Essay

CRACKING THE GENETIC CODE

It’s 50 years since two brash, ambitious scientists unveiled the double helix

ROBERT SHEPPARD March 24 2003
Essay

CRACKING THE GENETIC CODE

It’s 50 years since two brash, ambitious scientists unveiled the double helix

ROBERT SHEPPARD March 24 2003

CRACKING THE GENETIC CODE

Essay

ROBERT SHEPPARD

It’s 50 years since two brash, ambitious scientists unveiled the double helix

A FEW years back, not long after Dolly the cloned ewe was sprung on an unsuspecting world, an Australian researcher reported that DNA was so ubiquitous it was literally oozing out of our pores. We humans were leaving little biological Post-Its of ourselves on everything we touched. Little bits of genetic code—how to build a nose, how to fight disease—searching perhaps for a chemical soulmate.

For a writer, this was a notion almost as staggering as the invention of Dolly. (Even if you don’t read this article all the way through, Gentle Reader, touch the page and we will have danced the dance.) For one, it helped align the moral compass at a time when the genetic revolution seemed to be messing about madly in God’s tool box. Think of it this way: if DNA, the chemical blueprint that we store in almost every cell of the body, and that we share with mice and flatworms, is that pervasive, that relentlessly life-seeking, then maybe redirecting its course—by putting fish genes into plants or injecting adult brains with fetal cells—isn’t as Frankensteinish as it might appear. Though there has certainly been plenty of that to go around.

It’s 50 years since Cambridge-based upstarts James Watson and Francis Crick kickstarted the genetic revolution with their depiction of what deoxyribonucleic acid, or DNA, looked like (a double helix, like an entwined pair of circular staircases) and how it might replicate itself. A more accurate beginning would have been nine years earlier, in 1944, when cautious, Halifax-born Dr. Oswald Avery, and two associates at the Rockefeller Institute in New York, showed DNA was, in fact, the suitcase of heredity.

But in many ways the double helix proved to be the perfect up-and-down-staircase metaphor for an inventiveness that often held as much hype as promise. And Watson and Crick were perfect poster boys. Brash, competitive and on the make, both had migrated to genetics from other disciplines and had little time for the leadened ways of older practitioners. Watson, an American,

was only 24 at the time, a brainy, slighdy awkward birdwatcher who has since told the world way too much about his difficulties dating young women. Crick, at 36, was an unrepentant theoretician. He was the one who strode into a Cambridge pub on Feb. 28, 1953, and announced, “we have found the secret of life,” something his wife had heard several times before. (He would later theorize that biological life on earth had been seeded millions of years ago from outer space.)

Together they proved a fateful pairing of two brilliantly compatible minds obsessed with resolving the biggest intellectual challenge of their day, and unafraid to march over the less ambitious on their path to glory. Their big break came when a disgruntled colleague of King’s College rival Rosalind Franklin, a smart, tragic figure, surrepti-

tiously showed Watson one of her X-rays with the shadowy outline of the entwined helix. Franklin was proceeding more cautiously with her research. But for Watson, the imagery matched all that he and Crick had been talking about. So they dashed off a paper for the science journal Nature and, from those hothouse beginnings, it’s been pretty much a straight line to the sex-obsessed, jump-the-gun, let’s-clone-a-human Raelians, with stops en route at Dolly and Craig Venter, the science mogul who tried to patent the entire human genome.

It would be nearly 25 years before Watson and Crick’s double helix could actually be seen on a modern electron microscope. But this was a revolution that had no time to wait. In the early 1970s, scientists cloned the first small African tree frog and began the earliest experiments in genetic engineering. Among them was Vancouver’s Michael Smith, a transplanted Brit, who dis-

covered—after a series of propitious chemical explosions—how to produce what is known as recombinant DNA by altering the sequences of a gene in a lab. Rewriting, in effect, the chemical code of life.

His findings were so freakish that the leading journal of his day refused to publish them. He would later win a Nobel Prize (as did Watson and Crick in 1962) and earn a tidy fortune as his technique became the mainstay of the first bioengineering boom, in the 1980s. That was when scientists began talking about ridding the world of inherited disorders like Down’s syndrome, of tailoring drug treatments to an individual’s genetic makeup, of stopping cancer in its tracks, of finding the DNA switch to extend the human lifespan, of ending global hunger with disease-resistant foods, of growing new pharmaceuticals simply and cheaply in a field of wheat.

It was also a time when evolutionary bi-

ologists started hypothesizing genes for specific types of behaviour, everything from why certain men fool around so much to why some kill. By that point, anthropology was already being rewritten by the molecular biologists: the time since humankind broke from the apes was reset 10 million years closer to the present and the human tree was being much more precisely delineated. The law would be next.

The mysterious entity at the heart of the revolution, DNA, is a kind of chemical soup, an ultra-complex blueprint of nearly three billion possible connections for directing proteins, the building blocks of life, and telling individual cells what to do—to release insulin, say, when sugar levels are low, to send white blood cells to fight an infection, or to build an organ like the heart from scratch. DNA is a soup we share with all of life. But humans are also like snowflakes. No two of us are exactly alike (save for identi-

cal twins) and the tiny, less-than-one-per-cent difference in each person’s DNA makeup comprises a genetic fingerprint that transformed the legal system.

O. J. Simpson’s celebrity murder trial in 1995—and the much-debated bloody glovebrought DNA evidence to the tabloids. David Milgaard, Guy Paul Morin—the vanguard of Canada’s wrongfully convicted to benefit from DNA forensics—forever moved justice’s steely yardsticks. Today it is commonplace for national police forces to maintain a DNA database that can reactivate “cold files,” and Canadian judges routinely order the newly convicted to give over a DNA swab to see if there is a connection to an earlier crime.

DNA evidence, with the imprimatur of complex, confident science on it, revived the capital punishment debate in the United States and helped empty Illinois’s death row earlier this year. From there it was only

a short jump to prime-time TV, where DNAdominated police shows top the ratings. Everyone loves a mystery. Especially the kind we believe we can solve.

Disease, though, proved a harder nut. Some found it ironic that on Feb. 28, 50 years to the day since the Watson-Crick eureka, medical regulators in the U.S. met to pronounce an end to gene therapy, except when it might be a treatment of last resort. The reason: two young boys in France, injected with a genetically altered virus to give them an immune system where nature had not, had developed leukemia. It was not the first mishap. In 1999, Jesse Gelsinger, an 18-year-old from Tucson, Ariz., became the first known death by gene therapy. It was then revealed that hundreds of other “serious” reactions had not been reported to American authorities.

Canada’s role in all this has been modest but not insignificant. The good news, notes Alan Bernstein, president of the Canadian Institutes of Health Research and a genetics researcher of repute, is that we have the second largest biotech industry in the world. The bad news is that it’s made up mostly of small, undercapitalized companies in a country that ranks in the bottom third of industrialized nations in terms of per-capita research spending.

Still, federal funds are beginning to flow in handsome amounts (nearly $1.4 billion in the past three years just to the CIHR alone) and we’ve had our share of stars. Apart from Smith, the Nobel winner, and Bernstein, whose Toronto lab was among the first to introduce a genetically altered retrovirus into the stem cells of mice, one of the more far-reaching techniques, Canadians have taken the leading role in identifying key disease genes for cystic fibrosis, muscular dystrophy and early-onset Alzheimer’s.

We have set the gold standard—the Edmonton protocol—for modifying pancreatic cells to treat certain types of diabetes. We have also been in the vanguard of examining the environmental mysteries of genetic disorders. The ethical dilemmas, too— not surprising for a country that can ferret out how to inject altered DNA into a cell (Bernstein’s research among others) but has been reluctant to extend that to clinical use. “Yes, we haven’t moved as quickly into gene therapy as others,” allows Bernstein. “But maybe the rest of the world moved too fast.”

As revolutions go, DNA’s blustery march

For all her fame, Dolly the cloned ewe showed signs of old age by the time she died at six, half the normal lifespan of a sheep

has followed the historic pattern of advance and retreat. Dolly, the famous exact replica of an adult ewe, was beset by problems of old age before dying at six years, about half a normal sheep’s lifespan. Before and since her, animal clones have been born with horrendous abnormalities from which they did not survive. Genetically modified foods have been dogged by controversies over taste, their potential as a health hazard and their ability to spread into neighbouring crops, with a potential of creating a broad tolerance for herbicides or pesticides that could prove difficult to overcome. The great biotech promise can be summed up in part by the stock fortunes of Venter’s Maryland-based Celera Genomics: three years ago it traded at US$247, today it’s worth about US$8.20.

Still, thanks to gene therapy, at least a dozen young boys in France, Britain, Italy and the U.S. are living near-normal lives, released from the virusand bacteria-free “bubbles” where they’d been confined after being born without an effective immune system. So, too, is the first gene-therapy patient, 17-year-old Ashanti de Silva, 13 years after doctors in Boston injected genetically altered blood cells into her veins for the same problem. Cancer and genetic disorders like schizophrenia are no longer clinical black holes, void of understanding. And even if science can’t yet figure out the complex pathways to cure or switch off faulty genetic wiring—and remember, we are dealing with a minute, self-propagating strand with billions of complex chemical interactions twisted upon itself in a chromosome that can compress to a thousandth of a millimetre— the genetic revolution has fundamentally changed the way we think about disease. We have entered an era where many (and soon most) newborns have their genetic blueprint identified. That will give them advance notice of their predilection to one disease or another—adding, of course, as Watson and Crick did, to the burden of choice. That most human of dilemmas, it fairly oozes out of us. CT1