The Protein Pro

PHIL ANDREWS IS PIONEERING 'THE HOTTEST FIELD OF THE 21st CENTURY'

By Ken Garber

For Phil Andrews, words don't do justice to the remarkable changes he's witnessing in biology. The imminent completion of the Human Genome Project—the mammoth international effort to transcribe the human genetic code—is "a revolution, frankly," he says. "Having the whole genome is a lot like the astronauts looking out the window at the Earth for the first time. It changed their perspective."

With the genetic code deciphered, Andrews says, the truly meaningful work begins. The Genome Project "will be thought of something like the invention of the Gutenberg press," he says. "It created all the literature that came after that. Now we're going to start publishing all that literature, for biology."

Completion of the Human Genome Project means, Andrews says, "we'll spend the next ten generations of scientists trying to understand the organism: What makes an organism alive? What does it mean for an organism to get sick? Even, why does an organism act the way it does?"

Sought by the News Media
Andrews, a professor of biological chemistry and senior research scientist in the Medical School, has been preparing for this moment since arriving at the U-M a decade ago. In his Medical Science Building I laboratory, he has quietly been creating new methods and technology for use in the "post-genome" era. Science and Business Week call to ask his views on new developments, and his lab is bursting at the seams, filled with busy postdoctoral students from as far away as Australia. A file cabinet sits in the hallway, marked, "This File Cabinet Stays—It's In Use!"

Andrews himself is soft-spoken and unassuming, and he displays an almost child-like sense of awe when he talks about new discoveries. He grew up in Florida, son of a small-town doctor. Fascinated by the natural world, he recalls spending "hours in swamps and lakes—I had a great snake collection." Laboratory science seemed a logical way to understand nature better, and Andrews eventually graduated from Georgia Tech in chemistry. After a faculty appointment at Purdue (where he'd received his PhD in biochemistry), Andrews came to Michigan in 1990.

During his time at Michigan, Andrews has studied how insulin is processed by the body, examined how proteins are activated, and designed a drug to reverse the effect of heparin, an anti-clotting drug given to patients undergoing surgery. But in recent years he's focused on a new field that seems poised to take the spotlight: proteomics.

The Rush Is On
"Proteomics is going to be the hottest field of the 21st century, as genomics was in the century that just ended," says Steve Martin, who directs the Proteomics Research Center for PE Biosystems, the parent company of Celera Genomics. Celera, the Maryland company led by maverick scientist Craig Venter, is racing the publicly funded Human Genome Project to be first to decipher the entire genetic code. Venter recently announced that Celera will spend nearly $1 billion on a massive proteomics effort. "In the next year, this is going to take off exponentially," Venter said in a talk here last December.

PROTEINS ARE   TO GENES AS   BUILDINGS   ARE TO   BLUEPRINTS

What is proteomics, and why are Celera and others investing so heavily in it? An Australian scientist, Marc Wilkins, coined the term in 1994, to refer to the large-scale study of an organism's proteins. Proteins, not genes, do the work of biology. Proteins are to genes as buildings are to blueprints. The goal of proteomics is to make sense of the genetic code through an understanding of proteins.

Biologists have always looked at proteins, but until recently they have studied them individually. Proteomics proposes to examine thousands of proteins at once. Given that the human body may produce as many as 20 million different proteins, cataloguing the whole thing—proteomics' ultimate goal—is an enormous challenge.

Bigger Than Genome Project

Glossary of Selected Terms (Adapted from the Andrews Lab Web Site) Electrophoresis: The separation of ions in an electric field. For macromolecules, this is usually done in a water-swellable matrix like polyacrylamide or agarose which perform sieving functions and reduce convection. Functional Genomics: The study of the functions of genes and their interrelationships. Genome sequence is structure only. While bioinformatics allows us to infer function, in some cases, it is necessary. Genome: All the DNA in a cell, both chromosomal and extra-chromosomal. A Genome sequence is the sequence of all the DNA in a cell, genes, pseudogenes, as well as DNA that does not code for genes. Genomics: The study of the genome. Any study which takes as its basis a complete genome sequence and which deals RNA or DNA. High Throughput: A common, compound adjective used to describe many genome and proteome studies. High-throughput technologies are necessary in these disciplines due to the sheer number of genes to be studied. Mass Spectrometry: Any technique which measures the mass of an ion in a vacuum. This is, in essence, a very accurate and sensitive method to weigh a molecule. Proteome: All the proteins produced from all the genes of a genome. Proteomics: The study of the proteome. Any global analysis of changes in the quantities and post-translational modifications of all the proteins in cells taking genome sequence as the starting point. The changes may be brought about by growth differentiation, senescence, changes in the environment, genetic manipulation, or other events. Virtual 2-D Gel: A constructed 2- or 3-dimensional image of a mass scan of proteins separated on a one-dimensional gel (usually isoelectric focusing).

"We all assume that the amount of resources that will go into proteomics will dwarf the Human Genome Project," says Andrews. "But the payoff will be direct." Comparing the type and quantity of proteins in a normal cell to those of a diseased cell should yield drug targets for treating that disease. And measuring a drug's effects on proteins will help predict dangerous side effects.

Cataloguing the body's protein activity should yield new knowledge to illuminate the vast areas of biological ignorance. For example, biologists don't have the faintest idea what most of our 100,000 or so genes actually do. Proteomics, along with structural biology (the science of protein structures) and bioinformatics (see related story), will gradually fill in this huge knowledge gap.

Andrews's lab is developing cutting-edge proteomics technology. Among other things, he's working on ways to feed proteins—after separating them in a gel using electric current—into mass spectrometers for rapid identification. (Mass spectrometers identify proteins by giving them an electric charge, then propelling them through a magnet and analyzing their flight path.) Mass spectrometry is a major bottleneck in proteomics.

Andrews's lab is also developing bioinformatics software to catalogue the hundreds of thousands of pieces of data that will be generated. The immediate goal is a complete proteomics system capable of tracking all the proteins in a simple organism. But the real Holy Grail is biological understanding.

"The goal of bioinformatics is not to track all that information, but to find the hidden meaning in the genome," Andrews says. "Define the function of all the genes—that's what we're trying to do."

This is a far more ambitious undertaking than the Human Genome Project, and will take much longer. Ultimately, Andrews sees the new technologies he and others are developing as leading to a new holistic approach to biology. That means reversing the reductionist trend of the last century, which saw greater and greater emphasis on studying isolated parts of organisms in ever-more-specialized subdisciplines.

"We're going to be seeing a true integration of the life sciences, driven by the Human Genome Project," Andrews says. "We'll see a greater emphasis on studying the entire organism. Which [in a way is going] back where we were a hundred years ago, before we had the tools to study organisms on the molecular level."

The Genome Project's end, Andrews stresses, is really just a starting point for the new biology. "It gives us a whole range of new tools," he says, "but it's just a beginning to understanding."

Ken Garber is an Ann Arbor-based science writer.