IN BIOTECH THE FUTURE ARRIVES IN FITS AND STARTS

by Carl T. Hall

The future booms and busts of the biotechnology industry can be glimpsed in the laboratories of scientists like Frank McCormick, a top cancer researcher and head of the UCSF Comprehensive Cancer Center.

McCormick’s long record of scientific achievement includes work that led to an experimental cancer therapy at the East Bay biotech company Onyx Pharmaceuticals Inc., which McCormick founded and where he served as chief scientific officer from 1992 to 1996.

Known as Onyx 015, the drug is a modified form of the virus that causes the common cold. Early experiments showed it has a remarkable ability to destroy certain types of cancer cells. But whether this can prolong the lives of any actual cancer patients may not be known for some time—if ever.

That’s because development work on Onyx 015 was halted last year, when the Richmond company said it had more than enough on its hands with another promising cancer treatment, based on an entirely different technology that also sprang from work done in McCormick’s labs.

It’s not that Onyx 015 flopped in a clinical trial, as often happens. It just has been put on hold until the resources can be found to move it forward.

The rise and fall of new molecules in the real world of commerce often has little to do with science. In biotechnology, the future arrives in fits and starts. So all the drug developers can do is to keep working and hope the money doesn’t run out.

“These things depend on the level of interest of big pharmaceutical companies and biotech firms, and their agendas. (Scientists are) really out of the driver’s seat,” McCormick said.

Plenty of promising research is being done right now that has the potential to yield the Next Big Thing in biotech, be it a drug or just some fundamentally different ways of unraveling the complexities of human biology and disease.

Such possibilities are, by their very nature, unpredictable. “The thing about research is you don’t know until you know—you have to do the work and find out, and then go back and do some more work,” said Larry Goldstein, professor of cellular and molecular medicine at UC San Diego.

In the aftermath of [BIO 2004] the annual convention of the biotechnology industry, which drew some 17,000 participants to San Francisco, here is a look at two of the more promising areas of research.

Regenerative medicine

Stem cells, the all-purpose starting material that gives rise to the myriad cell types of the body, are widely assumed to be the basic building blocks of 21st century medicine.

One idea is to turn these cells into transplant materials for people with incurable diseases. It’s a fundamental component of a broad field of research known as regenerative medicine, where the idea is to create sophisticated replacement parts for those ravaged by disease or the wear and tear of aging.

The controversies involving embryonic stem cells—revived lately by a pro-research ballot initiative being put before California voters in November—often obscure what many scientists consider to be the real promise of the field. Surprisingly, it has little to do with medical cures as such.

Even the most virulent stem-cell proponents admit they don’t expect to see stem cells turn into commercial products any time soon. “Ten years? Maybe. OK, call me in eight,” said Fred Dorey, a longtime biotech-industry observer at the Cooley Godward law firm in Palo Alto, summarizing the view of venture capitalists.

Keith Yamamoto, an executive vice dean at UCSF and outspoken advocate of stem-cell research, said the most exciting prospect involves a fundamental understanding of how cells develop and differentiate and why some stem cells mature normally while others turn down a path that leads to a particular disease, often many decades after birth.

By watching stem cells in the laboratory, scientists hope to pinpoint how this happens and what signals the cells receive to guide their development.

Combining this knowledge with screening technology might revolutionize medical practice. Doctors, for instance, might be able to diagnose illnesses long before symptoms are apparent, based on readouts of cellular processes and genetic tests.

At the same time, drug developers could run early tests on human disease cells, rather than relying on animal experiments whose results often don’t apply to humans. Stem-cell research “might accelerate, and potentially might greatly accelerate, the process of drug testing,” Yamamoto said.

Many scientists maintain that stem cells, whether they are derived from embryos or adult tissues, are perhaps the single most important factor shaping biomedicine today, perhaps even on a par with genetic engineering, which formed the bedrock of early biotech about 30 years ago.

“This is a very flexible technology,” Goldstein said. “I view it as an enabling technology, like recombinant DNA, that will have applications all over the place. But there’s no way you can predict them all before you start.”

Systems biology

Dr. Leroy Hood, a leader of modern genetic research, who invented some of the most important tools of the trade, is now one of the pillars of a field known as systems biology.

Hood co-founded and serves as president of the four-year-old Institute for Systems Biology in Seattle.
It’s based on a simple idea with ancient roots: Rather than focus on the particular genes or cells or other component parts, better to look at the networks of these components, in the context of the whole organism, to understand how things really work.

A new crop of systems biologists—many of whom started out as mathematicians and physicists—has begun using computers and vast gene and protein databases to study body functions at the network level. The approach generated considerable buzz at last week’s BIO 2004 meeting in San Francisco, which Hood, a founder of several biotech companies, attended to pick up an award.

Completion of the Human Genome Project, he said during an interview, was the watershed event that set the field in motion, fueled by the advent of high- speed gene analysis, three-dimensional protein imaging, and easy Internet access to all sorts of raw data.

“Until very recently, we haven’t had the tools to look at all these interrelationships,” Hood said. “Now, for the first time, we have the tools to look at the true complexity of these systems and how they can be changed.”

Hood said he is convinced this will be “the major transforming force in medicine and biology in the 21st century, no question about it.”

Some of the first applications are expected to arise in the area of vaccines and other approaches to tweaking the immune system. The individual elements of the system, those disease-fighting T-cells and B-cells and macrophages, are among the most closely studied molecules in biology. But nobody really knows just how and why they do what they do.

“We know a lot about the individual components and the individual roles they play,” Hood said. “Now we can take a systems approach to understanding not only the parts list of the immune system but how they interact.”

It requires a highly quantitative, interdisciplinary approach to tie together mountains of data from multiple levels, starting with the genes and proteins, then on up to the cells and tissues, and ultimately to entire physiological systems.

Despite the daunting nature of the task, it’s catching on fast, not only in the United States but around the world. Nearly every major research center now has some sort of multi-disciplinary effort going on, such as Stanford University’s high-profile Bio-X project.

“It’s a very new field, but it really started taking off maybe five to seven years ago,” said Marvin Cassman, a former top scientist at the National Institutes of Health and early proponent of the systems approach in biology. He headed a multidisciplinary center at UCSF known as QB3 until last year and is now leading a study of international systems biology work, sponsored by the National Science Foundation and other agencies.

Outside the United States, significant national efforts have started in Britain, Germany, Belgium, the Netherlands and Japan. A few small companies have begun using something akin to the systems approach to help in such things as clinical trial design.

It’s anybody’s guess what might come of it. Cassman said it’s clear that it will take a lot of sophistication about biological networks to move biotech to the next stage — now that the low-hanging fruit of the business has been picked clean.

“If you want to talk about the major diseases that affect humanity—cancer, heart disease, lots of things—it’s a much more complicated situation than what we are used to dealing with,” he said.

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“Bringing Biotech Into the Real World: No Neat Fit Between Lab Work and the Road to Lucrative Patents,” San Francisco Chronicle, June 13, 2004.

Carl T. Hall is a science writer for the San Francisco Chronicle.