FOREVER YOUNG : In a Quiet Lab in Costa Mesa, Milan Panic and a Team of Scientists Are Close to Answering Mankind’s Enduring Question: Why Die?
MILAN PANIC SAYS: “Aging begins when the DNA code fails to send a message to repair itself. If we can assist the DNA in sending a message to repair itself, the cells will not age. If the cells do not age, you do not age. We have solved the problem.” Compact, well-dressed, handsome and fiftyish, Panic (pronounced Paa-nish) is nothing if not dynamic; his Eastern European accent and enthusiastic delivery make him sound equal parts Lee Iacocca and Boris Badenov. Panic is president and founder of ICN Pharmaceuticals Inc., a company whose anti-viral agent ribavirin, sold under the trade name Virazole, has become the treatment of last resort for thousands of AIDS victims. He is also a man with an idea. “Why die? When I was a kid, I always asked the question. Must be a reason to die; something must be wrong. The time has come to challenge death, challenge the concept.” Panic’s enthusiasm for his own endeavors is well known. ICN was created with $200 in 1959, and during the go-go period of the late 1960s, the company was a darling of Wall Street, marketing radio-isotopes and a generic version of the Parkinson’s disease antidote L-Dopa. And though it has had a roller-coaster financial history since, ICN has attracted major investors, including IBM and MCA. Two years ago, Eastman Kodak pledged $45 million to finance a six-year program in conjunction with ICN’s Nucleic Acid Research Institute to try to develop a drug that will slow, stop or reverse the aging process. “We are at the brink of a biological revolution,” Panic says. “The next five years may produce dramatic solutions to the problems of aging.”
Panic is seated in the modestly tony main conference room at ICN headquarters in Costa Mesa. We are on the third floor of the central building, a long, glass-sided monolith nearly as big as an aircraft carrier, with laboratories occupying the lower levels. ICN also has research facilities in West Germany, the Netherlands, France, Mexico and Canada. The company is aggressive. Panic recently put it to Business Week this way: “This is the final frontier. Today’s drugs fix kidneys and lungs, but all medical problems come from one cause--cells can’t repair. The future will be to improve cell repair, and anti-viral drugs are the beginning of that era.” Allows Science magazine editor Daniel E. Koshland Jr.: “ ‘DNA Valleys’ of the future may approach in size and importance the Silicon Valleys of today.”
The ICN-Kodak project employs 125 full-time scientists and researchers under the direction of Weldon Jolley, professor of surgery at Loma Linda University Medical Center. Jolley’s group hopes to isolate an organic compound, among the 100,000 or so already developed by the two companies, that will stimulate immune mechanisms eroded by the aging process. Jolley believes that viruses like those that produce measles, mumps and flu begin to destroy the immune system when they invade the body. ICN has already enjoyed considerable success with Virazole, which has proved effective against diseases ranging from A- and B-strain influenza to shingles. (Tests of ribavirin on AIDS patients have so far been promising but inconclusive.) Jolley postulates that development of a stronger “cousin” to this drug could serve literally as an elixir of youth. “If we are successful,” Jolley says, “the benefits to humanity would be spectacular.” To say nothing of the benefits to Kodak’s shareholders, and ICN’s.
Prescriptions promising the return of youth have always enjoyed a lucrative niche in the marketplace. In ancient Rome the physician Galen advised inhalation of the breath of virgins as a means of forestalling death, and Pope Innocent II is said to have sipped the blood of boys as a rejuvenating tonic. More recently, Dr. Paul Neihan injected luminaries ranging from Konrad Adenauer to Charlie Chaplin, Pope Pius XII, the Duke of Windsor, Winston Churchill and Christian Dior with fresh cells from unborn lambs. Lately, anti-aging research has been pulled firmly to the bosom of the American medical Establishment. The ICN research group, for example, includes former Guggenheim fellow and UCLA professor of biochemistry Roberts A. Smith and Dr. Roland Robins, director of Brigham Young University Medical Center’s Cancer Institute. Its scientific advisory committee is headed by Walter Koltun of the Harvard-MIT Division of Health Sciences and Technology. Altogether, a dozen universities in California and an equal number nationwide are vigorously engaged in anti-aging research, and leaders in the field are convinced that important, even spectacular, results may be realized soon. According to Dr. Robert N. Butler, founder of the National Institute on Aging, “by the turn of the century, we’re going to have many means of intervening in the aging process.” Some scientists, including Dr. Roy Walford, a pathologist at the UCLA School of Medicine, believe that the means are already available to significantly extend human life. Says Walford: “It seems fairly certain that maximum life span could be prolonged to 130 to 140 years by the exercise of very stringent measures.”
Which is to say, twice as long as most of us were expected to live when we were born. The social and economic implications of such a change are staggering. Apart from any medical breakthroughs, the aged population of the United States is already projected to increase dramatically in the next few years. Today, one American in 10 is over 65. By 2015, it will be one in four. Currently, the over-65 group accounts for a whopping 60% of the nation’s health-care expenditures. As the monster baby-boom generation creates, over the next 35 years, a bumper crop of brand-new oldsters, the elderly’s share of the national health tab will shoot to 75% or more. The financial effects of long-term, non-fatal diseases directly related to age could prove devastating. Alzheimer’s disease, for example: By the year 2000 it is estimated that it will be the single most prevalent health problem in the United States. Add to that the swelling ranks of victims of arthritis, glaucoma, and other age-related ailments and, in pure dollar terms, the toll becomes clear.
Pharmaceutical companies coast to coast have attacked the health problems related to aging on a broad front and are moving vigorously into genetic research, the key to understanding the aging process. Medical breakthroughs will be essential, not only to avoid bankrupting the health-care system, but to make long life worth living. “The idea of the second 50 years is beginning to receive wide acceptance,” according to Dr. T. Franklin Williams, director of the National Institute on Aging in Bethesda, Md. “The day is coming when middle age won’t end until 75.” J. Edwin Seegmiller, head of the Institute for Research on Aging at UC San Diego, says that old age need not be synonymous with disease and senility, that “it is within the range of science to extend healthy life into those years traditionally associated with disability and enfeeblement,” and that “we had better get on with it now before the baby-boom generation hits retirement age.” Seegmiller cautions against unrealistic hopes for a long-life miracle in the immediate future, however. “Application of that kind of research will probably take decades. People seriously concerned about prolonging their own lives now would do better spending 35 cents for the American Heart Assn. pamphlet ‘Eating for a Healthy Heart.’ It suggests the obvious: Cut down on saturated fats and red meat. Stop smoking. Watch alcohol intake. Exercise. Beware of salt and refined sugar. Be sure to get plenty of rest, and avoid unnecessary stress. Nothing very magical really, but it works.”
BY THEN-PREVAILING standards, Jesus Christ lived to His dotage. At the time of His crucifixion the average life span in Rome was only 22 years. By 1850, the average life span in the United States had advanced to 40; by 1900, to 47. Thanks to advances in medicine in this century, the average life span in Western countries is about 75. And, the fact remains, most people do not die of old age; they die of disease. Still, preventive medicine has limits. Public Health Service studies show that if all varieties of cancer were magically eradicated tomorrow, life expectancy would jump just two years and four months. If all heart disease simply disappeared, average life span would lengthen only six years.
So the new emphasis is on discovering and combatting the mechanisms of aging itself. Jolley, who did many of the immunology studies for the “Baby Fae” baboon-heart-transplant operation, believes the ICN research program may find ways to “reawaken the immune system by stimulating lymphocytes.” These white blood cells are largely responsible for the body’s ability to combat disease. Without lymphocytes and their attendant enzymes, hormones and antibodies, humans would be short-lived, indeed. Why does this system break down? There are nearly as many aging theorems as there are researchers in the field. Richard Bucala suspects that glucose is a key element in cell devolution, that it accretes along the DNA spiral and literally gums up the reproductive machinery. Another popular theory is that “free radicals,” unstable molecules containing only a single electron in their outer shells, “steal” electrons from stable molecules, thus damaging them. According to Denham Harman at the University of Nebraska, there is evidence “that the sum of these reactions constitutes the aging process.”
Corollary to that is the idea that much of the body, particularly nerve tissue, simply “rusts” with time. Says UC Irvine neurobiologist Carl Cotman: “Oxidation inactivates the growth factors that maintain vitality of neurons. In lab rats we’ve seen that some proteins require controlled oxidation reduction to stay active. If you could reverse this ‘rust,’ you might slow the aging process significantly.”
Dr. Bernard L. Strehler, a USC geneticist, believes that enzyme failure--and aging--may be the result of “the loss of a very, very few key genes.” Aging can be understood as a consequence of the instability of DNA, and the cure for aging--if such a cure is indeed possible--depends on whether bioengineered viruses or similar vehicles can be produced to repair the broken DNA strands. Rejuvenating a human body would mean returning billions upon billions of DNA strands to their virgin states. And consider the scale: Viruses are incredibly small. They are to thimbles what thimbles are to the state of Rhode Island. Yet already, revolutionary advances have been made.
THE PERFECT BEAST, a hermaphrodite, has only a thousand cells per animal: Witness the nematode Caenorhabditis elegans , better known as the roundworm. Barely visible without magnification, it twists and curls, forming tiny S’s and C’s under one of the microscopes in Tom Johnson’s laboratory at UC Irvine. Nothing new to look at, trillions of these creatures inhabit the earth. Yet these are different. The normal roundworm lives 20 days. Johnson and his colleagues have genetically altered the lab specimens so that they live an average of 35 days apiece. That’s a 70% jump in life expectancy, an astonishing achievement that may dramatically speed up the pace of aging research. By assaulting normal roundworms with a chemical mutagen, Johnson has been able to make a specific gene known as Age-One to--in effect--turn off. Johnson believes that this genetic mutation is what has allowed his special tribe of roundworms (now numbering in the millions) to almost double their life span. “There’s no a priori reason that a single gene couldn’t have similar effects in humans,” he says.
In the bowels of the university’s biology department, Johnson pulls the top off a cask called a liquid nitrogen Dewar flask and extracts a tube full of frozen roundworms. Beads of liquid nitrogen--emerging from the canister at a temperature of minus 273 degrees centigrade--spin and sizzle across a table-top. “Roundworms are very hearty,” he says. “You can freeze them like this and leave them--we’ve left some for seven years at a time--then take them out and they’ll begin to reproduce within a few hours after thawing.”
One important difference between the mutated, longer-living roundworms and their conventional ancestors is that the new roundworms reproduce at a much slower rate. Normal worms, in fact, reproduce five times as often. And Johnson speculates that, if humans were to be similarly mutated genetically, the results might be the same. In all organisms, including humans, senescence occurs within a certain time period after the end of the reproductive years. “In other words, we are selected to have a life span of 40 or 50 years or so--and after that it doesn’t matter. Central genes, or perhaps even one gene, exercises radically deleterious effects on the system, guiding it, in effect, to an early death.” Within the next several decades, Johnson believes, it may be possible to turn such a gene off, just the way he has been able to turn off the Age-One gene in the roundworm. “If it worked the same way, as soon as you had your children you would take some drug that depressed the level of protein in the gene to zero, so that the gene was basically turned off. That would decrease by 70% your rate of aging.”
Johnson hopes to isolate the Age-One gene in the roundworm within a year. Meanwhile, researchers at ICN have succeeded on another tack entirely: developing anti-viral agents designed to preserve the immune system simply by guaranteeing that it is left alone.
“ Virus! A perfect living specie. Almost. It was so perfect 5 billion years ago, it never advanced. Why didn’t it need to correct itself? To develop? To survive? Because it is so perfect. But when you find something to attack it, it mutates just a little, so that the same mechanism can’t destroy it. They are so perfect! But ribavirin can keep the virus under control.”
--Milan Panic
THEY LOOK LIKE little lunar landers. Each invades a cell by “touching down” on its surface and then burrowing through to the cell’s center. Viruses are known as “obligate parasites,” essentially not too much more than a bunch of chemicals put together in a rather mechanical-looking protein package. They can only reproduce in a living cell. They use the cell’s machinery to reproduce and multiply until the cell itself eventually explodes. In the past, the only way to kill viruses was to kill the host cell.
Until the advent of ribavirin. Less than a decade ago, ICN developed it as an anti-viral medication designed to knock out influenza. Ribavirin (Virazole) simply stops viruses from reproducing. ICN researchers aren’t exactly sure how ribavirin does this; in the case of flu it may inhibit the capping mechanism where the virus replicates. In any case, ribavirin is one of thousands of compounds synthesized in ICN’s labs since 1968. Says UCLA biochemist Roberts A. Smith: “The big areas we’re looking into are broad-based anti-viral and anti-cancer agents. We are evolving a group of nucleic-acid compounds that are immune modulators: one set of compounds that will stimulate the immune system against the long-term erosive effects of viruses and another that will inhibit the immune system in cases of some kinds of arthritis, lupus and ulcerative colitis, where the body attacks its own tissues as if they were foreign.” Smith feels that one of these agents may prove an “ultimate” anti-viral, capable of halting erosion of the immune system, making it an important step toward a kind of “limited” immortality.
Offers Roland Robins, director both of Brigham Young University’s Cancer Institute and of molecular research at ICN: “When I talk to people and tell them that aging is like a disease, that it almost certainly has a cure, a lot of them look at me like I’m crazy. People take the process of aging and all that goes with it as inevitable. When Granddad gets old and can’t remember how to get out of bed in the morning, most people take it for granted. They don’t realize that his senility may be caused by a massive viral invasion”--Robins taps his temple--”an invasion right into the brain.”
The ICN plan is three-phased: to develop anti-viral agents to protect the immune system, to stimulate enzymes responsible for DNA repair and to develop a prescription for “enzyme failure.” Robins sees DNA “cross-linking” as a major problem. “One strand wraps around the other so that it can’t peel out and replicate. It will not unwind because two molecules have formed a link between them. Enzymes are then brought to bear to fix the helix.
“As you grow older the whole repair process slows up considerably. It becomes difficult to replace proteins, and enzymes, and so the whole thing grinds down. The very enzymes needed to repair the cross-linking are unavailable because the DNA responsible for creating those enzymes are themselves cross-linked.
“If we can stimulate the process of repair,” Robins says, “we can perhaps change the whole picture. That’s a fantastic thought! We can already stimulate certain enzymes. If you can do this more effectively, there’s no reason to have hearing loss, senility, so many of these things associated with aging. And who set the limit for life, anyway? Some joker somewhere says 110. Some scientists will tell you there’s a genetic clock. I don’t believe it. I don’t think the system decides to wind itself down. I think you’ve got genetic mutations that slow the system down until it can no longer function. If we can knock out those mutations, then life should go on, theoretically, forever!”
