just after 8 a.m. On weekends, he usually spends 10 hours or so on scientific reading.

"He reads every scientific paper written," says Michael Pierschbacher, a staff scientist whom Ruoslahti brought to the lab nine years ago. "He has an immense knowledge of what's going on, and I think that's his advantage: being able to see what's coming."

In the early 1970s, while an assistant professor at the University of Helsinki, Ruoslahti began studying the interaction between cells and the extracellular matrix, a field that only a few scientists around the world considered worth pursuing. The matrix is a fibrous meshwork of proteins and other substances that a cell creates to lay between it and another cell. It fills in the tiny spaces between cells like mortar between bricks.

"I wanted to understand how you make a pattern, how you make a finger or nose or liver or whatever," Ruoslahti says. He wanted to know what mechanisms determine where a cell positions itself and what causes that mechanism to malfunction--as it does in cancer.

In 1973, he began to get some intriguing answers. Almost simultaneously, he and Antti Vaheri in Finland and two competing teams in London and Seattle discovered an unusual protein molecule sitting on the edge of cells that they later discovered was part of the extracellular matrix. This protein molecule was absent from cancer cell surfaces. They named the molecule fibronectin. Over the past decade and a half, a race has been on to find out exactly how fibronectin and all the subsequently discovered parts of the extracellular matrix interact with cells.

"I don't think any of us thought we'd work on one protein, or one protein and its associates, for 15 years," says Richard Hynes, a professor at Massachusetts Institute of Technology, who led the London team. "But the reason we all have . . . is it kept getting more and more interesting, taking on new aspects, getting into new areas of biology and molecular biology. It's very exciting. There's a paper a day published on fibronectin. It's kind of mind-boggling."

Scientists now know that fibronectin plays a critical role in cell adhesion. It works with a series of other chemical elements to hook normal cells onto the extracellular matrix, to hold them in place. In contrast, cancer cells often lack the ability to hook onto the matrix proteins. Instead, they pile on top of one another, forming tumors. They also divide and make new cells at an accelerated rate, increasing the pileup. Then, in the worst cases, the cancer cells break free from the tumor, float to another part of the body and create another tumor, setting in gear metastasis, the uncontrollable spread of cancer (illustration on Page 16).

A CHANGE IN STRATEGY

Metastasis is one of the most tragic words in a cancer doctor's vocabulary. To a patient, it means that the cancer cells have moved to other parts of the body to form new tumors. It means that treatment probably will have to be increased. New surgery may be required and more potent chemotherapy ordered. It also means that the chances of long-term survival have been diminished, sometimes to nearly nothing.

"There are a number of things about cancer cells that distinguish them from normal cells," Ruoslahti says. "I think the most important ones are that (cancer cells) proliferate faster, they fail to differentiate (specialize in function), and they migrate. I think it's useful to find ways affecting each one of these properties.

"All the existing cancer treatments are directed toward preventing proliferation," Ruoslahti says. Radiation, surgery and chemotherapy usually work by killing or removing cancer cells, thus stopping their ability to reproduce. The treatments don't change the cells' behavior. Ruoslahti wants his work to lead to treatments that do.

Ruoslahti believes that if scientists can learn how cells adhere to one another, they will be able to prevent cancer cells from moving throughout the body.

"If you can prevent invasion and migration of tumor cells to surrounding tissues, you have essentially converted a malignant tumor to a benign tumor," he said. Then conventional methods of eliminating a tumor will be more effective. The threat of metastasis will be removed.

IT'S A SMALL, COMPLEX WORLD

Yu Yamaguchi, a 33-year-old research associate from Japan, is at his bench in Ruoslahti's lab. He's using a thin tube attached to a tiny vacuum hose to slurp clear liquid from a plastic plate of pea-size cylinders. Just about any time of the day, somebody in the lab is going through this same motion. And even though the liquid is clear, and the plastic cylinders look as clean as ever, the scientists who work here assure a visitor that there is something very important being left behind on the cylinder walls. It may be a protein. It may be just a few links in a protein chain. Or it might be some other molecule that segregates itself from the rest of the cell proteins after being washed with tiny drops of chemicals and antibodies that identify these proteins.

To an outsider, this is the most confounding thing about the way biology is conducted today. Nothing is visible to the naked eye or, usually, even to the standard microscope. Biology is done at the tiniest, most basic, molecular level and is dependent on increasingly complex and expensive machinery. Instead of looking at a whole cell--as small as that is--the cell is broken into a conglomeration of smaller parts that have important, definable functions. The research goal becomes one of finding and understanding those smaller parts--proteins, enzymes, carbohydrates, nucleic acids.

In Ruoslahti's lab, about a dozen postdoctoral staff members--young scientists who have recently finished school or medical school--spend each day conducting this molecular biology to identify the different parts of the extracellular matrix and their functions. "Nobody knows where the answers are going to come from," Ruoslahti says. "But it is fairly clear that there have to be advances in the basic understanding of biology and molecular biology for one to understand cancer. It's a molecular disease."

When the postdocs first join the lab for what generally stretches into a three-year stay, Ruoslahti suggests that they tackle a problem that fits the path he believes the lab's research should be taking. As they conduct their experiments, Ruoslahti offers advice or proposes new questions. He doesn't have time to do experiments anymore, something he said he doesn't mind too much. But he makes sure his life isn't dominated by administrative duties by maintaining an active lab and meeting with its members twice a day, once in the morning and once in the afternoon.

In the past five years, Ruoslahti's lab has been on a roll, producing the kind of pioneering work that impresses other scientists when it appears--as it often does--in the elite journals of biology.

For instance, in the November issue of Nature, Yamaguchi published the results of an experiment he conducted last spring. He showed, in a test tube, that proteoglycans--a special kind of extracellular matrix protein--can transform a hamster cancer cell into a normal cell. Ruoslahti and Yamaguchi are not sure why the proteoglycans is able to do this, but Yamaguchi has already begun to look for the answer, a way to understand how this "off switch" works.

Ruoslahti is delighted with this new finding. It puts him a step ahead of other labs, which is precisely where he wants to be.

"Occasionally, I like to do something that takes a couple of years for people to really catch on to," he says, grinning. "That's really where the fun is. Otherwise, if you just barely make it before someone else, then you're just doing what was obvious because everyone else is doing it also. If you are a little different and not everybody immediately catches on, that may be more of a contribution in the long run."

As an executive seeking money for his foundation, there is a downside to the thrill of scientific discovery that Ruoslahti must guard against.

"For a scientist, it's very easy to end up in a mode where you just work to impress your peers and do the best possible research," he says. "There's nothing wrong with that in a sense because you never know where the important things come from. But in dealing with people from the community, you get a different perspective because they keep asking you, 'Does this offer hope in terms of treatment of cancer?' "

BUILDING A REPUTATION TO LAST

Scientists have two ways to reach for immortality. They can make discoveries that are so fundamental and so important that they achieve eternal celebrity status. Or they can build an institution that carries on important work. In 1976, at 62, William Fishman began to do the latter. He quit his job as director of Tufts Cancer Research Center in Boston and, with his wife, Lillian, moved his lab equipment to La Jolla. He had been impressed during visits with the area's scientific community, and he knew that the winters in Southern California would be more tolerable than those in Boston.

Fishman wanted to build an institution that would approach cancer research by examining how both normal cells and cancer cells develop. He had a solid reputation among cancer researchers and a long history of receiving substantial grant funding for his research from the National Cancer Institute. He quickly found rentable lab space and won a $200,000 planning grant from the NCI. He put together a small staff of scientists. It was a good-quality staff, he said, but by 1979, Fishman knew he needed a "star" who could quickly increase the foundation's status and help build it into something lasting.

That star was Erkki Ruoslahti.

Ruoslahti had moved in 1976 from Finland to City of Hope National Medical Center in Duarte. With him had come Eva Engvall, a Swedish scientist who had worked in his lab in Helsinki as a postdoc. As a graduate student in Sweden, Engvall developed the ELISA assay, a test now as common in labs as napkins are in restaurants and a tool used in AIDS diagnosis. At City of Hope, she collaborated with Ruoslahti to create a new method for separating fibronectin from the extracellular matrix, making it easier for biologists to study the protein.

At the La Jolla Cancer Research Foundation, Engvall, 48, is studying a protein called laminin, its interaction with cells and its role in nerve regeneration. She is 5-foot-3, has an Ingrid Bergman accent and is impatient with diplomacy when she thinks bluntness will do. One wall in her office is dominated by pictures of cats. She raises Abyssinians as a hobby, and a series of cat runs stretch from the garage at the ranch-style house she shares with Ruoslahti. She gives her cats scientific names such as Recombinant Red.

As she sits in her lab office down the hall from Ruoslahti's, she recalls the first time they visited La Jolla shortly after moving to City of Hope. They drove along the coast route between Del Mar and La Jolla, past the white sandy stretch of Torrey Pines State Beach. "We wondered, 'What the hell are we doing in L.A. when we can be here?' "

She and Ruoslahti are joggers and tennis players. By the time Fishman's invitation to join the lab came in 1979, they had had enough smog. Ruoslahti was restless, eager to break free of established institutions and try something new.

"It was kind of a risk to come here," Ruoslahti says as he leads a visitor on a tour of the foundation. "But Eva and I had good grant support, so we figured, 'What the heck? Let's give it a try.' It was the right thing to do. We built up something, the research has gone well and we've had fun in the process."

He has helped add a small library and a three-story lab and administrative building to the complex. The foundation's research has evolved into four programs run by 22 staff scientists and about 120 postdocs, visiting scientists and technicians. The programs reflect the latest and anticipated trends in basic cancer research and cover the areas of the extracellular matrix, carbohydrate chemistry, gene regulation and oncogenes (see Page 11).

For an institution of its relatively small size, the foundation has managed to attract substantial funding, and postdocs marvel at how little effort it takes to obtain equipment or supplies for experiments compared to the academic institutions they've come from. It is one of only three National Cancer Institute-designated basic research labs in California (the others are Caltech in Pasadena and Salk). The foundation operates on a budget of about $11 million a year. Although some of that money comes from private and corporate donors, most of the funding--90%--comes from government grants.

"I think he's done an extraordinary job with that cancer center," Kenneth Yamada says of Ruoslahti. Yamada, an NCI cell biologist and a competing extracellular matrix researcher, adds, "I think (its) reputation really rests on him and his collaborators."

Ruoslahti realizes this and says he will have to help other scientists build up their programs and prestige if the foundation is to outlast him. In the next 10 years, he wants to more than double the amount of lab space and the number of staff scientists. He also wants to recruit a senior scientist who has a world-class reputation in molecular biology. To do that, the foundation will need to establish a $1.5-million endowment.

Asked how he expects to do all of this and continue to oversee research, Ruoslahti answers without pause. "I'll just work harder. . . (and) I'll stay in the lab."

THE RUN FOR THE MONEY

The National Cancer Institute, the federal agency charged with promoting, conducting and funding cancer research, has a total budget this fiscal year of $1.57 billion. It sounds like a lot of money, but cancer researchers say it isn't enough. Only a portion is earmarked for research grants to labs outside NCI. Researchers say the NCI budget hasn't kept up with the real costs of research, particularly in an age when the basic tools of molecular biology--such as electron microscopes, DNA sequencers, mass spectrometers--cost $100,000 and more each.

"There's a tremendous concern about whether (Americans) are really serious about funding research," says John Laszlo, vice president for scientific research for the American Cancer Society. Scientists have been particularly depressed by NCI's budget for new research grants this year. All the grant applications must be approved through peer-review panels before they are considered for funding, and only a portion of those that pass peer review are funded. This year, NCI has announced that it will disburse less grant money to fewer grant applicants than last year.

In 1988, 35% of approved grant applicants won funding. That meant 979 research projects were awarded a total of $205 million. This year, the agency will fund only 25% of approved applicants. It estimates that 715 applicants will divide $161 million. Ruoslahti says the La Jolla Cancer Research Foundation will feel these cuts. Although its grant allocation will rise this year just as it has every year since its founding, the money will have to be shared by a larger staff of researchers.

NCI is on "a very tight budget this year," an agency spokeswoman said. "Demands keep growing, and the budget just doesn't keep up."

The total budget for 1989 is 24 times smaller than the $39.1 billion research and development budget for the Department of Defense. Cancer researchers are keenly and bitterly aware of this funding relationship.

With the amount of money spent to build a single B-1 bomber, "you could have supported 100 scientists for 10 years," says Mark Green, director of the UC San Diego Cancer Center.

The constant worry about diminishing grant funding has helped accelerate the emergence of the scientist /entrepreneur. Scientists used to confine themselves to research, and to publishing their findings. Creating practical treatments was left to market-wise pharmaceutical companies. Molecular biology and a wellspring of wealthy, science-savvy investors have helped change all that. In only a few other places is the change as apparent as in La Jolla.

Daryl Mitton, director of the Entrepreneurial Management Center at San Diego State University, has studied the growing biomedical industry, and he estimates that about 50 biomedical and biotechnology firms, all founded in the last decade, are operating in the San Diego area. Many of these have spun off of a few medically oriented research institutions that compose what Mitton calls a discovery factory.

Two years ago, Ruoslahti and Michael Pierschbacher, a 37-year-old staff scientist, pushed the foundation into discovery-factory status. Inspired by the entrepreneurial activity around them, they collected $4 million in venture capital to start Telios Pharmaceuticals. Telios has first refusal rights on the development of drugs to help treat any of the disease discoveries at the La Jolla Cancer Research Foundation's extracellular matrix labs. Ruoslahti hopes that foundation income from Telios eventually will be significant enough to establish a sizable endowment.

The company's primary purpose is to develop and market products created with RGD, a chemical chain that acts like a key that helps lock the matrix proteins--including fibronectin--to the extracellular matrix. Pierschbacher, vice president and scientific director at Telios, identified RGD as the principal binding site on fibronectin while he was a postdoc in Ruoslahti's lab. He has found in lab tests that RGD can be manipulated to promote and inhibit cell attachment. Theoretically, that means that it might be useful in preventing metastasis and in breaking down tumors.

But the first RGD products--which are in the latter stages of testing but probably won't be on the market for several years--will have nothing to do with cancer. Instead, they will help heal wounds or work to safely destroy blood clots or prevent clotting. Direct cancer applications are still out of sight.

"Cancer is a very complicated situation. It's not one simple disease that you can get a grip on," Pierschbacher says. "I wouldn't want to even hint at a claim for a cure for cancer. The idea is that we feel we have a new handle on potentially controlling tumor cell behavior.

"Going to the moon was a big goal, a big complicated goal that took years to accomplish. In the process, we learned to make better toasters and such," he says. "That's essentially what we're doing, spinning off things that are easier to develop while we're headed for the big goal."

How Cancer Spreads

Three healthy cells. Healthy cell changes into cancer cell and multiplies at abnormally fast rate, forming tumor. Detail Normal cells are hooked to extracellular matrix by protein molecultes. Cancer cells are not. Cancer cell invades and multiplies again.

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