James Watson and Francis Crick worked out the structure of the DNA double-helix at Cambridge University, announcing their much-celebrated discovery in a modest one-page letter to the journal Nature that was published 50 years ago today.

Not long after, the American-born Watson made it back across the Atlantic to the other Cambridge, where he joined Harvard’s faculty in 1956. His coming brought molecular biology to Harvard, a discipline that has seen explosive growth and advancement in the past 50 years.

Molecular biology takes a reductionist approach to living things, breaking them down into their smallest moving parts.

Despite the success of such reductionism, some scientists now find that reductionism is not enough to solve some of the most important problems in biology.

Instead of trying to understand the minute physical details of life, scientists have now begun to explore the complex ways in which networks of proteins interact in cells.

It’s the network, not the double helix, that is attracting the attention of more and more scientists. Fifty years after the structure of DNA invigorated the molecular biology revolution, a new more integrated approach to understand cells is gaining prominence.

This approach, called systems biology, is increasingly important in biological research at Harvard.

It’s All About Networking

The final draft of the human genome was announced this month. But the function of most of the raw sequence—a string of the nucleotide bases A,C, T and G—is still mysterious.

“Most of the information that’s encoded is completely obscure to us,” says Professor of Molecular and Cellular Biology William M. Gelbart. “It’s as if we unearthed some ancient tablet but you can’t read most of it, because you don’t have the dictionary.”

Now, the task for scientists is to study how these bases of DNA are grouped into genes, and how these genes help produce proteins that interact to keep a cell alive.

Researchers have long known how to find the function of specific genes, which is akin to knowing the dictionary definition of a word. Finding all of the words, and figuring out how they fit together is the goal of the network approach to biology.

“Interactions you wouldn’t dream of are being discovered,” says David Jeruzalmi, assistant professor of molecular and cellular biology. For example, it was recently discovered, he said, that ten genes interact to contribute to alcohol addiction.

“We’re not going to understand what’s going on in a cell unless we more or less look at what’s going on simultaneously,” he says.

Harvard’s main investment in this integrated approach to biology is the Bauer Center for Genomics Research, which was dedicated last year. According to Bauer Center director Andrew W. Murray, researchers at the center seek to eventually gain a comprehensive understanding of complete biological systems. He says that take a system-based approach “will tell us in some complicated way how biology is put together.”

“All of what science does is study some smaller part of science in a way that they hope will be relevant,” he says. “The only difference now is that the size of the part we are studying has gone up.”

Laura Garwin ’77, director of research affairs for the Bauer Center, says the more comprehensive approach to understanding how DNA directs the functions of the cell should not overshadow the importance of the reductionist approach used so successfully by Watson and Crick, and thousands of others.

“The big revolution that started in 1953 was a reductionist revolution,” she says. “And that was a success because it’s only by understanding what’s going on at a fundamental level that you can understand what’s truly going on.”

But the continuation of a details-based approach, she says, would be similar to a blind man’s quest to understand an elephant by feeling one small part of the elephant at time.

“The only way you can really know what the elephant is like is if you look at the whole elephant,” she says. “What we had until recently was just a list of the parts. But a list of the parts is just the bare minimum for what you need.”

She said that without new technology, however, scientists would have been incapable of taking a systems-based approach, which involves studying hundreds or even thousands of processes in the cell simultaneously.

Microarrays Lead the Way

One crucial piece of technology for understanding biological networks is the DNA microarray, invented in the early 1990s.  The microarray allows scientists to determine, all at once, the relative levels at which genes are expressed in cells.

Bauer Center Research Fellow Hans Hofmann uses the microarrays to analyze gene expression in cichlids, a type of fish.

Some of the fish are territorial and aggressive, while others fish are docile and spend more time eating. The fish Hofmann studies are special, however, in their ability to change their nature. They can transform from an extremely aggressive territorial fish to a well-behaved non-territorial fish.

To study how this change happens, Hofmann takes material from fish’s brains and uses it in microarrays.

“If you only looked at a single gene, you wouldn’t get the sum total of what’s going on in the fish to help make the transition,” says Garwin.

Hofmann says that knowledge of this “sum total” is necessary to study of all the genes in an organism, called genomics.

“Genomics means to be more integrated, to put more things together, to get a comprehensive understanding of what’s going on in the animal,” says Hofmann. “Genomics is a highly comparative science.”

Before technology such as DNA microarrays enabled scientists to study many genes at once, experiments were much more tedious and less efficient, according to Garwin.

Before microarrays, scientists “would spend months figuring out how one gene expresses itself in one tissue,” says Garwin.

Microarrays may also help in finding the genetic defects that cause certain diseases. Now, cells from non-cancerous and cancerous tissue can be analyzed so scientists have an idea of what caused the cancer to develop.

Such technology might one day help in understanding and treating human disease.

Drugs can have different effects on people who have slightly different genes. By finding out which forms of a gene a person has, the type and dosage of a drug can be chosen for maximum effectiveness.

“You focus on the average target, and some people deviate from the target,” says Jeruzalmi. But by analyzing individual genomes, he says, “you can synthesize the variant that’s going to be the best for you.”

Such advances, however, rely on further understanding how the proteins in a cell interact with each other, and being able to find the sequences of large genomes quickly.

“It would not shock me if 10 to 15 years from now, if you wanted to, you could go into a doctor’s office and get your DNA sequenced for two thousand dollars,” he says.

—Staff writer Nura A. Hossainzadeh can be reached at hossainz@fas.harvard.edu.