The Greatest Unanswered Questions of Medical Science

Perhaps nothing known to modern science is as unlikely and outrageous as the daily work of our genes. From food, water, and air, they make a human being. Genes make proteins. Proteins are us.

And from this audacious process come humans, who are themselves audacious. Not content simply to sit back and marvel at this infinitesimal artistry, people seek to control and improve it. Medical manipulators aim to insert a normal gene in place of a defective one, or perhaps more boldly, to insert an “improved” gene in place of a normal one.

So far, the Food and Drug Administration has not approved any human gene-therapy product for sale, but the day is coming. In 2001 Philippe Leboulch of MIT and Harvard University used gene therapy on mice afflicted with sickle-cell anemia and wrought what may prove to be the technique’s first outright cure. Human trials are about one year away.

In the future, some hope, diseases will have nowhere to run; they will be flanked and overwhelmed by the traditional top-down approach of drugs and surgery and the bottom-up techniques of genetic therapy. Little wonder, then, that optimism reigns in medical schools. “Students used to say, ‘I want to understand basic biology,’” says Tom Curran, a former president of the American Association of Cancer Research. “Now they are saying, ‘I want to cure something.’”

Despite the progress, they won’t lack for challenges. The looming riddles of medical research are still overwhelming and will require extraordinary amounts of money, as well as brainpower, to solve. Here are eight unanswered questions that leading medical researchers say will command most of the attention and funding in the next decade.

Over the last 20 years, the incidence of asthma in the developed world, and of related disorders such as eczema, hay fever, and food allergies, has tripled. Yet asthma and the rest don’t appear to be communicable, and two decades aren’t enough for a genetic change to have become so widespread.

“The question must be: ‘What has changed in the last 20 years?’” says Paul Hannaway, who is himself an asthmatic and head of the asthma-immunology division at North Shore Medical Center in Salem, Massachusetts. A clue has come from studies in Austria, Canada, Germany, and Finland, where researchers found that children raised on farms are less likely to have asthma than those reared in more populated areas. Other studies show that children in day care have less asthma and fewer allergies than those raised at home, and younger siblings have a lower incidence of these syndromes. In each case, an answer may lie in the amount of exposure to pathogens at an early age.

The biochemical on-off switch for asthma lurks within what are called T-helper cells, specialized white blood cells that marshal other kinds of T cells to combat invaders. There are two basic types of T-helper cells: Th1, or the nonallergic variety, and Th2, the proallergic sort. All healthy infants are born with a proallergic Th2 system, which protects the fetus from being rejected as a foreign object by its mother’s body. But, according to the hygiene hypothesis, early childhood exposure to the natural world’s microbial menagerie can reconfigure an infant’s immune system into the nonallergic Th1 variety, while antiseptically reared infants are stuck with Th2 systems and develop asthma.

Holes remain in the theory. “It doesn’t explain adult-onset asthma,” says Hannaway. “You’re 50 years old, and all of a sudden you get asthma out of a clear blue sky. How does that happen?” It also doesn’t explain why asthma is on the rise in some parts of rural Africa. Hannaway reckons the hygiene hypothesis will be part of the ultimate theory but adds, “in all likelihood there are many reasons for the emerging epidemic.”

Until the theory is complete, Hannaway thinks the case for the hygiene hypothesis is strong enough to warrant mixing some messiness into the spotless world of the modern infant. “There may indeed be some sense in letting your kid go outside and eat a little dirt,” he says. “And maybe we should not be such fastidious housekeepers.”

The demonization of cholesterol began in 1959, when nutrition researcher Ancel Keys and his wife, Margaret, published Eat Well and Stay Well, which linked diet, cholesterol, and heart disease. The idea that excessive cholesterol causes atherosclerosis and heart disease has since become close to dogma.

Yet the notion has plenty of detractors, including Swedish physician Uffe Ravnskov, author of the book The Cholesterol Myths and spokesman for the International Network of Cholesterol Skeptics, a vociferous group of physicians, researchers, and others.

“Many autopsy studies have shown there is no association between the degree of arteriosclerosis in the arteries and cholesterol concentration in the blood, taken either shortly or immediately after death,” Ravnskov says. At his Web site (www.ravnskov.nu/cholesterol.htm), he lists dozens of such studies from medical journals. Ravnskov vigorously disputes the lipid hypothesis, the view that dietary cholesterol and fat clog arteries and can ultimately harm the heart. Detractors of the idea have become so numerous that last May, the Weston A. Price Foundation devoted an entire conference in Washington, D.C., to the subject, titled, “Heart Disease in the 21st Century: Beyond the Lipid Hypothesis.” The subtitle: “Exposing the Fallacy That Cholesterol and Saturated Fat Cause Heart Disease.”

A featured speaker was Kilmer McCully, author of The Heart Revolution and a professor of pathology at Brown University. McCully proposed in 1969 that the cause of spiraling heart-disease rates was the modern diet of processed foods, which lack three B vitamins—folic acid, vitamin B6, and vitamin B12—that hold the amino acid homocysteine in check. Studies have shown that too much homocysteine in the blood correlates with an increased risk of heart disease. Denounced at first, the idea is catching on. Other researchers say rising rates of obesity and insulin resistance, linked to increased consumption of refined carbohydrates, are better predictors of heart disease than high cholesterol.

So why does the lipid hypothesis continue to hold so much sway? “There is prestige and money at stake,” contends Ravnskov, and much of it flows from the cholesterol-lowering class of drugs known as statins. Ravnskov does not dispute studies that show statins can lower the risk of heart disease, but he contends that they do this by a different mechanism from simple cholesterol reduction and says the drugs can cause severe side effects. Ravnskov and other critics of the lipid hypothesis argue that a vitamin and/or unprocessed-food regimen for keeping homocysteine levels low has no special interests to promote its utility.

“Obesity may soon cause as much preventable disease and death as cigarette smoking,” says former surgeon general David Satcher, and statistics back him up: About 300,000 deaths a year are associated with excess body fat (as opposed to roughly 400,000 from cigarette smoking). Clearly, endless exhortations to eat less and exercise more aren’t working in our increasingly wealthy and sedentary society. We are, after all, end products of a long evolution in which the anthropoid who gobbled the most chow and wasted the least energy was most likely to survive. The stuff-and-sit reflex may therefore be hardwired, leading at least some researchers to seek new solutions.

“Drugs are the future of treatment for obesity,” proclaims Richard Atkinson, president of the American Obesity Association and director of the Medstar Obesity Institute in Washington, D.C. “Diet and exercise haven’t worked for 50 years. Obesity fits the criteria for a chronic disease, and we don’t have any chronic disease that is not treated with drugs.”

What about gastric-bypass surgery? “Surgery works, and it’s the short-term answer for the next five or 10 years. But the question is, why does it work?” says Atkinson. “It is not because it creates a tiny gastric pouch that fills up quickly. Research shows it is far more complicated than that.” The surgery, he says, changes the body’s biochemistry, a process that is not well understood. Because surgery is expensive and risky, Atkinson says the goal is clear: “We need to develop a drug that does the same thing.”

There are already three classes of antiobesity drugs: adrenergic agents, which boost catecholamine levels to reduce appetite and enhance the sensation of being full; a combination adrenergic and serotonergic system that also inhibits serotonin reuptake; and lipase binders, which inhibit the body’s ability to absorb fat. All work, but not well enough. One drug can usually drop body weight by only 10 percent or so, Atkinson says.“We need to get more weight loss than that, but that’s going to be hard to do.”

Regulating food intake is one of the most primitive functions relating to survival, so the body has many redundant mechanisms that stimulate appetite and maintain body fat. “If you knock out one, others take their place, which is why we will need to use drugs in combination,” Aktinson says. He points out that users of fen-phen, a combination of fenfluramine and phentermine, achieved an impressive 18 percent average weight loss, but the now infamous tendency of fenfluramine to cause heart-valve lesions led manufacturers to take it off the market in 1997 in response to an FDA request.

The ultimate answer will most likely spring from unraveling obesity’s genetic source, and that will be difficult. “More than 250 genes and gene markers are involved with obesity, so there are obviously many different kinds,” Atkinson says.

And the story may turn out to be odder than anyone expected. “Obesity is exploding,” says Atkinson. “Researchers at the National Institutes of Health are saying we have never seen anything like this except in the case of infectious disease. Duh. We have been saying for five years that viruses cause obesity in animals, and we are just now getting our papers published in journals.” Atkinson says he and fellow researchers have found a human adenovirus that, when injected into chickens, mice, and monkeys, makes them fat. “And when we look at people who have antibodies to this virus, they are heavier. Somewhere between 20 percent and 30 percent of the obese people in the United States have antibodies to this virus,” which means they have been exposed to it.

Atkinson concedes that the virus-makes-fat theory is radical and has yet to be fully tested in the laboratory. “Until we can sort it all out,” he says, “it will be a long time before physicians can do anything to treat obesity but give it the old college try.”

Other diseases claim limbs or organs; Alzheimer’s devours the self, making it one of the few afflictions widely regarded as being worse than death. And it is on the rise. The progressive, degenerative brain disorder afflicts an estimated 4 million Americans and could strike 14 million by 2050. Memory and thinking go first; eventually, loss of brain function causes death.

Many researchers believe that the culprit is a surfeit of specialized enzymes that split off too much of a protein called amyloid beta peptide. These fibrous peptides glom on to healthy neurons to form amyloid plaque, making them weaken and die. The tendency to crank out the enzymes in excess is most likely genetic, which may be why Alzheimer’s tends to run in families.

Drug companies are vigorously seeking chemicals to block the enzymes, but whether that is the best therapeutic route is by no means certain. “Everybody is gung ho on this amyloid hypothesis, but it’s still just a hypothesis,” says Franz Hefti, an Alzheimer’s researcher and executive vice president for development at Rinat Neuroscience Corporation, a biotechnology company specializing in neurological-disorder drugs. “It could be part of the disease process, or it could be a sort of sideshow of the disease process.” A competing theory, Hefti says, holds that the growth of neuritic “tangles,” linked to specific proteins called tau proteins, is the primary cause, with the wayward peptide-splitting enzymes simply an offshoot.

“These are big questions, and the pharmaceutical industry is literally spending billions to get at the answers,” says Hefti. From the perspective of baby boomers slouching toward 65—about the age when the most common form of Alzheimer’s starts to manifest—it is money well spent.

Aging is the ultimate disease—everyone is born with it, and the survival rate is zero. Lifestyle changes can modify life span, but genes appear to set the upper limit. “It is gene expression that allows our bodies to undergo what we think of on a wholesale level as aging,” says Michael Fossel, editor of the Journal of Anti-Aging Medicine. Good genes no doubt explain why, despite smoking cigarettes for some 90 years, Frenchwoman Jeanne Louise Calment died in 1997 at 122 years of age, the longest life span yet recorded.

So can this limit be challenged? Instead of stretching life span within the framework of biomechanical aging, will we break the frame itself? “Can we arrest aging now? No,” says Fossel. “Do we have good reasons to think it can be arrested? Yes.” Fossel believes the first viable antiaging therapy will target telomeres, which are repeating DNA sequences at the ends of chromosomes. Each time a cell divides, some of the telomere is lost. When the telomere becomes too short, the cell can no longer function and dies. An enzyme called telomerase can elongate chromosomes after each division, theoretically making a cell immortal, but only fetal tissues, adult germ cells, and tumor cells use telomerase—in normal body cells, the stuff is virtually undetectable. “I think the most effective point of intervention will turn out to be telomerase,” says Fossel. By manipulating it, he says, “we can now show that you can prevent, or even reverse, aging with individual cells in vitro.”

Using the enzyme to slow aging in a whole human body will be tricky, he concedes. “Whenever you want to intervene in medicine, you have to ask yourself: Why did nature do it that way in the first place?” Fossel says the most likely reason for our cells’ finite life span is preventing “wholesale, unrestricted growth”—in other words, malignancy.

Another possible antiaging gambit may involve copying 13 specific genes from a cell’s mitochondria and transplanting them into the nucleus, where they would be protected from free-radical damage. “That’s a major undertaking,” Fossel admits. “That makes fooling with telomerase look like child’s play.”

So what, realistically, is the outlook? “It’s possible that 100 years from now, people could look back and say we really haven’t made any progress at all,” he says. “But my bet is that we will look back and say, ‘Right around 2005 or so, that’s about when we started to really alter the aging process.’”

Chop off a starfish’s arm or a salamander’s tail and the doughty little creature will promptly start growing a new one. A wounded zebra fish can regrow almost anything it loses, including skin, bone, joints, nerves, arteries, veins, muscle, eyes, spinal cord, and heart.

Human beings, however, have limited regenerative powers, which is bad news on several fronts. Not only is a severed arm lost forever, but the inability to regenerate robustly is the underlying cause of many cardiovascular and neurological disorders. A wide variety of conditions that affect human adults, with the notable exception of cancer and infections, could be aided if we could stimulate regeneration, argues Mark T. Keating, a professor of cell biology at Harvard Medical School.

“Actually, humans can regenerate to some extent,” he says. “We can regenerate skin and blood and the tips of digits, and we can regenerate the liver big time—you can remove half of a liver and it grows back.” Keating thinks we may have evolved this way because primitive humans suffered cuts and scrapes and damaged their livers eating questionable foods. “There was a great survival advantage to regenerating these elements,” he says, that was worth the metabolic cost.

Today’s maimed or paralyzed human beings would happily convalesce in bed for a few months to regrow lost parts if it were possible. The key to stimulating regeneration, Keating believes, will be inducing cells to undo their differentiation, the process by which a single cell becomes hundreds of distinct tissues such as muscle, blood, bones, and brain. Organisms like zebra fish readily dedifferentiate cells near the injury, undergoing a cellular age regression in which “they form something like stem cells, although they are not quite the same as stem cells,” says Keating. “Those cells are the source. They give rise to the daughter cells that the organism needs.”

Just what triggers the cells surrounding a zebra fish’s injury to start dedifferentiating is unknown, but Keating says regenerative therapy for human beings will in some circumstances involve transplanting stem cells to the injured area. “There are also molecular therapies. There’s already a drug called Epogen that increases the formation of red blood cells by your own stem cells,” he says. Keating guesses that an effective medicine that induces some degree of regeneration “will happen in 15 to 20 years, perhaps.” Regenerative medicine, he says, is a “cool, growing field. I am positive that a therapy will happen, but I’m not positive how long it will take.”

Marauding microbes continue to inhabit, sicken, and too often kill human beings. The rise of modern, deadly plagues such as AIDS and SARS is particularly devastating because the “golden age of immunization during the last half century gave us a sense of triumphalism about infectious diseases,” says Stephen S. Morse, a Columbia University biologist and cofounder of ProMed, a global program for monitoring emerging infectious diseases.

Some of that pride is justified. Immunization keeps measles, polio, diphtheria, and dozens of once-dreaded diseases at bay and actually eradicated smallpox entirely. Even now, immunization works remarkably well. “There is no evidence that immunizing whole populations leads the pathogen to evolve and make your immunization suddenly worthless,” says Morse. But antibiotics are a different story. “Dump antibiotics in a test tube and you quickly select for any bacteria that has some resistance. Now the whole world is a test tube into which antibiotics and antivirals are being dumped, and we simply may not have them on demand in the future as these microbes become increasingly resistant.”

The future of treating infectious diseases may turn to thwarting their mechanisms rather than killing the bugs, Morse says. One victory: Gilla Kaplan, now a researcher at the Public Health Institute in Newark, New Jersey, found that the drug thalidomide—banned in 1962 after it was linked to severe birth defects—could reduce inflammatory responses and might be valuable in managing HIV, tuberculosis, cancer, and autoimmune diseases such as lupus. “If we can disarm disease mechanisms, we’ll have a real therapeutic tool,” Morse says.

But in the meantime, the threat remains real and perhaps more worrisome than at any point in the last 50 years. “We are reaching the point of diminishing returns in our armament,” Morse says. “There is reason to be concerned.”

In 2000, 10 million people worldwide developed malignant tumors, and 6.2 million people with cancer died. By 2020, 15 million people could be afflicted, according to the World Cancer Report.

How many of these people will die? Some kinds of cancer, such as of the skin or the breast, already have relatively high cure rates, and as techniques improve, those rates should get better. But former American Association of Cancer Research president Tom Curran, a neurobiologist at St. Jude’s Hospital in Memphis, says two research themes hold the promise of actually vanquishing cancer altogether.

“The first theme is individuation; that is, an appreciation that cancer is many, many diseases,” he says. As researchers dig into the genetic basis of cancer, they will decode its signaling pathways—the chemical messages cancer cells send to other cells. “In the future, instead of telling someone, ‘You’ve got liver cancer,’ we may say to that person, ‘Your cancer is a defect in the ras pathway and in p53 signaling, so you need these compounds that are effective for those pathways,” Curran says. Tailoring the treatment to the specific cancer could make cure rates soar.

The other theme is the advent of targeting therapies. For decades, anticancer chemicals have been “basically poisons,” according to Curran. “The idea was that the poison would kill cancer cells faster than it would kill normal tissue.” In recent years, however, Curran says, research has gravitated toward nontoxic drugs that attack specific signaling pathways. The most prominent example so far is the drug sti571, known as Gleevec, which in a recent clinical trial put an amazing 53 out of 54 patients with chronic myelogenous leukemia into remission.

“It surprised a lot of people that it worked,” says Curran. “It raised hope in a lot of people, but it wasn’t an easy victory. That therapy was based on 30 years of fundamental research.”

The most hopeful fact in cancer research, in Curran’s view, is that “the genome is finite. There is a finite number of signaling pathways that work together to promote normal growth, so there is a finite number of things that can go wrong and give rise to a tumor.” But he concedes that the process of uncovering all those errant pathways, and learning how to suppress them, will take researchers many years.