Winning the battle to extend human life!
Scientists are on the verge of revolutionary success in stretching the lifespan limits!
As our immune system declines with age, some of us will die, some of us will endure tragic or chronic disease – simply because our defenses are down.
But what if could stave off the decline, so that our immune system functioned with the vigour of youth?
That’s no longer a pipe-dream: it’s becoming a distinct possibility as the eye-opening evidence piles in from all over the world…
During 90’s Steven Rosenberg, chief of surgery at the National Cancer Institute in Bethesda, Maryland, took a dramatic measure to try to save the lives of two cancer patients. The patients, a 29-year-old woman and a 42-year-old man, were both suffering from a lethal variety of skin cancer known as metastatic melanoma. In a procedure that lasted only 20 minutes, Rosenberg injected the two patients with about 100 million immune-system cells, taken from their own tumours, which had been removed and genetically altered to produce a potent natural anti-cancer substance called tumour necrosis factor (TNF). Rosenberg’s hope is that these genetically-altered immune cells will home in on the patients’ tumours, releasing the cancer-destroying TNF.
At that time the procedure represents a signal event in the history of medicine. It was probably the most sophisticated attempt made to manipulate and strengthen the human immune system to fright disease.
That effort, now being carried forward on a broad front, has tremendous implications for the battle to extend human life expectancy. As we get older, the immune system responds with less vigour to challenges from disease-causing denizens – bacteria, viruses, fungi and cancer cells. With the aging of the immune system, some of us will die – or spend our later years in bad health – simply because our defenses are down.
But what if we could bolster our flagging immune system so that it performed with the vigour of youth? That hope, which motivates hundreds of scientists, is looking more and more like an eventuality as eye-opening evidence accumulates from laboratories around the world. Some experts think that in the foreseeable future a number of approaches, taken either alone or in combination – diet and food supplements, exercise, stress reduction and a growing pharmacopoeia of immune-stimulating drugs – may so fortify our immune system that in middle and even old age we will resist many kinds of diseases as stoutly as we did in youth.
“If we can rejuvenate the immune system,” says Michael Osband, director of the joint clinical immunotherapy programme at the Boston University School of Medicine and the New England Baptist Hospital, “it could have a huge impact on the aging process.”
The hopes – and the burgeoning scientific effort – are in large part stimulated by the capabilities of the immune system itself, which is often likened to a defending army. Indeed, the astonishing beauty and complexity of its organization would be enough to arouse the admiration of a General Norman Schwarzkopf Trillions of cells are involved, many with a breathtakingly specific job to do. There are cells that latch onto bacteria and viruses, tagging them with chemical “flags” that identify them as invaders. There are cells that “escort” captured invaders to other cells or chemicals (antibodies) that bind the invaders, setting them up for a kill or disposal by scavenger cells. There are “natural killer” (NK) cells, which may perform “immune surveillance”, shooting down cells that have turned cancerous. Thera are “memory” cells that remember what an invader looks like so as to prompt the system to quicker action the next time one of its kinds shows up. There are even specific “suppressor” cells that call off the immune counter-attack when an invasion has been subdued. And these remarkable cellular forces are commanded by dozens of molecules that act as sentries, messengers and even assassins.
OLD IDEA – NEW SHAPE
The idea of manipulating our natural immunity to strengthen or reinforce it is not a new one. Over the last three centuries, immune-estimulating vaccines – which introduce a touch of disease that stimulates the immune system to produce the appropriate disease-fighting antibodies – have all but quelled such former killers as smallpox, polio and measles. Scientists hope that the upcoming years will see the development of successful vaccines for malaria, AIDS and the common cold.
But vaccines against specific diseases are by no means the only way to bolster the immune system. It may be that certain foods and food supplements can help as well. Although the possible connection between diet and immune function is still considered controversial, there are tantalizing hints that the link is real. For example, a research team at the American Health Foundation in New York City found that 17 young men who ate diets in which they got only 25 per cent of their calories from fats (the American average is about 40 per cent) enjoyed a 49 per cent increase in the activity of NK cells – immune-system “soldiers” that attack viruses and incipient cancers. And a number of animal and human studies have suggested that supplements of vitamin C can help, increase the immune system’s ability to fight infections.
Of all the nutrients that have been tentatively linked to the healthy functioning of the immune system, the one that currently seems to show the most potential promise is Vitamin E. At the USDA’s Human Nutrition Research Center on Aging at Tufts University in Boston, nutritionist Jeffrey Blumberg and his colleagues gave 800 international units (IUs) of vitamin E a day for 30 days to 18 healthy volunteers over age 60. The volunteers’ immune function was checked periodically through blood tests. When the month was over, Blumberg says, the result showed that vitamin E supplementation “unequivocally increases immune-system responsiveness in healthy older adults.”
Immunologist Adrianne Bendich, of pharmaceutical giant Hoffmann-La Roche, who conducted similar tests in rats, states the case plainly: “Vitamin E is the most important immune stimulant I have ever seen.”
If diet and food supplements like vitamin E can play a role in immune function, so, it appears, can exercise. Although scientific research on the exercise-immunity link is still in its infancy, there are early indications that point in that direction. At Loma Linda University in California, a research team led by then health science department chairman David Nieman took 50 moderately obese, sedentary women and divided them into two groups: one that remained sedentary and another whose members walked 45 minutes a day, five days a week for 15 weeks. Blood tests showed that in the walking women, activity of NK and other immune cells increased from day one. This increased immune function seemed to pay off in better health: whereas the sedentary women were sick an average of 10 days during the test period, the walking women were sick only five. “Walking,” concludes Nieman, “seems to prime the immune system for action.”
It’s possible that “action” may mean defense not only against infectious diseases such as cold, but even against cancer. An eight-year study of 10,000 men and 3,000 women by the Institute of Aerobics Research in Dallas showed that people whose fitness level was equivalent to that of someone who walked briskly for half an hour every day were less likely to die of cancer. No one is certain why this should be the case, but John Morley, professor of medicine at St. Louis University, offers a possible explanation: “Think of tumour cells forming and escaping into the bloodstream,” he says, “looking for a place to land. While they’re trying to choose the ideal place to settle down, exercise triggers a sudden temporary burst of immune cells that come out and overwhelm the tumour cells – that’s one possible scenario.”
If there is a connection between exercise and immune vigour, the watchword seems to be moderation. Too much of a good thing may become a bad thing: A number of studies indicate that heavy exercise, such as running a marathon, can actually cause temporary suppression of the immune system. “For six hours after heavy exercise, there’s a ‘window of opportunity’ when disease causing agents can get in. The only thing one can do about it is to try to avoid exposure to bacteria and viruses both before and after heavy exercise.” says Nieman.
THE BRAIN-IMMUNITY LINK
If exercising the body can affect the immune system – either positively or negatively – so, it appears, can exercising the mind. Over the past 15 years, evidence has mounted that the link between the brain and the immune system is a biochemical fact. Nicholas Plotnikoff, Ph.D., formerly of Oral Roberts University, found that some kinds of immune-system cells had receptors for endorphins – natural, opium-like substances produced by the brain. Then J. Edwin Blalock, Ph.D., of University of Texas Medical Branch at Galveston found that adrenocorticotropic hormone, supposedly an exclusive product of the brain’s pituitary gland, is also manufactured by cells in the immune system. As time went on, Candace Pert, Ph.D., and Michael Ruff, Ph.D., at the National Institute of Mental Health, found that glia cells in the brain had receptors for molecules made by the immune system, while some immune cells (monocytes and macrophages) have receptors for virtually every known messenger chemical or neurotransmitter, produced by the brain.
While these scientists continue to work at unravelling the intricate chemical interconnection between brain and immune system, others are trying to determine to what extent the interconnection actually influences the workings of the body’s immune defenses. One of the classic experiments was conducted by virologist Roland Glaser and psychologist Janice Kielcolt-Glaser, both of Ohio State University. The husband-and-wife team looked at first-year medical students just before and during exam week – a period of high stress. They found that immune function, in terms of both, numbers of available cells and the vigour of those cells, declined significantly. By the time the students came back from their presumably low-stress summer vacations, their immune function had returned to normal.
CHEMICALS TO JUMP-START IMMUNITY
The work of Pert and Ruff, the Ohio State researchers, and many others has helped show that the way we feel mentally can have a direct and profound effect on the vitality of the immune system. Meanwhile, other scientists are looking for substances that can give the immune system a chemical jump-start. A number of such substances have shown early promise as immune stimulators. Of particular interest to many scientists is a large class of substances known as biological response modifiers (BRMs). These substances are all produced by the human body – part of its repertoire of hormones, proteins, etc., that help stimulate or regulate the incredibly intricate workings of the immune system.
The BRMs with perhaps the longest research record are the thymosins, a group of hormones extracted from the thymus gland. The thymus is considered the “master gland” of the immune system – it has been likened to a school where immature immune cells enter in an unspecialized state and emerge “trained” and ready to do specific job in fighting off disease. About the size of a walnut in young people, the thymus gland begins to shrink in puberty and by old age has all but disappeared.
Some scientists think that this shrinkage – and a corresponding reduction in output of thymosins – has a great deal to do with the overall decline of the immune system as we age. One of the most prominent of these scientists is Allan Goldstein, chairman of biochemistry and molecular biology at George Washington University in Washington, D.C. Goldstein began isolating the thymosins to treat a five-year-old girl who was suffering from a potentially deadly condition known as thymic aplasia, in which the thymus gland’s failure to produce an adequate number of T-cells leaves the victim vulnerable to endless infections. Treatment with thymosins effected a spectacular cure, and the girl led a relatively normal life until she died, the longest-known survivor of the disease.
Since then, research on the thymosins has continued at dozens of laboratories, including those of Goldstein’s Washington-based company, Alpha 1 Biomedicals, Inc. In Europe thymosins are routinely prescribed to stimulate the immune system in the treatment of certain cancers, influenza and infectious diseases like herpes.
Treating disease is one thing, but Goldstein foresees an even broader application for thymosins. “If we can give (older people) enough thymosins to keep their T-cell levels high,” he concludes, “we should be able to enhance immunity throughout old age.”
Another class of BRMs that seems to hold promise as immune boosters is the interferons, a family of hormones that helps regulate the activity of T-cells. One of these, called alpha interferon, has been shown to block the reproduction of some viruses, and is FDA-approved for treatment of hepatitis C, two kinds of cancer (hairy-cell leukemia and Kaposi’s sarcoma, a skin cancer that often attacks victims of AIDS) and genital warts. Another form, interferon gamma, is already approved for treating a hereditary immune disorder called chronic granulomatous disease.
A similar group of hormones, the interleukins, tell the appropriate immune system cells to multiply once an invader has been captured and identified. At least one of the interleukins, IL-2, has what one of its discoverers, Dartmouth University professor of medicine Kendall Smith, M.D., calls “obvious applications as an immune stimulant.” Because IL-2 promotes the multiplication of T- and B-cells, one of those applications could be as a vaccine booster. Indeed, human tests conducted by Stefan Meuer, M.D., of the University of Heidelberg in Germany have already shown that IL-2 is safe and effective in boosting the potency of a hepatitis-B vaccine. At the same time, Rosenberg and his colleagues at the National Cancer Institute have used a combination of IL-2 and IL-2-stimulated NK cells to treat patients with three types of cancer (malignant melanoma, kidney cancer and colon cancer). Although only about 20 per cent of the patients in these trials responded favourably to the treatment, many of those who did respond have had stable remissions of their cancers, and have needed no further therapy.
Equally promising as immune boosters are a class of biological response modifiers known as colony stimulating factors (CSFs). First discovered in the mid-1960s, these substances are manufactured by certain immune cells; their job is to stimulate the development of immature bone-marrow cells into functional immune-system components. So, far tests on CSFs have focused on stimulating the bone marrow after transplantation or cancer chemotherapy; and on increasing the effectiveness of anti-AIDS drugs. But some experts think that CSFs may eventually help boost the ability of people with weakened immune systems – the elderly, for example, or some kinds of diabetics – to fight off infectious diseases. According to David Golde, M.D., chief of the division of hematology and oncology at the UCLA School of Medicine, CSFs may ultimately prove to be “as big a step for medicine as the introduction of antibiotics.”
MORE CAUSE FOR EXCITEMENT
An even more recent discovery has scientists equally excited. In 1990, three groups of researchers (from Amgen, Inc. in California; Immunex Corporation in Seattle; and Memorial Sloan-Kettering Cancer Center in New York City) simultaneously announced the isolation of a protein that may be the broadest and most fundamental of all the immune substances. Variously called stem cell factor, mast-cell growth factor or Kitligand (each research team has its own name for the substance), the protein activates primitive bone-marrow cells, called stem cells, prompting them to divide and differentiate into the progenitors not only of the red blood cells that carry oxygen to the body’s tissues but of every variety of cell in the immune system. Because of its potential to treat patients with a wide variety of bone-marrow failures – resulting, for example, from cancer chemotherapy or radiation treatment, aplastic anemia, or toxicity from the anti-AIDS drug, AZT – Jerome Groopman, chairman of the advisory committee on drug factors for the FDA and chief of hematology and oncology at Boston’s New England Deaconess Hospital considers the newly-discovered protein “extraordinary exciting.”
Thymosisns, interferons, interleukins, colony stimulating factors, stem cell factor – used individually, each of these biological response modifiers has shown at least some promise as an immune-system builder. But the most current approach at the research level is to formulate so-called cocktails – mixture of two or more of these, or combinations of BRMs with vaccines or standard therapies (chemotherapy drugs or radiation). Theoretically, these combinations could be more potent than many of the substances used singly.
COCKTAIL VS. CANCER
The cocktail approach is already showing promise in combating some kinds of cancer. In a trial of 19 patients with breast cancer or lymphoma, James Neidhart, M.D., of the University New Mexico Cancer Center in Albuquerque, combined heavy-dose chemotherapy treatment with a colony stimulating factor. Astonishingly as many as half of the patients achieved complete remission and 60 per cent of the remitted lymphoma patients have survived without relapse for an average of 2.2 years. Meanwhile, at the National Cancer Institute, Steven Rosenberg mixed IL-2 with tumour infiltrating lymphocytes (TILS), a variety of T-cell that homes in on some kinds of cancer cells, and gave the mixture to a group of patients with advanced cases of melanoma. Again, the results were dramatic: As many as 40 per cent of the patients experienced remission of the disease.
Rosenberg is in the process of taking the cocktail approach a giant step further by altering immune cells genetically to produce tumour necrosis factor in amounts as much as 100 times greater than normal. The procedure in which Rosenberg gave his two melanoma patients massive infusions of TNF-rich immune cells were the first of a series.
In a variation on the Rosenberg approach, Michael Osband at New England Baptist Hospital removed immune-system memory T-cells from 45 kidney-cancer patients. In the laboratory, Osband and his colleagues activated the immune cells so that they would search out cancer cells, and then re-inserted them into the patients. Those who received this treatment, known as autolymphocyte therapy (ALT), lived two-and-a-half times longer than a control group of patients. “The result,” Osband concludes, “was much slower tumour growth.”
Altering immune system cells in the laboratory to increase their effectiveness evidently holds great promise as a treatment for some kinds of cancer. But is there an even broader application? Could they be used not only to fight disease but to prevent them? Could they help shore up our immune defenses as we grow older, extending our years of life, healthy life, in the process? “There’s no question in my mind,” says Osband, “that theoretically, if we could do this sort of thing for people, beginning at age 50, we’d see a significant improvement in their health in general. But proving that could take couple of decades; we need a lot of money and a creative way to do it sooner.”
Still, Osband’s and Roseberg’s work with altered-cell therapy adds to the growing indications that we are standing on the threshold of a new era. In time, applications of these and other immune-boosting techniques could give us the ability to routinely fortify our natural resistance to life-shortening diseases so that each of us can hope to live out our allotted lifespan in greatly improved health.