The Biotech Century

There's a revolution brewing in the lab, and the payoff will be breathtaking

The grand, tumultuous pageant of human history is, in a large part, propelled by technology. Metalworking and improved agriculture carried civilization out of the Stone Age. In the 19th century, the Industrial Revolution gave rise to mighty machines and sprawling cities. In the 20th century, physics became king. Physicists split the atom, explored the bizarre worlds of relativity and quantum theory, and harnessed the power of tiny chips of silicon. Along the way, they transformed the world with the atom bomb, the transistor, the laser, and the microchip. But now, many experts believe, humankind is poised to ride a new wave of scientific knowledge in the headlong rush to the future. "This was the century of physics and chemistry," proclaims 1996 Nobel prize-winning chemist Robert F. Curl of Rice University. "But it is clear that the next century will be the century of biology."

On Feb. 22, that century was suddenly upon us--arriving years sooner than anyone expected, not like a lion but in the guise of a lamb. A previously obscure 52-year-old Scottish embryologist, Ian Wilmut, stunned the world by announcing that he and his team at the Roslin Institute outside Edinburgh had created an exact copy--a clone--of an adult Dorset sheep. The historic lamb, created from DNA extracted from the sheep's mammary gland, was named Dolly. "We couldn't think of anyone with a more impressive set of mammary glands than Dolly Parton," says Wilmut.

Wilmut's trick was to replace the genes in a normal sheep oocyte, or egg, with DNA from an adult sheep mammary gland. He prodded the egg to grow and inserted it into the womb of another sheep. Last July, Dolly was born--an exact genetic copy of the adult whose mammary gland was tapped for DNA.

Wilmut and other scientists say that in principle, the same technique should work for any other mammal--including humans. Dr. Jon W. Gordon, an obstetrics researcher at the Mount Sinai Medical Center in New York, notes that cloning a human might not be so simple. Some genetic experiments that work in mice don't work in rats, and vice versa--suggesting that all mammals are not quite the same. And the first step, he said, will be for others to repeat Wilmut's dazzling experiment--to be certain that the results are correct.

If Wilmut's work is confirmed, it suddenly becomes possible to imagine some mind-bending consequences. Improvements in sheep and cattle ranching would be only the beginning. If the cloning of humans ever became practical, grieving parents might conceivably choose to clone a dying child. Some individuals might make a desperate grab for immortality by trying to clone themselves. Already, scientists are joking that the richest and most egotistical among them are hopping the next plane to Scotland. "It's an incredible development," says Arthur L. Caplan, director of the Center for Bioethics at the University of Pennsylvania. "Unfortunately, we don't have the legal and ethical basis to handle it yet." Two days after the cloning was announced, President Clinton asked for a national commission to review what the White House called the "troubling" implications of cloning.

And yet, the headline-grabbing lamb represents only a tiny slice of what's just around the corner in biology during the coming century. Science is on the brink of an unprecedented explosion in its ability to understand and manipulate life. Until recently, researchers were forced to painstakingly search for genes one by one. The effort to nab the cystic fibrosis gene took 10 years and cost more than $150 million, for example. To isolate one obesity gene required a decade of work.

Now, however, gene sleuths are approaching from the other direction. They are deciphering the entire genetic code--known as the genome--of a wide variety of organisms, from humans to microbes. As these genomes are being decoded, or "sequenced," researchers are separating the individual genes and beginning to discover what each of them does.

Already, the fully sequenced genomes of six microorganisms have been published, and the cost is now as low as $300 per gene. Some 50 more, including those of the devastating malaria parasite and other disease-causing organisms, will be finished by the end of the 1990s. And thanks to the ambitious Human Genome Project and similar efforts in plants and animals, scientists will hold in their hands the complete blueprints of everything from nematodes and mustard plants to mice and men by the first decade of the 21st century--all neatly catalogued in computer databases.

Eric Lander at the Whitehead Institute for Biomedical Research in Cambridge, Mass. likens these complete genomes to the periodic table of elements, the basis for 20th-century research in chemistry. Stanford University geneticist Richard M. Myers says having the genomes "is expanding people's imaginations, allowing them to think on a grand scale, asking and answering questions they would never have dreamed of before." Adds Monica Riley, senior scientist at the Marine Biological Laboratory in Woods Hole, Mass: "In the near future, we will know everything that goes into making up a living cell. It's an exhilarating time to be doing science."

No one doubts that the payoff will be immense. By 2003, farmers may be growing plants that make enough plastic to reduce our dependence on oil. The massive amount of information holds the promise of a slew of new drugs and treatments--and a far deeper understanding of human behavior, health, and disease. "It gives us tremendous hope we can finally win the battle against bacteria," says J. Craig Venter, president of the Institute for Genomic Research (TIGR), a pioneer in gene sequencing.

Moreover, the spillovers could reach outside biology. Motorola has a team of researchers exploring the potential of gene splicing and genome engineering for computing. The idea is to use the DNA molecule as the basis for computers vastly more powerful, for some calculations, than today's digital machines. University scientists have already built primitive DNA computers. Even further afield, the genome information will illuminate previously dim corners of history--by analyzing genetic variations among populations. "We can ask: `Where did we come from? How many migrations did our ancestors make out of Africa?"' explains Mary-Claire King, a gene hunter at the University of Washington.

Of course, none of this will be easy. The discovery of a gene or the elucidation of a complicated biological pathway may be only a small step toward a cure or useful medicine. The gene for sickle-cell anemia is one example. It was identified 20 years ago, but there still are no cures. Now, with thousands of new genes being discovered every year, pharmaceutical and biotech companies are awash in potential targets for drugs. "But drug discovery has turned out to be a bear," says Larry M. Gold, chief scientist of NeXstar Pharmaceuticals Inc.

What's more, the biological century will bring myriad moral and legal conundrums. Should doctors, for example, test for genetic conditions or predispositions they can do virtually nothing about? Will employers and insurance companies get access to the results of those tests? Should they be able to use that information to deny employment or insurance coverage? Already, British companies say they have been using genetic information to set rates and eligibility criteria for buyers of life insurance.

These hurdles and dilemmas, however, are far from the minds of many scientists toiling in university and company labs to understand the biology laid bare by the new genetic information. What they see instead is the chance to transform not just science but the world of the next century, just as the microchip changed this one. And the story really starts with one of the simplest forms of life--bacteria.

In July, 1995, Venter's team made history by completing the first full gene sequence of a living organism other than a virus. The bacterium was Hemophilus influenzae, which causes meningitis and children's ear infections. In the two years since, researchers have used the sequence to uncover what Venter calls a "remarkable biological mechanism that could totally change the basis of vaccine and drug development."

Geneticist Richard Moxon of Oxford University discovered that the bug is essentially preprogrammed for constant evolution. Like all cells, its genes contain the information to make proteins. But special sequences tucked in its genome cause the process to go awry periodically, creating new forms of key proteins. That enables H. influenzae to evolve on an hourly basis, evading the human immune system. Standard vaccines also target these proteins, which is why they don't work very well. The trick will be mining the genome to dig out more obscure proteins that the bug can't change so rapidly. Researchers at MedImmune Inc. in Gaithersburg, Md., are using this strategy to develop better vaccines.

PINCH OF YEAST. Drug companies are also interested in searching the genome for places to attack with new types of antibiotics. To help put a price tag on this sort of genetic information, Genome Therapeutics Corp. in Waltham, Mass., recently sold the sequence of Helicobacter pylori, the bug that causes ulcers and possibly stomach cancer, to Swedish pharmaceutical giant Astra for a cool $22 million.

Higher up the evolutionary ladder, sequencing the genomes of creatures like yeast, nematodes, and fruit flies is leading to advances. Once nature finds a biological pathway that works, she tends to use it over and over. As a result, "the majority of human disease genes that have been found have counterparts in yeast" and other simple organisms, explains S. Michal Jazwinski, professor of biochemistry and molecular biology at Louisiana State University in New Orleans. Just as important, the animals can be experimented on to understand these shared genes and biological pathways, something that can't be done in people. Geneticist Michael Wigler of Cold Spring Harbor Laboratory in New York used yeast to figure out the biology of a gene, called ras, that when mutated causes human cancers.

Scientists at NemaPharm, in Cambridge, Mass., are using the nematode C. elegans in a similar fashion. One target: Alzheimer's disease. Researchers have found a human gene, dubbed presenilin, that is linked to the disease. The gene is also present in the worm. So NemaPharm scientists are now disabling the worm's gene to figure out what it was doing--and how it interacts with other genes. "We're looking for suppressors of the gene," explains Timothy J. Harris, research and development chief at Sequana Therapeutics Inc., which recently bought NemaPharm. And when the entire C. elegans genome is sequenced by early 1998, says Harris, the worm "will be helping us in all our internal R&D programs at Sequana." That includes searching for the human genes that code for conditions from asthma to obesity.

The new genomics also is having a more direct impact on the diagnosis and treatment of human disease. One tack, used by companies like Human Genome Sciences Inc. (HGS) in Rockville, Md., is to pluck out all the genes that are actually turned on in a cell. Many of them are unknown. By figuring out their function, researchers may stumble across potential new drugs and drug targets. HGS, for instance, is about to begin clinical trials with previously unknown proteins that help heal wounds or fight arthritis. And HGS partner SmithKline Beecham has used the method to find promising new drugs against osteoporosis and other diseases.

Meanwhile, other companies are using technology to create what are known as DNA arrays, or DNA chips. The basic idea is to put thousands of different pieces of DNA onto a silicon chip, each at a different spot. The chips are designed in such a way that they can find the genetic differences between, say, a cancer cell and its noncancerous precursor. Using this method, Darwin Molecular Corp. researchers in Bothell, Wash., have found some 500 genes that are altered when prostate cells turn cancerous. Those genes may hold the clues to better diagnostic tests or to biological processes that could be blocked to stop the cancer.

On a lower-tech level, the expansion of genetic knowledge also is aiding more traditional searches for human disease genes. In an approach called positional cloning, scientists first search for large families that suffer from an inherited disease. Then they look for bits of genetic material shared by the family members carrying the disease. When they find those "markers," they know the gene must be nearby.

Until recently, these searches have been hampered by a dearth of markers. But in the past few years, researchers have been mapping new markers by the thousands. "We used to say, `We can't find the disease genes because there are not enough markers,"' says Howard Jacob of the Medical College of Wisconsin. "We fixed that. We used to say, `It's too expensive.' And we fixed that."

That's why researchers are scouring the world, searching for families or isolated groups with rare inherited diseases. At the University of Washington, for instance, King is closing in on a gene that causes deafness in families from Costa Rica. Sequana scientists are using people from Tristan da Cunha to nab genes for asthma. A group of Germans who used to live in Russia have a unique gene for Alzheimer's. Such family lineages may soon help scientists find not just the genes for diseases caused by single defects, but for more complicated conditions like manic depression, high blood pressure, or heart disease. "We're making progress toward the real frontier of the more complex disorders," says Dr. Francis Collins, director of the Human Genome Project at the National Institutes of Health.

CANCER HELP? While all these disease-causing genes are rare, elucidating their mechanisms may have widespread usefulness. In the case of the breast cancer gene called BRCA-1, only a small portion of breast cancer victims actually inherit mutations. But the protein encoded by the gene may play a major role in noninherited forms of breast and ovarian cancer. Dr. Jeffrey Holt, professor of cell biology at Vanderbilt University in Nashville, Tenn., has shown that mice with ovarian cancer live much longer when given a normal version of the gene. Washington's King now wants to start a clinical trial in ovarian cancer patients to see whether the technique works in people. "This shows how we can use the gene to develop a therapy," she says.

In addition to new medicines, this information offers a new window into human history. "As people move around the world, their genes move with them," explains King. Geneticists have shown, for instance, that one breast-cancer mutation predates the destruction of the second temple of Israel. Another mutation moved from the Baltic to America to Israel in Jewish migrations.

Yet the explosion of genetic knowledge will reverberate far beyond new drugs or history. "The biological century will arrive on three fronts--medicine, environmental remediation, and agriculture," predicts TIGR's Venter.

Take pollution cleanups. New studies show that, during the course of evolution, nature has repeatedly added or excised clumps of genes from microorganisms, much like an engineer adding and deleting software routines while fine-tuning a computer. But if nature can do it, so can today's gene jockeys, creating a new field dubbed "genome engineering." One bug now being sequenced at TIGR can withstand astonishing amounts of radiation. By inserting the string of genes coding for the uranium-gobbling pathway, scientists might fashion a cell that can clean up highly radioactive waste.

Venter and other visionaries have dreams of a greener, more productive economy created with the help of organisms capable of doing everything from cleaning up waste to making methane--natural gas--from inorganic fuel, solving our pressing pollution problems. Genome engineering "isn't science fiction anymore," says Venter.

Indeed, the first steps are already being taken. Four years ago, Chris Somerville, head of plant biology at the Carnegie Institution of Washington, slipped a gene for making plastic into Arabidopsis, a type of mustard plant. The gene turned the plant into a biological plastics factory. Now, Monsanto Co. scientists are turning the concept into commercial reality. "We're expecting to see it planted in thousands of acres by 2003," says Somerville.

Just as exciting is a recent discovery by Calgene scientists of the gene for the enzyme controlling the formation of cellulose in plants. After 30 years of fruitless biochemical search for the enzyme, "this is our first break in understanding how to control biomass," Somerville explains. Genetically boosting the enzyme could make it possible to create trees with much higher proportions of cellulose--the plant kingdom's structural fiber--and less than the normal amounts of other cell wall components. Because these secondary components are what make the pulp- and papermaking process polluting and inefficient, scientists say, the engineered trees could help clean up a major industry. Beyond that, "there is a mad scramble in plant biology to find the most useful genetic sequences," says Somerville. "The world hasn't even seen the tip of the iceberg."

DOLLY'S DEBUT. Of course, the world did get a stunning glimpse of a bold new future in agriculture with Ian Wilmut's Dolly. According to biological dogma, the feat was unlikely at best. The reason: All cells possess a full complement of genes, and thus the basic instructions to create an entire organism. But during the delicate dance of development, when embryonic cells become skin, or heart, or brain, all the genes not needed for these new specialized functions are turned off. And most textbooks say they can't be turned back on again.

Wilmut and his team found a way. They extracted cells from the mammary glands of an adult sheep. Then they starved the cells. That apparently changed the complicated protein scaffolding around the cells' DNA, which plays a key role in determining which genes are active or inactive. In essence, he coerced the specialized cells into believing they had returned to a stage in which all things are possible. The genes that had been turned off were primed to turn on again.

From there, it was a simple matter of using standard high-tech methods. Wilmut took the nuclei, and thus all the genes, out of sheep oocytes. Then he placed each oocyte next to one of the treated mammary gland cells. One pulse of electricity caused the two cells to fuse, dumping the adult sheep's genes into the egg. Another pulse prodded the oocyte to embark on the journey to make Dolly, the clone.

The process still has plenty of bugs. It took no less than 277 tries to make Dolly. "They killed a lot of embryos and made a lot of malformed sheep," says Pennsylvania's Caplan.

DNA CHIPS. But the feat does help pave the way to barnyards filled with new types of livestock. Companies like Alexion Pharmaceuticals Inc. in New Haven and PPL Therapeutics PLC in Scotland already have altered pig genes to make hearts, kidneys, and other organs that could be transplanted into humans, and they have engineered cows that make drugs in their milk. The cloning process will enable these so-called transgenic animals to be duplicated much faster than by traditional breeding. "It's not an overnight revolution, but there is significant potential for research and improvement of domestic animals," says Christopher Bidwell, an animal geneticist at Purdue University.

Some scientists believe that the biological century will usher in a new era in electronics as well. The lure of genes as the basis of computation is that the twisting helixes are jam-packed with information--millions of times more than on the densest microchip. True, performing a mathematical calculation might take an hour using DNA, compared with a fraction of a second for silicon, said Dan Boneh of Princeton University at a recent meeting on DNA computing. Chips can do only one thing at a time, compared with a DNA computer, which can theoretically do 100 million billion things at once. But DNA still has a long way to go before it can hope to challenge silicon.

Already, the world is racing headlong into the biotech century. And not even the scientists leading the way know where it all might lead. TIGR's Venter wonders whether we even possess the intellect to understand how humanity's 80,000 genes can work together in intricate harmony to produce a being that is capable of contemplating its own origins and destiny. But it is clear that as we enter the new millennium, biotechnology is about to weave its own threads into the great tapestry of human history.


University of Pennsylvania bioethicist Arthur Caplan and BW's John Carey will answer questions about this Special Report on America Online in the Globe on Sunday, Mar. 2, at 9 p.m. EST.

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