The Doric Column

August 31, 1999

Shoestrings, Telomeres, and the Great Chain of Being
TTAGGG, a Code for Keeping It Together
Cancer: A Cell's Quest for Immortality
The Experimental Road to Paradox

Shoestrings, Telomeres, and the Great Chain of Being

I felt myself unraveling as I waited for my daughter to finish tying her shoes.

The door was open. The van was running. Her brother was packed into it, ready to go. We could still make his 8:05 am. school bell and he wouldn't have to serve "detention" after school.

But there was a hitch. His little sister wasn't ready. She was tying her shoes. No one is allowed to interfere with this ritual, even in the interests of expediting it, even in the interests of her brother making it to school on time and avoiding detention, perhaps even in the interests of advances in quantum string theory and bidirectional time travel. Time and theory were beside the point. She was tying her shoes.

This experience, which was repeated countless times last winter, is seared into my memory banks. It is called up whenever I contemplate the subject of biology and aging. I do that a lot these days. I get plenty of help from news organizations run by baby boomers who think medical science is a body shop set up to restore wrecks.

The shoestring, you see, has come to symbolize certain features of our biological destiny. The shoestring is a common metaphor for the human chromosome, the string-like body in the nucleus of the cell that serves as a packing plant for our DNA, our genes. It certainly was in the 1980s when I worked with Jorge J. Yunis, a University professor of laboratory medicine and pathology who pioneered high-resolution chromosome banding.

One of the reasons is that the shoestring comes outfitted with little plastic sleeve around its ends to prevent its unraveling and to facilitate lacing. The chromosomal equivalent of the plastic sleeve is its "telomere" at each tip (from the Greek telos meaning "end" and meros meaning "part").

The "unraveling" effect I experienced waiting for my daughter to tie her shoes is the sequential loss of telomeric DNA, a normal consequence of the aging of cells. With each cell division, the cell's chromosomal telomeres become shorter -- until the cell dies.

But the plastic tip, it turns out, may be a red herring. Carol Greider and her colleagues at Johns Hopkins University reported last spring that telomeres actually form a loop. ["Chromosomes Have a Loop at Each End, Scientists Find," New York Times, May 14, 1999] Not an ordinary loop, mind you. Telomeric loops may hold our biological destiny. "Will the circle be unbroken?" You better hope so.

Since that report, I have discovered a new patience with my daughter as she ties her shoes. I give her plenty of leeway to make and secure the loops. The sight of a loose end makes me cringe in mortal anxiety. Surely stress can only expedite the shortening of telomeres and prevent them from forming secure loops. If it's a matter of my telomeric loops being secure or her brother's detention, I am Darwinian to the core.

Thus I yield to her impertinent admonition: "Calm down, Dad."

TTAGGG, a Code for Keeping It Together

Leonard Hayflick of the University of California in San Francisco discovered in 1961 that human cells in culture divide a limited number of times, then stop dividing. Normally, cells hit their limit after about 50 doublings. But no one really knew why.

A quarter century later, Elizabeth Blackburn, another UCSF researcher, discovered the RNA-protein enzyme telomerase which rebuilds telomeres. She proposed that active telomerase is a factor in allowing cells to keep on dividing -- that they stop dividing when their telomeres have wound down and they have no telomerase left to rewind them.

I remember reading about Blackburn's work in the late 1980s when I was employed at a local biotech firm. The firm subscribed to a number of leading scientific journals, including Cell. Blackburn's research group published frequently in that journal. They reported their findings from experiments on Tetrahymena, a single-cell protozoan whose chromosomes perform well and are easily tracked under the microscope (see the work of Team Tetrahymena at St. Olaf College).

Blackburn found that telomerase rebuilds the chromosomal telomeres of Tetrahymena by repetitively adding the DNA sequence TTAGGG (thymine - thymine - adenine - guanine - guanine - guanine).

Indeed, this modest sequence may hold the key to the biology of aging. If you have plenty of it in the right places or the means to make it, you may avoid the consequences of aging such as disease, disability, perhaps even hair loss.

But could a massive infusion of telomerase throw your current biological program into reverse? Is telomerase the key to bidirectional time-travel? Is it the pathway to the Ponce de Leon's elusive magical waters?

Or is our fate more mundane? Is it, as New York Times columnist Maureen Dowd wrote recently after laser eye surgery to reclaim 20-20 vision, "a losing battle" despite the growing billions of dollars spent on aging research and anti-aging ingestives and devices? ["Eyes Wide Open," July 28, 1999].

"The Age of Aquarius has become the Age of Collagen," Dowd writes. "We can play with our lasers and magnets and suction and magic elixirs all we want. We can get phosphatidylserine and phyto-nutrients pumping. We can Viagrandize to the max. But gravity and french fries will eventually have their way."

Cancer: A Cell's Quest for Immortality

Despite the omnipresence of gravity and french fries, the scientific effort to turn back the biological clock goes on.

Two years ago the Nobel-prizewinning biochemist Thomas Cech of the University of Colorado, working with colleagues at the California biotech firm Geron Corporation, isolated the human gene for telomerase reverse transcriptase (hTRT), a catalytic protein that can influence a cell's destiny. Although gene for telomerase is present in all cells, they found that hTRT is present only in "immortal" cells where presumably it restores chromosomal telomere in perpetuity.

With hTRT in hand, early in 1998 researchers from Geron and the University of Texas Southwestern reported that they had extended the life of human cells beyond the Hayflick limit.

Then earlier this month, Robert Weinberg and his colleagues at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, publishing in the journal Nature [400: 464-468, 1999], described how they used the telomerase gene to make cancer cells from normal human cells. ("To Build a Cancer Cell," Newsweek, August 9, 1999).

This is no small feat. Researchers have known for a long time how to make animal cells cancerous, but human cells had been intractable, stubbornly resistant to revealing the steps that would allow scientists to track precisely what happens when our cells turn against us.

For decades, the mantra in the research community has been: "Cancer is a multistep process." As a scientific editor, I helped to ensure that the phrase appeared in the appropriate place in all scientific papers I had a hand in.

I got to know about Weinberg and his work in the early 1980s when I was working with Jorge Yunis. Using his refined banding techniques, Yunis had found the exact site on human chromosome number 13 that is deleted in patients with retinoblastoma, a rare eye cancer that afflicts children.

At the time, the rage in the scientific community was the discovery of so-called oncogenes, genes typically associated with animal viruses that could cause mammalian cells to become cancerous. It turns out that the viral genes have similar DNA sequences in cellular genes that regulate growth and which can contribute to the development of cancer through inappropriate "activation" of cellular growth if they are disrupted--whether by viruses (typically not) or mutagens in food or the environment or through genetic inheritance.

One of the first such oncogenes was discovered by Weinberg in 1980. It is call H-ras and it can transform animal cells in culture and produce malignant tumors in laboratory animals. But not human cells. So Weinberg, turning to the retinoblastoma model, considered that perhaps genes accidentally deleted represented another step in the multistep process of cancer. By the mid-1980s he and his colleagues had identified a "tumor suppressor" gene for retinoblastoma. Tumor suppressor genes are critical to limiting growth in a healthy cell. When they are deleted or disrupted--when the "brake" is removed--the cell spins into a reproductive binge.

But even the combined effect of genetic "activation" (oncogenes) and "suppression" (tumor suppressor genes) was not enough to recreate the "multistep process of cancer" in human cells. Despite billions of dollars and billions of hours spent in research laboratories around the world, the process of cancer adamantly refused to be extricated from the realm of mystery.

The lure of human immortality was proving to be a awesome force indeed, even for magnificent human brains in search of the pathways by which some human cells attempt to live forever.

If we have always sought the "Fountain of Youth" and the prospect of life everlasting, why in the world wouldn't our cells seize the chance, however ultimately self-destructive. Anyway, self-destruction is not exclusively the province of cells gone awry. Their hosts frequently behave that way. That means you and me.

The Experimental Road to Paradox

But, just maybe, this time the secret of cellular aspirations for immortality through cancer is finally out of the closet.

Weinberg and his colleagues used a multistep approach to transform normal human cells into cancerous cells, including the introduction of the oncogene H-ras and disruption of a mechanism that normally signals cells to stop growing. But the final step proved to be the crowning one--by giving the cells the ability to recap their chromosomal telomeres ad infinitum.

The researchers added the telomerase catalytic enzyme hTRT. That final act, call it the "madcap" step, gave the cells license to divide uncontrollably and take on other characteristics of human tumor cells. For the first time, the complex mechanisms that human cells use to maintain order and discipline and prevent uncontrolled growth were overridden by systematic manipulations in the laboratory.

The paper in Nature that resulted, "Creation of human tumour cells with defined genetic elements," produced a mild stir in medical circles. New York Times science reporter Gina Kolata observed that the research team had succeeded in a task "that sounded simple but which had eluded molecular biologists for more than 15 years." ["In Finding Way to Create Cancer, Hope for a New Test," July 29, 1999.]

I watched attentively as Weinberg explained his "breakthrough" and answered questions about it on the PBS's "NewsHour" with Jim Lehrer. It is uncanny, in the hands of a media-savvy scientist like Weinberg, how quickly the language of discovery and excitement becomes the language of qualification and caution, followed by the almost predictable "It's a step forward, but [there are] many more steps to go." I remember well how the discovery of oncogenes captivated Lehrer's former partner Robin McNeil in the early 1980s. Yet here we are nearly 20 years out and still we don't know for sure if we've finally pinned down "the multistep process of cancer."

And we may not know for a long time. And what time are we talking about? Greenwich mean time? Internet time? Cell-cycle time?

Perhaps science and its exasperating little steps to possible understanding is best comprehended in the paradoxical worlds of writer Jorge Luis Borges (about whom I have written in a previous column) and philosopher Arthur O. Lovejoy.

Through his masterpiece The Great Chain of Being (1936), Lovejoy formed the "perfect fit of the discrete into the continuous," in the words of philosopher and former computer programmer Harvey Blume ["Caught in the Flash," Atlantic Monthly, December 16, 1997].

Lovejoy wrote: "There are not many differences in mental habit more significant than that between the habit of thinking in discrete, well-defined, class concepts and that of thinking in terms of continuity, of infinitely delicate shadings--off of everything into something else."

Blume applied this dichotomy to the current tug-of-war between a rising "digital" world and a familiar "analog" world and the paradox of how something increasingly discrete could in fact produce something continuous, maybe infinite.

Which brings us back to telomeric loops and the superstring theory of theoretical physics. As I understand it, string theory helps us to bring together quantum mechanics and its general relativity with observed nature, particularly gravity.

There are two types of string theories: those with closed loops, and those with open loops once closed. Apparently, physics can go either way when it comes to theoretical loops.

Chromosomal telomeres, on the other hand, clearly prefer closed loops, perhaps symbolizing the aspiring continuity and forever-elusive immortality of biological life.

Somewhere between the far reaches of the universe and the microscopic world of cells I have actually seen both types at once: closed loops, and open loops once closed.

In my daughter's shoes.

    --William Hoffman

Disclaimer: The opinions expressed herein are the writer's own.

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The Doric Column



The enzyme telomerase "caps" the ends of chromosomes with a sequence of DNA (TTAGGG) that is repeated hundreds of times. These "telomeres" are believed to shorten with each division of the cell. Old cells have short telomeres. Because telomerase can rebuild telomeres, it may play a role as an "immortalizing enzyme." Animated image (c) the Geron Corporation. All rights reserved.