Biologist as watchmaker, cells as parts

In the early rounds of the global battle against severe acute respiratory syndrome (SARS), few prizes have been more highly sought than the genetic "parts list" for the virus that scientists have linked to the disease.

Now, only a month after identifying the virus, research teams in several countries have produced full genome sequences for five strains of the virus and partial sequences for five more.

They did it with technology that, when first proposed in the 1980s, was viewed as Quixotic, according to Leroy Hood, its inventor.

"In the 1980s, when we were developing the gene sequencer, I remember putting two grants in to the NIH [National Institutes of Health], and we got neither," Dr. Hood recalls. The grants' reviewers either "said it was impossible or [that] graduate students could do it cheaper."

Today, the impossible has become the indispensable. One machine can process and analyze in one day more genetic material than 100 scientists using manual techniques could process in a year.

"Hood's work on the auto sequencer is just astounding," says Rob DeSalle, an evolutionary biologist at the American Museum of Natural History in New York. "It's allowed all fields in biology to advance much more rapidly."

Through his inventions, and his early and enthusiastic backing of the just-completed human-genome project - which determined the order in which human DNA appears in cells - Hood has placed himself on the vanguard of a revolution in biology.

After centuries of taking the biological "watch" apart to see what its components are, researchers are now asking how the pieces fit together to form a functioning organism. And some, such as Hood, are looking for the laws governing those actions in an emerging interdisciplinary field he dubs "systems biology."

In recognition of the key role his inventions have played in this revolution, Hood received the $500,000 Lemelson-MIT Prize late last month for invention and innovation.

During an interview at the Whitehead Institute for Genomic Research in Cambridge, Mass., Hood traced his love for biology to his rural Montana boyhood, and his roots as an inventor to biologist William Dryer, his PhD adviser at Cal Tech.

"What was remarkable about Bill Dryer," he says, "was his belief in two things, which are the foundation of how I look at my science. One is: You should always work at the leading edge of biology; it's more fun and exciting. And two: If you really want to transform biology, you should develop technologies that can open up these horizons."

In applying these to his own career, Hood says, he also began to reach out to specialists outside his field of molecular immunology. This became the foundation for his later efforts to build bridges between scientific and engineering disciplines with the aim of tackling some of biology's toughest questions.

It has been a bumpy road, however. Hood says he ran into resistance from colleagues at Cal Tech and later at the University of Washington, many of whom remained wedded to a mode where individual scientists or small collaborations worked on problems piecemeal.

Hood ran into similar resistance when he and a handful of other scientists first proposed sequencing the human genome in 1985 and tried to outline their vision of what that information could eventually do to improve medical care. Even now, the gene-sequencing technology is the subject of a lawsuit that seeks to nullify Cal Tech's patent on the devices.

Michael Phelps, who heads UCLA's department of molecular and medical pharmacology, notes that Hood found himself in a position familiar to creative people who help push boundaries of thought.

"When you go out of bounds you have few rules to limit you, and few to protect you," says Dr. Phelps, who invented the medical imaging technique know as positron-emission tomographic (or PET) scanning. "You know you're out of bounds when people start attacking you. If you are successful, more will come out of bounds with you, and eventually you create the new inbounds.

"When that occurs," he adds, "you must go out of bounds again."

Hood's latest excursion out of bounds came in 2000, when he left the University of Washington to set up the Institute for Systems Biology in Seattle.

"In systems biology you look at all the elements in a system and look at interrelationships," rather than looking at genes or proteins one at a time, he says. As an example, he cites work the institute has done on yeast.

For 30 years, he says, researchers have studied the way yeast cells process sugars. "We asked: Could systems biology learn anything new?" So he and his colleagues took selected genes out of the nine-gene system for metabolizing sugar and watched the effect on the yeast cells. "We began to see the whole network architecture of how the cell's biology operates," Hood says.

Researchers at the institute aim to apply a similar systematics approach to the human immune system. They hope that by all but eliminating the costly trial and error that leads to new medicines, firms can develop safer, more effective vaccines less expensively. Such speed could be critical, he notes, to dealing with bioterrorism or emerging infectious diseases.

Hood says systems biology may ultimately lead to healthcare that prevents illness, rather than intervening after it appears.