21st Century Gold Rush

Now that mapping is complete, the human genome project shows incredible promise, including curing cancer, warding off old age, and, for some, making billions of dollars.

By Joannie Fischer

illustration by Rob CadyIn the months since the human genome project announced its successful mapping of human DNA in July, a new catch phrase has been echoing through the halls of academia and industry alike: "So many genes, so little time." The stampede is on, as whole new companies and even whole new fields are arising day by day to mine the treasures found deep in the core of each one of our cells. The potential for profit, in terms of both cash and the welfare of humanity, is almost limitless. At stake are new diagnostics, treatments, cures or preventions for every known disease, a greatly extended life span, the ability to enhance human traits such as looks and intelligence, and even the ability to design a "perfect genome" for future generations. "Understanding the genome will undoubtedly have been the most important achievement of the 21st century, and perhaps of all time," says Eric Lander, director of the human genome center at MIT's Whitehead Institute, one of the key labs involved in mapping the 3.1 billion chemical "letters" that spell out a person's genetic code.

To turn the promise into reality, though, players from dozens of areas of science and technology must pool their brainpower to make the so-called "genetic revolution" a success. Already, unprecedented alliances have formed between private and public entities, academics and industry, and even firms that are otherwise serious competitors. That's because the know-how needed to comprehend how the billions of components inside our DNA all interact is so complex that the best and the brightest in fields ranging from combinatorial mathematics to molecular biology to computer chip design must work side by side to have any shot at unraveling the mystery. As the genetic sleuths explain their field of expertise to one another, stockbrokers and biotech trade groups are holding seminars in Sheratons across the nation to explain to would-be investors what all the new terms mean. For example, there's "genomics," referring to any attempt to identify and understand genes, and "functional genomics," the study of what role a given gene plays in the body and how genes interact. Then there is "proteomics," the study of the millions of proteins that are created by the genes, and what importance each protein has in the body. "Pharmacogenomics" refers to the attempt to parlay discoveries about genes into specialized new drugs. And "bioinformatics," the hot new field of the next decade according to some Wall Street watchers, is the business of keeping track of the mind-boggling amount of data in computer formats that allow researchers to pull out what they need, and compare and contrast it to other pieces of information.

The jargon multiplies daily, but that doesn't stop investors from pouring big bucks into the business of the genome, making it one of the fastest-growing sectors in history. "Genomic stocks are like biotech stocks on steroids," says Alexander Hittle, a biotech analyst for AG Edwards & Sons. IBM executives estimate that the market for genomics hardware and software alone will nearly triple, to reach $9 billion, over the next year. Investors aren't the only ones intrigued by the industry; an increasing number of academics are leaving behind their dusty university labs and taking top posts at high-tech ventures.

One leading mind who made the jump is Stanford geneticist David Cox, who left his post to become the scientific director of a new venture called Perlegen Sciences, Inc. The company will attempt to put microscopic detectors that can read the entire human genome onto a set of glass chips that can be used to match a person's genetic patterns with those known to be involved in disease. Cox says his reason for leaving academia behind is that it was taking too long to see genetic research turn into real medical treatments. For the past three decades, Cox says, he has hoped that this kind of technological revolution would come along so that he could live to see his efforts bear fruit.

But leaders of the genetic revolution warn that, as fast as the research is moving, it will still take considerable time to truly solve many of DNA's vast mysteries. "In some ways, the effort is more difficult now," says J. Craig Ventor, CEO of Celera Genomics and developer of the "shotgun sequencing" technique that spurred the Human Genome Project to completion years ahead of schedule. "Now that we have the whole, we're not looking at one gene at a time, but at thousands of genes and millions of protein products in a hundred trillion different cells." In past years, adds Harold Varmus, former head of the National Institutes of Health, researchers hoped to understand diseases like diabetes or cancer by watching a particular gene. Now they need to readjust their whole mindset to think in terms of a massive system instead of just one of its parts. "Even the best scientists conceptually have trouble thinking in a combinatorial fashion," notes National Institute of Mental Health chief Steve Hyman. Yet, that's an area where systems engineers can enter the picture and be of immense value, says Lander. "In some ways, it's a very straightforward systems engineering problem," he says. "You have all the factors, and now you study what they do in concert."

Predicting Health

One area of genomics that is already yielding quick results, though, is the area of individualized medicine. It is made possible by the hunt for "snips"—a nickname for single nucleotide polymorphisms, which are the spots along the DNA chain where one person's lettering differs from another's. The human genome project mapped out a sort of composite "everyman's" DNA sequence, formed by the long chain linking four different types of chemicals known by their first letters: A for adenine, G for guanine, T for thymine, and C for cytosine. But each of us has up to 10 million spelling differences from that average along our DNA strand; these are the differences that give a person blue eyes, a tendency to gain weight easily, a high susceptibility to contracting malaria, a vulnerability to breast cancer, or a toxic reaction to certain medications, just to name a few. In some ways, the hunt for snips and how they affect an individual is an even more massive task than mapping out a generic strand of DNA. That's why 13 of the world's largest pharmaceutical companies banded together with government, academic, and nonprofit agencies to form the SNPs Consortium. Like the human genome project, the hunt for snips has been greatly aided by advances in high-speed computing, and this fall the consortium announced that it had identified more than a million snips, years ahead of schedule. The consortium will take out a patent on the findings, then surrender the patent so that they are freely available to all.

Other firms, like Ventor's Celera and Incyte, are creating their own proprietary databases of snips, which pharmaceutical companies can use to find targets along the genome for new drug development. Current medicines are designed against just 400 known genetic targets, but the new databases have offered drug developers thousands and thousands more virtually overnight. Some universities are using the information to try to avert disaster in the emergency room. For example, researchers at the University of Cincinnati, in collaboration with Genaissance Pharmaceuticals, are testing asthma patients as they come in for help. It turns out that certain snip groupings, called "haplotypes," will predict whether the patient will respond to the most commonly used asthma drug, Albuterol. And cardiologists at Cincinnati are using similar information to see whether the standard treatments for congestive heart failure will be enough to save a patient, or whether that individual's best hope is a heart transplant.

Dale Pfost, the head of Orchid Bioscience, says the industry's development efforts are moving so fast that there will be dozens of these types of new diagnostic and drug-related tests in the doctor's office in a few years, and literally hundreds by the end of the decade. In one sense, it will be a win-win situation for patients and insurance companies alike; one health maintenance organization CEO says his company spends more money each year on hospitalizations due to adverse drug reactions than on coverage of drugs themselves. But the new tests will also present whole new sets of problems, say all the experts, because of the public's notoriously poor understanding of the nature of genetic probabilities, and the likely misinterpretation and over-interpretation of test results.

Losing Privacy illustration by Rob Cady

Nonetheless, insurance companies, mortgage lenders, schools, the criminal justice system, and employers would all love to know an individual's genetic makeup. And some indications are that they will have it. England has just given insurance companies permission to access all genetic test results, something that health activists say will discourage people from getting early warning and help with diseases like Alzheimer's and prostate cancer. "If we sequenced everybody's genome, and really understood the links between risk and disease," objects Ventor, "we would all be uninsurable." In the U.S., some criminologists and social scientists favor doing genetic profiling of children to see who is prone to violence, so that they can be enrolled in preventive programs. But many object that this will only serve to mark the children as "born bad." "We're looking for answers in genes that aren't in the genes," says Lander. "The gene pool hasn't changed in the last 10,000 years. And yet, the crime rate in New York City fluctuates over the course of a decade. It ain't genes." And, of course, any genetic traits carried by members of a certain ethnicity will fuel talk of racism.

It's little wonder that no one wants to participate in the DNA tests that will help the science progress, says Arthur Holden, chairman of the SNPS Consortium. In October, Holden announced that he is partnering with IBM to launch First Genetic Trust, a gene bank that will guarantee the privacy of anyone who donates a DNA sample. If authorized, the bank will send the sample to a person's physician, or to a study that could benefit.

Potential abuses and privacy concerns are frustrating complications of otherwise hugely beneficial work, says Lander. "We're not trying to subdivide and pigeonhole people," says Lander. "We're trying to find the mechanisms underlying illness. We don't know what causes asthma, diabetes, hypertension, heart disease. Now we stand a real chance of knowing how to address all the major diseases." Researchers at the Sanger Center in Cambridge, England, reported in September that they had found 2,730 snips on chromosome 22, the body's second-smallest chromosome, one that carries genes that have been linked to some 35 disorders, including schizophrenia and heart disease. With so many factors to sort through, far more sophisticated technology is now needed, says Stephen Fodor, CEO of Affymetrix—creators of the gene chip, a central piece of technology for the new era. Just five years ago, says Fodor, his company surveyed scientists studying cancer to see how many genes they would want to be able to monitor at once. "Eighty-five percent of them said 'I can't imagine needing more than 25 or 50'," recalls Fodor. "Our hottest selling item today looks at 60,000 at once."

Affymetrix is the parent company of the Perlegen venture that aims to quickly analyze a person's DNA on a set of glass chips. The two companies will etch millions of microscopic pillars into 5"-by-5" pieces of glass. At the top of the pillars they will place genetic "probes," which are actually tiny fragments of DNA that scientists are already familiar with. Then, DNA will be taken from human cells, multiplied a billion times over in the lab, and then poured in a solution over the glass chips. If any portion of the person's DNA matches any portions already lodged on top of the pillars, the two will bind together. A fluorescent dye will reveal the presence or absence of these significant stretches of code for a given person.

Theirs is just one example of myriad technologies now in the works to study all kinds of organisms. The view of genomics is often myopic, and people often "commit the sin of humanizing the conversations," says Varmus. "In fact, genomics is about all genomes. Plant genomes. Microbial genomes. We have drugs against AIDS today in part because we did genomics on the AIDS virus." And, of course, genomics will be used to create better crops, better meat, more sophisticated robotics, new materials, and even whole new forms of life. Still, for all the new applications the "post-genomic era" will give rise to, it is above all in the medical arena that it will be most celebrated. Until now, say medical researchers, new treatments for the plagues of society were a matter of chance, luck, and trial and error. "People looking back 50 years from now will consider medicine a barbaric, random process," says Lander. "If the promise of genomics is fulfilled, it will transform the lives of everyone."

Joannie Fischer is a freelance writer living in Palo Alto, California.