The Wall Street Journal February 21, 2003

Biologists' New Approach: Do Not Shoot the Radio

by Sharon Begley

How would a team of biologists fix a radio ? First, they'd secure a large grant to purchase hundreds of identical working radios . After describing and classifying scores of components (metal squares, shiny circles with three legs, etc.), they'd shoot the radios with .22s.

Examining the corpses, the biologists would pick out those that no longer work. They'd find one radio in which a .22 knocked out a wire and triumphantly declare they had discovered the Key Component (KC) whose presence is required for normal operation.

But a rival lab would discover a radio in which the .22 left the Key Component intact but demolished a completely different Crucial Part (CP), silencing the radio . Moreover, the rivals would demonstrate that the KC isn't so "key" after all; radios can work fine without it.

Finally, a brilliant post-doc would discover a switch whose position determines whether KC or CP is required for normal operation. But the biologists still can't fix the blasted radios .

For those of you who haven't looked inside a radio lately, the Key Component is the wire connecting the external (FM) antenna to the innards of the radio , the Crucial Part is the internal (AM) antenna and the switch is the AM/FM switch.

Biologists can't repair radios because their part-by-part approach fails to describe the radio as a system -- what's connected to what and how one part affects another.

Biologists' affinity for the one-part-at-a-time approach, argues biologist Yuri Lazebnik of Cold Spring Harbor Laboratory on New York's Long Island, who dreamed up the radio analogy, is "a flaw of biological research today."

For that, thank the events of 50 years ago.

On Feb. 28, 1953, a Saturday, James Watson spent the morning at his Cambridge, England, lab piecing together cardboard representations of the "base pairs" in the DNA molecule. With that, he and Francis Crick realized that the master molecule of heredity is shaped like a spiral staircase, or double helix.

This discovery ushered in the era of the gene and gave birth to a new field: molecular biology. The study of living things became a science in which progress meant describing the smallest bits possible, usually one at a time -- one stretch of DNA, one RNA, one protein. The double helix, Harvard University naturalist E.O. Wilson once said, "injected into all of biology a new faith in reductionism" -- a "shoot the radio " approach.

As the world celebrates the golden anniversary of the discovery of the double helix with symposia, galas and media paeans, let me be contrarian: The reductionist paradigm launched by the double helix is just so 20th century.

Don't misunderstand. Molecular biology was a rousing success. It reached its pinnacle with the sequencing of the human genome, whose final draft will be unveiled in April. But all good things must end, and there are signs that biological reductionism is one of them. It's pretty clear that making a parts list for an organism, even if you annotate it with those parts' functions, is no more adequate to understanding the complexity of a living thing than is listing the parts of a Boeing 777. Instead, you have to ask how the parts fit together and work together.

The new approach is called systems biology, and it represents a huge departure from the reductionist paradigm. "Biology undergoes these revolutionary waves from time to time, after which nothing is ever the same," says biologist Eric Davidson of the California Institute of Technology, Pasadena. "This is one of those times."

Catching the wave, the Massachusetts Institute of Technology last year launched a systems-biology program melding computer science, engineering and biology. In November, Eli Lilly & Co. established a systems biology lab in Singapore, where it expects to spend $140 million over five years, and several biotech start-ups are hitching their stars to the new paradigm.

Systems biology analyzes a living thing as a whole, not one gene or one protein at a time. "You have to look at all the elements in a living system to understand how they function," says biologist Leroy Hood. His seminal work on DNA-sequencing technology fell four-square in the reductionist camp, but in co-founding the Institute for Systems Biology in Seattle in 2000 he became one of the first and most prominent defectors.

Not surprisingly, the systems approach represents an unsettling shift that "is not exactly welcomed" by many biologists, says Mr. Lazebnik.

Partly, that's because "doing systems biology requires a huge change in the research culture," says Prof. Davidson. "In traditional molecular biology, each scientist works on his own gene, but the systems approach requires determining the effect of every gene on every other. You have to give up this 'my gene, your gene' stuff."

But the payoff could be tremendous. At MIT, quantitative models showing the interconnections among cellular components -- much like the wiring diagram for a computer chip -- promise to predict unexpected properties of anticancer drugs such as Herceptin, says MIT's Peter Sorger. With any luck, the models will predict how to tailor cancer treatment to individual patients.

File Date: 02.26.03