May 7, 2001 -- The leftover champagne has gone flat and the euphoria in the scientific community over publication of a working draft of the human genome -- the 'blueprint' for how to make a human being -- has died down. In the sober light of day, researchers are turning their attention toward what many believe will be a far more difficult challenge: figuring out what materials are needed to make a human and how they're put together.
Forget genomics, the study of genes. The new buzzword is proteomics, the study of proteins that genes direct the body to make. If genes constitute the blueprint, "proteins constitute both the operating machinery and the brick and mortar of cells," says Joshua LaBaer, MD, PhD, director of the Institute of Proteomics at Harvard Medical School in Boston.
LaBaer and colleagues from academic and commercial research centers plan to embark on an ambitious cooperative plan to create a freely available public repository of DNA-based research tools that any scientists can then use to help identify the proteins that make body tissues and help control body processes, or cause disease when they're missing or go awry.
LaBaer described the consortium, dubbed the FLEXGene Project, at a scientific seminar hosted by the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology in Cambridge, Mass.
When the first "working drafts" of the human genome were published last February in the journals Science and Nature, researchers reported that the "book of life" contained about 30,000-40,000 genes, on par with that of roundworms and mustard plants, far less than many scientists originally thought. "The modest number of human genes means that we must look elsewhere for the mechanisms that generate the complexities inherent in human development," wrote J. Craig Venter and colleagues in Science.
The mechanisms the authors refer to are proteins, which are highly complex structures that come in many shapes, sizes, and flavors. "Biological function does come down eventually to the protein level. Those are the business molecules that make the cells function the way they do, and that's the key," said Paul Freimuth, PhD, a biochemist at the U.S. Dept. of Energy's Brookhaven National Laboratory in Upton, N.Y., an interview with WebMD earlier this year.
Finding out which proteins do what and how and under what circumstances, however, may be a far greater hurdle to surmount, says protein researcher Michael J. Dunn, PhD, professor of biochemistry at the Imperial College of Science, Technology, and Medicine in London.
"The challenge is that we've got a lot of potentially novel gene products -- that's proteins -- and we don't really know what those proteins do; we've got very little clue as to what functions they have and how they interact," Dunn tells WebMD. "What we're mostly interested in is how all that controls ... what makes organisms and man work and what's wrong with them in dysfunction and disease."
Identifying which proteins are responsible for causing or failing to prevent a disease can help medical researchers devise new treatment strategies for, say, specific types of cancers, or drugs that are designed to hone in like smart bombs on a specific target site, treating diseased tissues while leaving healthy cells pretty much alone.
"But I think that the general consensus of those of us in the field is that it's going to be much more difficult to establish the human proteome than it was to establish the human genome," says Dunn.
Just as the sequencing of the human genome was greatly accelerated by the introduction of high-speed computers and automated processing equipment, the search for specific proteins will be accelerated by technologies still under development.
"In my mind, it's really the next step after the Human Genome Project," LaBaer tells WebMD. "The Human Genome Project provided us with the order of the letters that are in the genome, and it's all information that is in computers. The key now is how do you translate that [computerized] information into true biological product that can actually be used to experiment on and study the genome."
LaBaer and others have figured out a way to let computers do the heavy lifting by sorting through bits of DNA and directing other machines to create specialized tools called primers that are designed to capture specific genes found on stretches of DNA inside every cell in the body.
With genes in hand, researchers can manipulate them in various ways to see how and where they work in the body.
Structural biologist Cheryl Arrowsmith, PhD, tells WebMD that there are many different ways to look at what a protein does, either from a functional viewpoint (how does it affect the body), a genetic standpoint (how do changes in a gene affect the protein), or from a biochemical perspective.
"At the chemical level, we ask what does a protein molecule do chemically in a cell, and that is determined by its three-dimensional structure," says Arrowsmith, a senior scientist at the Ontario Cancer Institute and associate professor of medical biophysics at the University of Toronto.
The three-dimensional structure she refers to can be quite complex. For instance, depending upon the protein, it may look (at least in a computer model) like a ball of multicolored ribbon all jumbled together and folding back upon itself. But although it may appear haphazard to the untrained eye, how a protein folds is crucial to how it works, researchers say.
The weird shapes, variety and complexity of proteins is enough to keep many a PhD working busily for decades to come, but don't count out the geneticists.
"The human genome is passé," says Eric Lander, PhD. But as a director of the Whitehead Institute for Genome Research and one of the key figures in the Human Genome Project, you can bet he says it tongue in cheek.
There's plenty of work ahead for the scientists, including completing the final, definitive draft of the genome itself; comparing the genomes of many different species to determine which genes seem critical to the evolution of the species, and classifying diseases based on patterns of gene expression rather than on symptoms. Lander and colleagues have already applied these methods to various forms of cancer, diabetes, high blood pressure, and dwarfism.
In other words, there's life in the old genome yet.