Blessings From The Book of Life

David Stipp
March 6, 2000
Fortune

In 1998 biotechnology's jauntiest visionary, J. Craig Venter, stunned fellow scientists by declaring that a company he was forming would decode human DNA's sequence of chemical building blocks by the end of 2001--at least two years before an international team led by the National Institutes of Health hoped to reach that goal. Now Venter, president of Celera Genomics, says his brash prediction was off. "We're going to sequence the entire genome in nine months," he said last fall. "If you'd told me that two years ago, I'd have said you were nuts."

Such is the pace in biotech: Even its bold optimists suffer nuttiness deficits when guessing what will happen next. Who would have thought, for instance, that electric fans would be needed to help decode the genome? As raw data avalanched out of Celera's DNA-sequencing machines last year, the supercomputers it uses to crunch the data heated up like John Henry's hammer--fans had to be wheeled in to cool the big iron.

The National Human Genome Research Institute is also speed-reading DNA and plans to assemble a 90%-complete "working draft" of the genome this spring. (DNA, of which genes are made, consists of chemical units strung together like letters in a sentence. The order of the letters, which is spelled out by sequencing, determines everything from eye color to disease risks.) By combining the federal institute's public data with its own, Celera hopes to parse all but a tiny fraction of our book of life this year--a spectacularly fitting first to open the biotech century.

Sequencing the genome is often called "biology's moon shot." That's wrong: Getting to the moon was a joy ride to a dead end--it had no lasting effect on our everyday lives. Decoding the genome will trigger developments that will change our daily lives as much as westward expansion changed the U.S.

Biotech pioneers will seek out the genetic bad actors behind our worst scourges, from arthritis to Alzheimer's, which in turn will lead to hundreds of new therapies. They'll find genes underlying idiosyncrasies like aptitude for math or low pain threshold. They'll pinpoint the scant 1% or so of our DNA that separates us from chimps. They'll trek into deep time to investigate how ancient networks of genes taught themselves to assemble the fabulous jack-in-the-box a newborn's brain and the monstrous one of a tumor cell.

Some of their forays may go awry, of course. Insecticidal genes placed in food plants may jump to other species, creating superweeds. Biotech may also yield the bitter pill of thwarted hope--if it turns out that a confusing multitude of genes, rather than a few clear-cut culprits, engender our major afflictions, the quest for cures may get mired in complexity. There's sure to be endless debate about the rising costs of biotech drugs. And genetic studies are likely to reveal patients' disease risks long before cures arrive, causing great frustration. "We'll be going through hell" because of the latter problem, Francis Collins, the genome institute's chief, warned fellow researchers in a recent speech. "But as Winston Churchill said, 'When you're going through hell, keep going.'"

Here, then, are some guesses about where we'll all be going during the next few decades.

BY 2010...

We'll start winning the war on cancer.

Say you experience back pain, night sweats, and loss of appetite, and then find an egglike swelling under your arm. Today a doctor would analyze biopsied cells from your lump with an instrument using 400-year-old technology, the microscope, and make an educated guess: You have non-Hodgkins lymphoma. You'd get one-size-fits-all chemotherapy that might work. If it doesn't, your doc would tell you not to despair--other drugs might save you.

In 2010 your doctor will scan your biopsied cells with a DNA array, a computer-chip-like device that registers the activity patterns of thousands of genes in cells. It will quickly establish that your lymphoma is actually one of six genetically distinguishable types of T-cell cancer, each of which is known to respond best to somewhat different drugs. Another gene-testing device called a SNP ("snip") chip will flag medicines that won't work in your case because your particular liver enzymes tend to break them down too fast.

Since your first round of therapy will hit your tumor cells square on, your odds of achieving lasting remission will be very good. You'll have years and years to stop and smell the roses--your favorites will be the bioengineered blue ones.

The most exciting thing about this scenario is that it's already in the works. With DNA arrays made by Affymetrix of Santa Clara, Calif., researchers at the Whitehead Institute in Cambridge, Mass., recently showed that they could distinguish different forms of leukemia according to abnormal patterns of gene activity in cancerous blood cells. This tumor "genotyping" helped cast suspicion on one patient's diagnosis--a separate genetic analysis proved it was wrong, prompting a change in treatment.

In a recent study with SNP chips made by Orchid Biocomputer of Princeton, N.J., researchers at the University of Cincinnati found that by examining a single DNA letter in a gene that helps regulate blood pressure, they could predict whether a patient with congestive heart failure was likely to decline rapidly on standard drugs for the condition, and hence might need more aggressive treatment. (SNP chips read off selected DNA letters that tend to vary from person to person. These "single-nucleotide polymorphisms," or SNPs, are thought to underlie many of our idiosyncratic traits.) Orchid plans to introduce such SNP tests via the Internet this year. A patient will scrape a few cells onto a cheek swab, mail it to the company, and then later tap a password-protected computer file to see an analysis of the results.

As for that horticultural grail, the blue rose: Australia's Florigene is working on it--the biotech company has already created violet carnations implanted with petunia genes.

Health sites on the Web will try to grab you by offering inexpensive genotyping services that predict your responses to scores of drugs. For a sizable fee, they'll perform more extensive genotyping to estimate your future risks of developing heart disease, various cancers, and other major killers.

Reproductive clinics will offer prospective parents the ability to screen embryos generated through in vitro fertilization for hundreds of inherited diseases. Such tests will be conducted on cells culled from the embryos before implantation in a mother's womb, enabling parents to select babies-to-be that are free of genetic glitches that cause diseases such as cystic fibrosis.

Debate will intensify about whether prospective parents should be allowed to reject embryos because they carry gene variants only loosely linked to later disease, such as ones that pose a 30% higher than normal risk of diabetes. Following media reports that a couple has discarded embryos carrying genes linked to attention deficit disorder, an outraged dot-com billionaire with ADD, nicknamed the "hyperpuppy" by his subordinates, will orchestrate a massive study showing that roughly half of FORTUNE 500 CEOs carry such genes and manifest the disorder's telltale behaviors.

Scores of capital-starved biotech companies will disappear in mergers, buyouts by drug companies, and liquidations. Some hot new replacements will emerge, including developers of a technology called proteome analysis.

Just as a genome, roughly speaking, is a creature's collection of genes, its proteome is its collection of proteins, the main constituents of cells. Genes serve as blueprints for proteins. But for all their power, gene-scanning biochips can't say much about how levels of various proteins change in cells as tissues form and diseases develop. (By analogy, detailing all the laws that define a government gives only a rough idea of how it works in practice.) Thus the need for proteome scanners. By measuring the levels of thousands of proteins in cells, they will vastly enhance researchers' ability to analyze our metabolic idiosyncrasies, what goes wrong when we get sick, how drugs work--and why they sometimes don't.

Look for Venter to announce an astoundingly ambitious proteome venture comparable in scope to Celera.

Genomics will dramatically alter drug industry dynamics. Consider the root cause of the industry's recurring merger fever: Only 25% of drug-development projects lead to compounds that work well enough to warrant clinical tests. Of those reaching the clinic, just 20% get on the market. Of those, less than 10% top $ 350 million in peak annual sales. No wonder the pharma companies continually swoon into each other's arms.

"Many drugs fail in clinical trials because they turn out to be toxic to just 1% or 2% of the population," says Mark Levin, CEO of Millennium Pharmaceuticals, a Cambridge, Mass., genomics company. With genotyping, drug companies will be able to identify gene variants underlying severe side effects. That will let their occasionally toxic flops fly--the drugs will be safe to use with gene tests that tell doctors who shouldn't get them. Levin predicts such "pharmacogenomic" advances will more than double the FDA-approval rate of drugs that reach the clinic. That will help alleviate the industry's merger fever.

Researchers will decode hundreds of germs' genomes, enabling them to ferret out the bugs' Achilles' heels. That will lead to potent new antibiotics with novel modes of action, such as MedImmune's Synagis, whose bioengineered immune molecules ward off pneumonia in newborns. Gene-inspired drugs to blunt diseases of aging will begin arriving to help deal with the T. rex of demographic trends: the baby-boomers' long goodbye. Cancer will loom as the killer issue for boomers, as heart disease did for their parents' generation. But just as drugs to control risk factors, plus cardiac surgery, have largely turned heart disease into a "manageable" chronic condition, biotech will push death from the big C ever further into old age.

Here's how that precisely genotyped T-cell cancer you got a few pages back might be treated circa 2010: More than 99% of your tumor cells will wither during the first round of therapy, consisting of a cocktail of "oncogene inhibitors" tailored to quell run-amok growth promoters that the genotyping has revealed to be driving your cancer. The first round will also include "angiogenesis inhibitors," which will block formation of new blood vessels that tumors need to grow larger than a millimeter in diameter.

The second round, wiping out more than 99% of the first-round survivors, will consist of monoclonal antibodies, bloodhound-like molecules that sniff out and destroy cells sporting telltale proteins that your tumor cells are making in abnormally large amounts. Finally, you'll get a "cancer vaccine" that induces ongoing immune protection against any incredibly lucky tumor cells that escape the first two rounds.

Gene therapy will start delivering on its huge promise.

Attempts so far to treat diseases by inserting corrective genes in patients' cells have proved disappointing, and the recent death of a patient in a gene-therapy trial at the University of Pennsylvania has whipped up concerns about side effects. This rocky road isn't too surprising. Most gene therapy to date has been "like taking a Swiss watch, cramming in a new gear, and hoping it meshes," says William Haseltine, CEO of Human Genome Sciences of Rockville, Md. Despite the bad news, though, researchers are beginning to get it right.

One recent advance is a technique that co-opts cells' own DNA-repair mechanisms to fix gene glitches. Being developed at Kimeragen, a biotech company in Newtown, Pa., it has enabled researchers to permanently fix with a single drug dose a faulty gene in animals. Another promising approach involves injecting genes that trigger natural healing processes when taken up by cells. Using this strategy, Haseltine's company is co-sponsoring trials in which a gene called VEGF-2 is injected into cardiac patients' hearts through small chest incisions. When incorporated into cells, the gene makes a protein that triggers growth of new blood vessels, alleviating the pain of angina.

Several inherited diseases, such as hemophilia, will be curable by gene therapy. Arguing that a few injections of its new gene-fixing drugs can dispense with decades of costly chronic therapy, a biotech company that has spent a fortune developing them will price the medicines at $ 20,000 a dose, prompting congressional hearings on rapacity in the biotech sector.

Rising consumer resistance to bioengineered foods will peak and begin subsiding after 2005, when rice implanted with genes that make vitamin A precursors begins preventing vitamin deficiencies that annually blind up to 500,000 kids worldwide; fruits tweaked to deliver vaccines begin preventing infections that kill millions; and bioengineered grains with extra iron begin reaching the two billion people worldwide threatened with anemia.

Meanwhile, the rage for nutraceuticals--foods and dietary supplements laced with trace nutrients thought to stave off diseases of aging--will help sell biotech foods in the developed world. A raft of studies suggest that taking supplementary vitamin E, an antioxidant, cuts the risks of heart disease and certain cancers. Dozens of foods will contain more E if recent work by University of Nevada biochemist Dean DellaPenna and a colleague pans out--they've boosted the levels of vitamin E in plants' seed oil by 800% by inserting extra copies of a gene that naturally exists in the plants and makes the vitamin.

BY 2020...

Drug development will be vastly accelerated by techniques akin to testing new aircraft designs in wind tunnels, predicts Joshua Boger, CEO of Vertex Pharmaceuticals, a Cambridge, Mass., biotech company. Researchers will begin clinical trials by giving safe, tiny doses of, say, half-a-dozen possible variations of a new medicine to volunteers. The drugs' effects on thousands of genes and proteins will be monitored and analyzed by computer to predict how higher "therapeutic" doses will affect people of various genotypes. That will enable researchers to select the optimal molecules and immediately begin large, pivotal clinical trials, skipping initial phases of testing that now often take years.

The result: Gene-based drugs geared to patients' genotypes will be available for most major killers. Some big diseases will be on the way outÑrheumatoid arthritis and other autoimmune diseases such as lupus will be essentially curable by drugs that selectively switch off parts of the immune system that attack patients' own tissues. Potent new therapies will be available to treat once mysterious diseases, such as schizophrenia and narcolepsy, at the level of root causes.

Dozens of gene-inspired "lifestyle" drugs will be available, from rejuvenators of fading hair-pigment genes to his and hers libido boosters. In a naked appeal to wilted flower children, an ad campaign for one such booster will feature Mick Jagger, at 73, belting out, "You can't always want what you get," to the melody of an ancient song, followed by a well-preserved groupie intoning, "Oh, yes, you can."

If your finances aren't devastated in the crash of 2011, you'll be able to afford treatments that let you look as if you've hardly aged during the past decade. If you're male, gene therapy shampoos will reverse your pattern baldness. If you tend toward obesity, drugs tailored to your genotype will let you benignly alter your energy metabolism and fearlessly chow down. Biofacials will rev up dermal genes that make antioxidants and DNA-repairing enzymes, slowing time's toll on your face.

Comprehensive drug-based personality tune-ups will be in vogue among the wealthy, just as psychoanalysis once was. If you feel bad, you won't blindly try one antidepressant after another--you'll undergo molecular neural analysis to guide the prescription of a cocktail of highly selective neurotransmitter modulators. You'll select the new inner you from a psychic-dimension menu whose options will include items like "desired obsessive-compulsive activation" and "preferred excitability level."

Reproductive clinics will begin cautiously testing biotech's equivalent of atomic fission: germ-line gene therapy. Its promise has long been obvious: Thousands of inherited diseases, such as cystic fibrosis, might be eliminated by patching faulty genes in reproductive cells, causing the fixes to be passed to future generations. In principle, it's already technically doable. But making it safe and effective will be far trickier than most futurists realize, preventing its widespread use for many decades.

The main problem is that many of our genes have multiple roles in widely dispersed tissues. Permanently altering a gene to fix a disease process in one place is likely to have hard-to-foresee effects elsewhere. Those unforeseen effects will usually be bad--after all, evolution has over eons optimized genes as multipurpose cogs in different cellular machines. Worse, the fallout may not show up for years.

Web-based premarital counseling services will offer genome screening to help customers select mates. Before getting serious, couples will be able to check whether their children would be at high risk from combinations of disease-predisposing genes they carry. (We all carry such genes.) Dari Shalon, director of the Harvard Center for Genomics Research, predicts that bionerds will embrace a new fad in personals ads: reference to possession of gene variants linked to mental acuity, a tendency to take risks, and other presumably desirable traits. The fad will fade quickly, but not before wags have had a field day with lines like "Will you take this genome to have and to hold until cryopreservation do you part?"

Genomic genealogy services will proliferate, letting you get to know your family in fascinating detail, predicts Stephen Fodor, CEO of Affymetrix, the biochip company. You'll be able to order up genetic profiles of various family members that show how gene variants associated with things like perfect pitch, high excitability, and light spirits have passed from grandparents to certain of the grandkids.

Pet shops will be filled with novelties, such as bioluminescent cats of varying hues, whose glow will come from genes benignly transplanted from fireflies. Wolves will become popular pets--implanted with genes from domestic dogs, they'll be as docile as beagles. Cows outfitted with human genes will give a perfect facsimile of human milk for infant formula. All these animals will be routinely cloned to prevent sexual reproduction from diluting their carefully crafted genomes.

Experiments will be under way to make normal animals smarter, stronger, and longer-lived--a prelude to the bioenhancement of humans. But enhancing people will be harder than suggested by recent media reports on bioengineered mice with improved memories. "It's much trickier to develop drugs to get supranormal performance than to treat disease," says Tim Tully, a scientist at Cold Spring Harbor Laboratory on Long Island who is known for sharpening fruit flies' memories via gene tweaking. "If you're dealing with disease, you can accept some bad effects as part of the usual risk-benefit tradeoff. But not if you're trying to enhance normals."

Still, the lure of enhancement will become a major driving force in biotech. A drug company consortium will initiate an annual "superbeast" Olympics for enhanced mice, dogs, racehorses, and other animals. Graying business luminaries, hoping to benefit from the human spinoffs, will shell out millions to back research teams that enter the competition. A very smart, long-lived mouse named Zippy 2.3, implanted with bat genes, will become the contest's first four-time gold medalist in the maze event. His team will win a Nobel Prize.

Regenerative medicine will take off as researchers develop ways to create new tissues from biodegradable polymers and "stem cells," potent cellular generalists that give rise to the various specialized cells in our organs. There will be "living insurance" companies: places where people deposit such cells for later use in generating immune-compatible tissues to patch or replace failing organs.

In 2020 your pancreas will be severely damaged by a rare autoimmune disorder. Luckily, back in 2014 you socked away some of your blood stem cells, culled from blood taken during a checkup, paying out of pocket to have them cryopreserved in your local cell bank. Your HMO has agreed to pay a company named RegenerUs Inc. to tweak the cells so that their gene-activation profiles resemble those of pancreatic cells, and then multiply them inside a biopolymer matrix to implant in your damaged organ. You're going to be just fine.

BY 2040...

Individualized preventive medicine will be the gold standard. Gene therapy, as well as more traditional gene-based drugs, will be available for most diseases. It will be possible to hold most cancers in check for many years. Alzheimer's disease, which will be detectable before symptoms appear, will usually be preventable.

The average life span in the developed world will top 90. U.S. health costs will reach a third of GDP.

Key genes involved in aging will be identified, and clinical trials of anti-aging drugs will be under way. A consortium of life insurers will help fund the trials, counting on the medicines to boost their profits by delaying boomers' life-insurance payouts.

Clinical trials of drugs to boost IQ, memory, and other mental powers will be under way. Heated debate will begin about whether the NIH should fund research on germ-line gene therapy to enhance future generations' cognitive performance. Proponents will warn that the U.S. could lose its competitive edge to nations that apply such technology en masse before it does.

Cryopreserved embryos of endangered animals, many of which will have become extinct since their embryos were put on ice, will be thawed and cloned. The animals will be placed in special animal refuges for the remembrance of things past.

Your heart will finally start to give out. Not to worry: The stem cells you banked more than two decades ago can now be used to generate a reasonable facsimile of your ticker, thanks to the latest advances in regenerative medicine. In fact, most of your tissues and a number of major organs can be similarly regenerated over periods of weeks to months. Such replicas will cost hefty sums though, making regenerative medicine the focal point of heated debate about unequal access to biotech's bounty by the rich and poor.

Artificial life forms will be reproducing and evolving in the lab. They won't be mini-Frankenstein monsters. "They'll be autonomous, self-reproducing systems created to do useful things in specific environments," opines Stuart Kauffman, a theoretical biologist in Santa Fe. For instance, DNA-like nanomachines will be engineered to spread through patients' cells and churn out selected proteins in quantities geared to correct out-of-kilter metabolic states.

To prevent flare-ups of your cancer, you'll be injected with antitumor biobots that install genetic "applets" to switch on when incipient tumor processes are detected and kill precancerous cells.

A startup company named Transubstantiation Inc. will be developing ways to replace various kinds of biomolecules with sturdier synthetic ones. You'll be one of the first volunteers for its clinical trials. After all, by then you'll be 95 years old. A person that age has to think of the future.