A Real Blast: Defusing ‘Genetic Time Bomb’
In one laboratory hallway at Geron Corp., a Bay Area biotech firm, are photos of the scientists rafting down a river together and dancing at a Christmas party. A poster advertises a company ski trip.
Then, in another hallway, a different side of life there is revealed in pictures taken last summer during a round-the-clock race with competing labs to pinpoint a hotly pursued gene. A shot of the parking lot one Saturday shows cars aplenty. Desks sag under data printouts. A bearded man sleeps on a couch.
Pointing to the contrasting pictures, the chief scientific officer, Calvin Harley, summed up the staff’s philosophy: “Work hard, play hard--and try to do science that changes the world.”
Clearly, the hard work paid off with Geron’s dramatic announcement last week that it had used genetic engineering to extend the life span of normal human cells. Whether the new research, conducted with University of Texas researchers and published in Science, will change the world remains to be seen.
But the advance is so basic that scientists imagine numerous practical uses, including new tools to diagnose and treat cancer and many age-related diseases, from vision loss to hardening of the arteries.
The finding also bears on questions that longevity researchers are keenly debating. Is the generally accepted maximum human life span of 120 years irrevocably fixed in our genes? Is death primarily caused by bodily machinery falling apart from wear and tear? Or is it the result of a genetic program to shut us down after we have outlived our usefulness to the species?
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At its essence, though, the discovery marks another leap in science’s mastery of the intimate workings of the cell, the most fundamental unit of life. Ever since a biologist first gazed on cells in living tissue a century and a half ago, they have inspired speculation and controversy about the nature of life and death, immortality, even God. Recall the furor last year over the cloning of Dolly the sheep using one genetically manipulated udder cell.
The new research is “comparable to a Dolly result,” said Michael Rose, an evolutionary biologist and longevity expert at UC Irvine, in that it represents a “wonderful technical breakthrough in cell biology.”
In an interview at Geron, Harley said he and co-workers are not “tinkering” with the human life span but are narrowly focused on diagnosing and treating diseases. “I don’t spend much time thinking about the broadest possible philosophical implications,” he said.
The Geron and Texas scientists showed for the first time that the life span of some normal human cells is controlled by gradual shortening of a piece of chromosome called the telomere.
Sometimes compared to a shoelace tip, a telomere rests at the end of a chromosome and consists of a cluster of six chemical subunits repeated over and over. In the early 1970s, a Russian scientist suggested that a telomere might be a sort of biological clock, dictating like a player piano roll how many times the cell would be allowed to divide before dying off.
By the late 1980s, scientists had discovered an enzyme, called telomerase, that maintains telomere length. Cells that stopped dividing had little or no telomerase, whereas cells loaded with the enzyme appeared to hold on to their doubling capacity.
In 1990, Harley and another researcher proposed a new theory with Carol Greider--a Johns Hopkins University scientist who co-discovered the telomerase enzyme in a single-celled pond dweller. In an article, they said telomere shortening in the absence of the enzyme was the key mechanism determining the life span of certain types of normal cells.
The discovery and cloning of the gene for telomerase last summer--celebrated at Geron under a banner saying that the company won the “TelomeRACE”--set the stage for the finding announced last week.
The Geron and Texas researchers inserted part of that gene into two types of normal human cells that were destined to stop dividing and coaxed them to produce telomerase. That spurred the cells to keep dividing long after similar, untreated cells gave up the ghost.
To demonstrate the feat, Harley and Andrea Bodnar, a co-author of the study, displayed a few flat-sided flasks of living human cells. Called fibroblasts, the cells form part of the skin’s complex, many-layered tissue. Originally, these samples came from the foreskins of newborn boys removed during routine circumcisions.
A long-puzzling quality of fibroblasts and certain other human and animal cells growing in test tubes is their starkly limited life span. After doubling a number of times, depending on the cell type, they stop dividing and slip into a low-key metabolic phase called senescence, a prelude to dying.
The number of doublings in a given cell type is so consistent that it is known as the “Hayflick limit,” after Leonard Hayflick, the UC San Francisco cell biologist who discovered the phenomenon nearly 40 years ago. To be sure, the limit pertains only to the so-called somatic cells. In contrast, sex cells, like those in the testes, and other continuously replaced body cells, like those in the lining of the gut, divide indefinitely. So do cancer cells.
Bodnar put a flask of untreated fibroblasts under a microscope lens. She said the thin pinkish layer of cells clinging to the flask’s side represented the offspring of 80 doublings, a typical limit for this cell type. They slipped into senescence in mid-December. The long cell bodies were oddly shaped, some oval and some vaguely hexagonal, and big spaces appeared between them, giving the impression of a scattered, random collection.
Next she placed a flask of genetically altered cells under the lens. These were the same chronological age as the others, but were still actively dividing after 108 doublings. The cells were sardine shaped, densely packed, crowding into the dish. They resembled young cells, Bodnar said. Evidence of their vigor, she added, was the color of the fluid washing over them: yellowish, tinted by the waste products of their still-cranking metabolism.
As far as Harley and Bodnar could tell, these altered cells could keep dividing indefinitely. Harley declined to say if he thinks they are immortal, because the term is loaded and only time will tell. But Hayflick is convinced that the scientists “essentially immortalized” the cells.
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It is a matter of fierce scientific debate as to what extent the fate of fibroblasts growing in a dish parallels that of intact body cells. Harley and others say it does. The thinning and sagging of skin that accompany old age, and the decreased ability to repair cuts and other damage, result from the buildup of older fibroblasts nearing or in senescence, he said.
Also, researchers have long suspected that the elderly’s increased susceptibility to infectious disease results from the immune system’s reduced capacity to launch microbe-fighting cells, he said.
Other researchers say that although giving cells a new lease on life is an amazing feat, it has little to do with manipulating the longevity of a whole human. “This is a very interesting piece of biology, which will give some insight into why some cells divide forever and others stop,” said Caleb Finch, a USC neurobiologist specializing in aging. “It has to do with a phenomenon in cell culture that may or may not be the same in the organism.”
Eugenia Wang, an expert on the cell biology of aging who works at the Lady Davis Institute for Medical Research in Montreal, said the new work was “outstanding.” But she questioned its therapeutic potential, given that the two most important organs--the brain and heart--comprise cells that stop dividing in youth. (The heart grows because its cells get bigger, not more numerous.) Although there is usually some deterioration of brain and heart function with old age, it is not because of senescence, she said.
In addition, numerous scientists have voiced caution about the prospect of genetically altering normal somatic cells to boost their telomerase activity. The risk, they say, is cancer. Some researchers view the lack of telomerase in normal somatic cells as a prime defense against the runaway division and growth that is malignancy. To circumvent that defense could be dangerous, they say.
But Harley, who originally helped establish that cancer cells activate telomerase, argues that the threat may not be as great as assumed. Telomerase does not appear to start cancer, he said, only maintain it once other biochemical events have set it in motion.
Among the earliest medical applications of the enzyme might be a telomerase-based diagnostic test for certain cancers. Other researchers have shown that a telomerase test can pick up bladder cancer cells sloughed off into urine before other tests can, and thus could function as an early warning for recurrence of the disease in patients undergoing treatment. A National Cancer Institute workshop last summer concluded “that detection of telomerase activity may be a new and independent early marker of cancer.”
The sudden publicity generated by last week’s announcement belies the years of incremental, painstaking, collaborative research that led up to it. And Harley, said Rose, “is really the driving force behind the telomerase story.”
Harley, 45, began his research career 23 years ago trying to disprove the Hayflick phenomenon. Geron recruited him from an academic post in 1993.
Though the telomere mechanism is often referred to as a “biological clock,” he is not fond of the expression because it implies a passive monitor. He recently described it instead as a “genetic time bomb.” “This,” he said, “is the program for cellular aging as far as we can tell.”
