Stuck With Freedom
Last week, some of the world’s leading molecular biologists gathered to announce the first publication of the rough draft of the human genome, the catalogue of our genetic code. The media framed the event as a sporting contest. A biotechnology firm, Celera Genomics Corp., published one draft, a government-funded public consortium another. The Republicans versus the Democrats of biology. Whose rendering of the book of life was better? As with the presidential race, the finish was more or less a dead heat, with a lot of bickering afterward about the results.
The event fostered the impression that the pace of biological advancement has quickened dramatically. One headline even blared: “Gene Map May Be Secret of Eternal Life.”
But, like everything else related to molecular biology and the biotechnology industry, first impressions are deceptive. The quick and simple--find the gene, cure the disease--often founders in the messy soup that is biology.
In fact, leaders of the effort to decode the genome did not hold out hopes of Methuselean life spans. They pointed instead to a more humbling implication from their findings. The estimated number of genes, perhaps 30,000, was one-third to one-fifth the expected number. Albert Einstein only had 1% more genes than a mouse and 50% more than a roundworm. And we have a lot more in common genetically with cats, dogs, monkeys and bacteria than some people might think. J. Craig Venter, president of Celera, remarked that these discoveries put us in our place in the same way as Copernicus deflated our egocentrism about having reserved a spot at the epicenter of the universe.
Completion of the human genome does not mark the capturing of the “biological grail.” Rather, it is just a peeling away of another of the layers of the complex biological onion. Something else is needed to explain why one species concocts a general theory of relativity, while the pinnacle of achievement for another is running a maze or tunneling through dirt.
The glib answer to this conundrum: It’s the proteins, stupid. Individual genes code for multiple proteins and the more complex the organism, the more proteins are involved. A better understanding of the nature of disease will require that we deduce the structure of proteins that the genes encode and the way those proteins interact among themselves, an immensely more challenging task than the just-finished sequencing of the genome.
This lesson--that it’s not all in the genes--is a cautionary tale that runs as a theme throughout the 25-year history of the biotechnology industry. Time and again, the industry has marshaled insights from genetics to devise elegant but deceptively simple solutions for making new drugs, diagnostic devices and gene-altering therapies. Some of its products, such as recombinant insulin, have preserved health in countless patients.
But, unlike the lightning pace of the genome project, the industry has been frustrated in achieving its goals because scientists, business executives and regulators have barged ahead, assuming that if you could just find the gene and tinker with it, you could lick the disease. As with the genome announcement, the biotechnologists have confronted the sobering reality that while a gene may be a critical disease link, it is not the only one that must be accounted for in biological systems.
If the genome was thought of by some as the biological grail, gene therapy--in which bad genes replace good ones--was to become the realization of that vision in medical therapeutics. The organism would restore a function--blood clotting in hemophiliacs, for instance--and that person would go about life miraculously restored without the need for regular drug dosages. But scientists have encountered great difficulty in delivering genes where they are needed in the body and triggering their activation in cells. The gene-therapy field is still recovering from the death in September of 1999 of a patient from an apparent immune system reaction to the protein used to coat a virus that delivered the replacement gene into the patient’s liver.
Following that tragedy, it was revealed that nearly 700 incidents of “serious adverse events,” including other deaths, had occurred during gene-based treatments. Recent reports of success with gene therapies for hemophilia and other disorders provide some grounds for optimism. But Harvard biologist Richard Lewontin warns in his writings about gene-therapy trials: “Over and over, reports of first isolated successes of some form of DNA therapy appears in popular media, but the prudent reader should await the second report before beginning to invest either psychic or material capital in the proposed treatment.”
Using a pharmaceutical to shut down the activity of a gene seems a marvelously simple and elegant way to treat a disease. Deploy a highly specific stretch of DNA to bind and block the messenger RNA that carries instructions to make a protein involved in a disease. The drug designer for this antisense approach only needs to elicit the relevant gene sequence to devise a drug. But researchers ran into difficulties because the drugs were broken down by enzymes in the body and, in some cases, triggered unwanted immune responses. One relatively minor antisense drug has reached the marketplace and more are in the product pipeline. But Isis Pharmaceuticals, the leader in the field, had to lay off workers about a year ago after a drug failure in clinical trials, and the company is a long way from becoming the next Microsoft, as one business magazine predicted in the mid-1990s.
If many early expectations for straightforward genetic manipulation have been dashed, one outcome of knowing the number of genes will have a lasting effect on medical research. Fewer genes make it less likely that single genes can account for the range of diseases that appear in the “Merck Manual of Medical Information” on a physician’s desk. “The notion that one gene equals one disease, or that one gene produces one key protein, is flying out of the window,” noted Venter. That, in turn, should have a corollary benefit of dampening the frustrated efforts of behavioral geneticists to seek out and publicize genes that predispose people to alcoholism, pathological gambling and impulsivity--and, who knows, perhaps one day even a liking for chocolate ice cream. It has become axiomatic that every time a behavioral geneticist takes a small sample and finds a link between disease and behavior, other research groups cannot repeat the results.
In principle, fewer genes might mean it’s easier to find the ones tied to disease. But if it’s all in the proteins, life for molecular biologists gets tough quickly. The estimates for the number of proteins range from a few hundred thousand to a million (remember, these are the same folks who thought there were about 150,000 genes). And, in the 100 billion human cells, proteins get expressed in some cells but not in others, and at varying concentrations. Sequencing genes, moreover, is a hack: gene sequencers chop up the DNA in the chromosomes into pieces, read the letters and then reassemble the disparate blocks. The tool set for proteins is much more rudimentary: No one has figured out how a linear string of amino acids, the building blocks of proteins that DNA encodes, can fold up into an intricate three-dimensional molecule. “The genome project is in a sense a triumph of engineering,” notes Robert Elliot Pollack, a professor of biological sciences at Columbia University. “We’re now back to very primitive science. We have no algorithms for deducing protein structure nor for protein-to-protein interactions.”
But, even if we do one day sequence the proteome, the protein equivalent of the genome, there would be one more layer of the onion to strip away--one that would prove both impenetrable and that would quash any lingering notions of biological determinism. That layer is the corrugated surface of the organ that defines who we are. There are approximately 1 million connections among brain cells for each of the 3 billion units of DNA, and these linkages constantly change, as we do things like butter toast or struggle through tensor calculus. “When you have full knowledge through the proteome of how a brain assembles itself from a fertilized egg, you still have no idea of what this learning machine can learn,” Pollack says.
That means that neither the genome nor the proteome is a software program that predetermines what happens in our lives: We will always have the capacity for good or evil, altruism or apathy, chocolate or vanilla. “We’re stuck with freedom,” Pollack says. “We can’t push it off on the genome.”
