SCIENCE: HOLDING BACK THE YEARS (MAYBE)
Gene therapy could one day provide a treatment for cancer, or even halt the human ageing process, claim those who are developing this fledgeling science. But in America John Hands discovers commercial interests and intellectual rivalries are causing dissent
Sunday 20 October 1996
Instead of treating the symptoms of disease, the gene therapist seeks to correct the gene or genes which cause the disease.
Our genes make us what we are. They determine our height, the colour of our hair, eyes and skin, and all of our physical characteristics. Each of us has about 100,000 genes, which are sections of DNA that act like a biological computer instructing each of our 100 trillion cells to make the proteins or enzymes which are essential for creating or maintaining our bodies. A malfunctioning gene instructs cells to make the wrong amount of protein or else a mutant form of it, and this can cause an illness. The particular illness depends on which gene or genes are defective.
But Fossel thinks of going beyond current experimental gene therapy techniques, which treat particular diseases. He believes that manipulation of one key gene can kill all types of cancer cell and prevent all ageing-related diseases. That gene, which produces an enzyme called telomerase, is one of the hottest topics in molecular biology today.
In August 450 scientists from all over the world flocked to Cold Spring Harbor Laboratory (CSHL), on the wooded north shore of New York's Long Island to participate in a meeting on cancer suppression. The highlight was the Saturday afternoon session devoted to the latest research on telomerase.
The CSHL is one of the principal intellectual machines driving the fledgeling science of gene therapy. It was here in 1972 that James Watson had the insight which led to the current fascination with telomerase.
Watson is best known for his co-discovery of the structure of DNA for which he shared the 1962 Nobel Prize in Physiology or Medicine. DNA, he and Francis Crick found, usually takes the form of a double helix, a structure which resembles a twisted rope ladder with the genetic coding elements forming the rungs. A strand of DNA is the main constituent of each of the 23 pairs of chromosomes found in every cell of our body, and the Watson- Crick discovery explain-ed how the genetic code is passed on when a cell divides and reproduce.
In 1968 Watson became director of CSHL, a renowned but financially endangered non-profit-making biological research institute. He attracted funding and steered the laboratory in a new direction by tackling cancer from a DNA standpoint. Four years later he was trying to understand how the DNA of a chromosome copies itself when a human cell divides. It occurred to him that a section at the end of each chromosome must be lost at each division.
The end of a chromosome consists of a repeated DNA sequence called a telomere, which acts like the plastic tip at the end of a shoelace. It protects the main length of the chromosome, containing the genes, from fraying and damaging those genes. When genes get damaged the cell they are in dies. So, if part of the telomere is lost each time a cell divides, this progressive erosion would eventually eliminate the telomere and start eroding genes, producing cell death. But germline cells - those reproductive cells which carry a set of genes from parents to offspring, and so on down the generations, are immortal. Hence, Watson speculated, a mechanism must exist to compensate for telomere loss.
Watson submitted a paper to the magazine Nature, but it kept getting rejected by sceptical peer reviewers who demanded to see evidence. Watson, now 68, grins impishly. "I really had to press John Maddox [the editor] to get it published."
It was 12 years before Watson was vindicated. Graduate student Carol Greider, working with her professor, Elizabeth Blackburn, at the University of California at Berkeley, proved that an enzyme she named "telomerase" rebuilt the telomeres at the end of the chromosomes of tetrahymena, a single-celled pond-living micro-organism. When Greider finished her PhD degree, CSHL offered her a post-doctoral fellowship to pursue her research.
The next part of the telomere story was supplied by Cal Harley of McMaster University in Canada. Around the time that Greider was proving the existence of the telomerase enzyme which rebuilt telomeres and immortalised cells, Harley was investigating how cells age. He knew that if you take a renewable tissue, like human fibroblast, and grow it in culture in the laboratory, the cells will divide and reproduce themselves only a finite number of times. Then they stop dividing, become senescent, and eventually die.
Harley's collaboration with Greider and Bruce Futcher, also of CSHL, showed a striking correlation between the age of cells and the length of their telomeres, reinforcing Watson's insight and leading to the conclusion that telomeres function as the clock for cell ageing. Telomeres shorten each time a cell divides until they reach a critically short length, at which point the cell ceases to divide, becomes senescent, and dies. But - shades of Watson's experience - sceptical peer reviewers rejected their paper, before pressure from Watson finally led to its publication in Nature in 1990.
Other researchers were already in the race to investigate telomerase. They discovered that, while the telomerase enzyme is found in immortal germline cells, it is not normally found in other kinds of cell, except for immortal cancer cells, which generally have short but non-reducing telomeres. This led some scientists to believe that telomerase confers immortality on a cell by rebuilding telomeres, thereby preventing the cell from ageing. If you stop the telomerase gene from producing this enzyme, so the theory goes, then cancer cells will age to death. And this should work for all types of cancer, making it potentially the most powerful gene therapy treatment of all.
More controversially, Fossel and others believe that if you can turn on this gene in non-cancerous human cells you will stop them from ageing, and consequently prevent ageing-related diseases in the body, like atherosclerosis, Alzheimer's, osteoarthritis, and osteoporosis.
Harley left McMaster University and became vice president responsible for research at the Geron Corporation, the only biotech company devoted exclusively to cancer and the diseases of ageing. Its research programme hinges on telomerase and its function of rebuilding telomeres. Greider and Watson accepted invitations to join its scientific advisory board.
In September 1995 Geron and Greider's laboratory announced jointly that it had identified a key component of human telomerase, a unit of RNA (cousin to DNA) which was the template for rebuilding the telomeres. Moreover, when they blocked the action of the telomerase enzyme in immortal cervical cancer cells in culture, the cells stopped their lethal replication and aged to death within a matter of weeks.
The sceptics muttered that it was one thing to play around with cells cultured in a laboratory, but it was quite another to kill real tumours in living animals, not to mention human beings. So Greider set about breeding mice that lacked the gene coding for the RNA component of mouse telomerase. If telomerase was essential for the immortality of germline cells and cancer cells, then mice lacking it should escape cancer but would cease breeding after several generations because their germline cells, like their cancer cells, would age to death. It was her preliminary results with these so-called "knockout mice" that attracted rapt attention at last August's meeting.
Greider and Harley aren't the only fish in a very competitive sea. "I know about 30 to 40 labs that are now working pretty much on telomeres," Greider says, "and there are probably others that I don't know of."
It was evidence accumulated from all these laboratories that led Fossel, an analyst of ageing research, to draw his conclusion that when telomeres are lost from non-cancerous dividing cells, some of these cells would reach senescence and trigger ageing in the body. The scientific world, however, is not only competitive, it is also rife with egos, reputations, and vested interests. Greider, a self-confident 35-year-old, is dismissive of Fossel. "He never once talked to me about my work. Fossel extrapolates from cell experiments to human ageing in a way that is at best misleading and at worst simply wrong."
Her attitude mirrors a division that has existed since research into gene therapy began around 20 years ago. Clinicians, like Fossel, want to cure their patients of horrible, sometimes fatal, diseases. Academics, like Greider, want to understand how nature works and to publish their findings in prestigious peer-reviewed journals. They frequently accuse clinicians of two of the cardinal sins of research: going beyond the data and selecting data to support their case.
"Cell division in laboratory culture correlates with telomere length," Greider explains, "but there is no correlation with ageing in the body. Absolutely no evidence."
But wait. Hasn't a connection between cell ageing and human ageing been claimed by her collaborators at Geron, of which she is an adviser?
Two-and-a-half thousand miles away at the Geron Corporation in California's Silicon Valley, Cal Harley, a mild man, chooses his words carefully. "Substantial evidence published recently shows that senescent cells exist and accumulate with age in the human body," he says. "When I last talked with Carol, she held the view that correlation between cell senescence and human ageing does not mean that cell senescence causes ageing."
Does Harley believe that cell senescence causes human ageing? "We know that senescent cells in the body show an altered gene expression compared with dividing cells. Sen-escent genes increase the production of damaging proteins and reduce the production of beneficial ones. If this triggers the ageing process we don't know. lt certainly contributes to ageing-related diseases."
Downtown Los Angeles houses the University of Southern California, where Caleb Finch is Professor of the Neurobiology of Ageing. His reputation rests in large measure on an encyclopaedic tome published in 1990. Longevity, Senescence, and the Genome documents all the known ageing factors, such as DNA damage caused by UV light, damage to DNA, proteins and cells caused by oxygen free radicals and spontaneous gene mutations.
Finch fixes you with his blue eyes. "There's not a shred of evidence to link ageing with replicative senescence, apart from, maybe, some connective tissues," he says. "The two most important cells in the body are brain cells and heart muscle cells. They don't divide, therefore, I don't buy this theory."
If the absence of telomerase ...
"That mythical enzyme?" he asks scornfully.
Surely the RNA component has been cloned?
"The whole enzyme hasn't yet been cloned. Geron has got a company to sell."
This attitude typifies a new division in the gene-therapy field that looks set to outstrip the division between basic scientists and clinicians. Many university researchers are deeply suspicious of the vested interests of former colleagues who have forsaken the underfunded groves of academia for the commercial realities of corporate life.
Clinician Michael Fossel is undeterred by these attacks on his theories, "Caleb Finch is simply wrong. A growing body of evidence suggests that cell ageing lies at the root of ageing in the body. Non-dividing cells suffer ageing damage because the cells on which they depend - glial cells for neurons and vessel cells for heart muscle - undergo replicative senescence. In the long term I'm confident that manipulation of telomerase will enable us to prevent cancer and all ageing-related diseases."
Unjustified speculation or pioneering insight which a conservative scientific community is reluctant to accept? Do Greider's mice give us the answer? Her research is not complete, but early results make James Watson nervous. "These mice are in the fifth generation and seem perfectly normal. It may be that their telomeres are so long that it will take several more generations of no telomerase production to reach cell senescence. If they go beyond this, it means that either another gene is involved in maintaining telomere length or else mice have another method of bypassing replicative cell senescence. I'm also very nervous that telomerase has been discovered in human stem cells [precursor cells of our blood and other cells]. Inhibiting telomerase to prevent cancer may produce toxic side effects."
What about using telomerase to prevent ageing diseases?
Watson the scientist replies. "It's a very interesting science right now. We've such a long way to go."
So the jury is out on telomerase, but what about the long-term future for gene therapy? Watson the visionary replies. "It's a question of whether evolution will play a role in future human development. We're trying to control our own fates."
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