The Wall Street Journal - October 18, 1999
Ron Winslow, Robert Langreth and Michael Waldholz of The Wall Street Journal

Making such predictions, of course, is a hazardous business. After all, back in the early 1970s, when the nation launched the "War on Cancer," scientists were sure they would have the disease beat by the end of the century. Here we are, and the disease remains the nation's second-leading killer.

But, caveats accepted, a revolution in molecular biology as well as important new advances in a wide array of current medical therapies and technologies foreshadow sweeping changes in the treatment, diagnosis and prevention of major diseases.

One hope, of course, is that these advances will significantly improve the fortunes of people once they are sick with major symptoms of heart disease, cancer and other maladies, making their treatments more effective, less invasive and, perhaps, less costly. Another is that new discoveries in genetics and in our basic understanding of the molecular processes that lead to illness will pave the way for new techniques to determine who is at risk of developing serious diseases and to develop more-effective strategies to prevent their consequences.

Indeed, some scientists believe we are on the threshold of a new era when new genetic maps will provide people with personal profiles of their medical risks and information on how to live healthier lives. For those who get seriously ill anyway, doctors will be armed with new information on how to tailor treatments to the biological needs of individual patients, significantly enhancing the effectiveness of care.

Here is a disease-specific look at some of these advances and their potential implications for patients:

Heart Disease

Each year, more than 1.5 million Americans undergo coronary angiography to take X-ray pictures that check for obstructions in the coronary arteries that could lead to heart attacks.

Now, researchers are on the verge of making it possible to use magnetic resonance imaging instead to inspect the coronaries. Such an advance would be less invasive and less expensive, researchers say, and would amount to a fundamental change in cardiology's most common major procedure.

Angiography, in which a catheter is inserted through an artery in the groin and threaded into the heart, is best for detecting deposits called plaques that obstruct, say, 70% or more of the blood vessel. These deposits may cause pain, but they are much less likely to cause heart attacks than smaller, more volatile plaques whose danger isn't apparent when viewed with angiography.

MRI, or MRA, for magnetic resonance angiography, as it's being called, looks directly at the walls of the artery. The hope is it will help doctors detect life-threatening plaques and prescribe treatment before they cause heart attacks.

On other frontiers, several companies are in a race to determine whether gene therapy and related techniques can be used to promote the development of new blood vessels in the heart and enable patients to grow their own bypasses around obstructed vessels.

Cardiologists are also hopeful that delivering doses of radiation directly to the coronary arteries will be soon be approved as a way to improve the effectiveness of tiny metal devices called stents that are used to prop open diseased arteries. For some patients, arteries with stents reclog in the weeks after treatment, and radiation appears to stanch that tendency.

Robotics are destined to help surgeons make heart surgery more patient-friendly, And heart pumps, which help patients with severe congestive heart failure survive until a heart transplant is available, are advancing in trials to see whether they can enable patients to skip the transplant altogether.

Meanwhile, a flurry of new research into the causes of atherosclerosis, the underlying cause of heart disease and strokes, may lead the way to new drugs to prevent diseased arteries from causing life-threatening events.

None of this research, however, diminishes the importance of patients heeding the known risk factors for cardiovascular disease. Quitting smoking remains the fastest way to reduce risk from heart attacks, while lowering so-called LDL, or bad, cholesterol proved so effective in recent trials that heart experts may recommend even lower treatment goals in a coming review of national cholesterol guidelines.

Cancer

The war on cancer has quietly moved into high gear, as major drug and biotechnology companies rush to test a treasure trove of gene-based cancer treatments that are expected to be far more powerful and far less toxic than anything tried before.

If the new drugs work, researchers say, they could dramatically improve the patient survival rate for many cancers that have for years been resistant to new treatments. Some of the drugs could help turn cancer into a chronic disease that, although still hard to cure outright, can be lived with for years.

The new medicines are the product of decades of research on tumor genetics and biology. They aim to attack cancer in radically different ways than the standard chemotherapy or radiation. Existing mainstay medications assault all cells, causing severe, even lethal, side effects. But the new drugs home in on the machinery inside tumors that allows them to grow rampantly.

Companies are taking at least three different approaches. The first idea involves targeting the mutant genes that regulate tumor growth. These gene mutations occur as molecular typos accumulate in a person's DNA over many years; enough gene mutations eventually overcome the molecular machinery that stops cells from unrestrained growth.

One such drug has already been approved -- Herceptin, from Genentech Inc., South San Francisco, Calif. It's aimed at the one-third of breast cancers in which a gene called HER-2 plays a big role. Drugs against another gene, EGF receptor, are in human testing at AstraZeneca PLC of the U.K., Pfizer Inc., New York, and other companies. These drugs could help against breast, prostate, lung, and head and neck cancers. Merck & Co. of Whitehouse Station, N.J., Johnson & Johnson of New Brunswick, N.J., and New York-based Bristol-Myers Squibb Co. are testing drugs against a third gene, RAS, that is involved in colon, lung and pancreatic cancers. Researchers plan to target many more cancer-causing genes over the coming years.

The second thrust aims not at the cancer cells themselves, but at their blood supply. The idea is to starve large tumors by blocking the blood vessels they need to grow. Despite wide publicity last year over one such treatment that eradicated tumors in mice, many drug-industry scientists say the blood-vessel-blocking medicines are unlikely to cure cancer outright in humans.

Instead, they are more likely to simply prevent further tumor growth, and perhaps make the tumors more susceptible to chemotherapy. Companies testing anti-blood-vessel drugs in humans include Genentech, Warner-Lambert Co. of Morris Plains, N.J., and Pharmacia & Upjohn Inc., Peapack, N.J.

Other scientists are looking to prod the immune system into ambushing and killing cancer cells. They are designing a variety of so-called cancer vaccines, which despite the name, will be used to treat the disease, not to prevent it in healthy people. A few of these vaccines are now in advanced human testing.

Alzheimer's Disease

Very few treatment options exist now for Alzheimer's disease. The few drugs that are available only temporarily alleviate symptoms.

But there is a glimmer of hope that the situation will change over the next decade or so. A new class of drugs that aims to halt the long and fatal decline of brain cells should enter human clinical trials soon. These drugs block telltale protein clumps called plaques from accumulating in the brains of Alzheimer's patients.

Still, the outlook isn't as promising as it is for cancer because, unlike cancer, the causes of Alzheimer's disease are still a matter of controversy. The leading theory holds that so-called amyloid plaques that crowd the brains of Alzheimer's patients actually cause the ailment. Much circumstantial evidence supports this view -- in particular, patients with certain rare gene mutations that cause them to produce large amounts of the protein usually get the disease at an early age.

Several major drug companies, led by Bristol-Myers Squibb, are now racing to test plaque-blocking pills. Another company, Ireland's Elan Corp., plans to soon begin human tests of a vaccine that keeps laboratory mice from developing plaques. But there's no proof the plaques actually cause the disease. And it will be years before anyone knows whether the antiplaque drugs work.

In the meantime, some researchers argue that biochemical processes other than plaques may be more responsible for the disease. One theory targets "tangles" of a hair-like protein called tau that clog up neurons in Alzheimer's patients. Drug-industry research on tangles is at an earlier stage, but it may also be possible to come up with drugs to prevent tangles.

Yet another theory connects Alzheimer's disease -- and possibly tangles -- to a gene called APO-E. People with a certain version of this gene have a much higher risk of developing the disease. By unraveling how this gene works, researchers at Glaxo Wellcome PLC in the U.K. and at other companies believe they can eventually devise powerful anti-Alzheimer's medications.

Finally, a number of existing drugs may prove beneficial in treating the disease. In particular, Merck has begun two large clinical studies to see if its Cox-2 inhibitor, Vioxx, for arthritis, may slow the progression of the disease or delay its onset. And researchers at American Home Products Corp., Madison, N.J., and other companies are studying whether estrogen-replacement drugs can prevent or even treat the disease.

AIDS

The medical battle against AIDS will very likely be waged for many more years -- perhaps for decades or even longer -- as scientists struggle to solve one of the most perniciously puzzling viral diseases ever.

As is well-known by now, medical therapy based on combining three and four different types of relatively new and powerful drugs has revolutionized the treatment of AIDS in the U.S. and other developed nations. Since early 1996, when the drug "cocktails" were introduced, the annual death rate from HIV, the virus that causes AIDS, has plunged almost 70%. Once a near-certain death sentence, an HIV infection now can often be stopped from causing lethal illnesses, though doing so requires adherence to one of the most demanding and expensive medicinal regimens ever created, consisting typically of six to 20 pills a day that may have to be taken for a lifetime.

"The development of the new anti-HIV drugs is one of the truly remarkable medical advances of recent times," says Joep Lange, an AIDS researcher at the University of Amsterdam. "But to defeat this virus, we must do much more, and I believe we must do it soon."

That's because research now suggests that, despite early hopes, the new drug combinations don't seem quite strong enough to eradicate every last particle of HIV from the body. Even healthy HIV-infected people in whom the most sensitive diagnostic test can't detect the virus still seem to harbor a minuscule bit of it. When drug therapy has been stopped for some long-treated patients in experimental trials, the virus has typically re-erupted, though in a few patients the returning virus seems to be kept in check without resuming the drug therapy. In instances where patients did resume therapy, the virus was quickly driven once more to levels below detection.

Still, the discovery that some tiny amount of HIV can hide within certain human cells where they are able to withstand even the most powerful daily drug bombardments has frustrated scientists seeking to vanquish the virus. At a recent scientific conference, New York researcher David Ho challenged drug companies to work harder, arguing that these hard-to-reach, "drug-resistant" infected cells may yield only to even more powerful drugs and drug combinations.

The growing understanding that an HIV infection may last forever is persuading several major drug makers and numerous academic researchers to step up efforts to come up with new medicines to defuse the virus. Sales of HIV drugs will soon top $2 billion a year world-wide, making it one of the largest and most lucrative prescription-drug categories. As a result, Glaxo Wellcome, Merck, Abbott Laboratories of Abbott Park, Ill., Bristol-Myers Squibb, Roche Holding Ltd. of Switzerland and many biotech companies are racing like never before to tap into this large and growing HIV market with numerous new efforts to design stronger versions of existing medicines, as well as drugs that work in totally new ways.

But it's likely that even the most creative efforts under way may never match the virus's tenacity. That's mainly because of two characteristics that set HIV apart from almost every other virus known to cause disease and death. For one, HIV infects and cripples the immune system, the very army of defense that, in most cases, eventually drives a viral infection out of the body. In addition, the virus mutates often into robustly dangerous versions, meaning that even under blistering attack from the new drugs, the virus eventually produces strains of itself that are resistant to the drugs and can spread as well as the virus's so-called wild type.

"Emerging resistance is one of the greatest challenges we face now and may face for as long as we try to beat back the virus with drugs," says John Mellors, a University of Pittsburgh AIDS researcher.

This prediction has especially disturbing implications for fighting HIV in sub-Saharan Africa and Asia, where it's spreading most ferociously. Few of the 27 million infected people in the developing world can afford the drug cocktails. And infectious-disease experts fear that even if the drugs are made available by reducing prices, the eventual rise of drug-resistant strains in poorer nations may be more difficult to handle than in the U.S., because identifying and countering the mutant strains is very expensive. That would create a crisis even worse than exists now, especially if such drug-resistant strains spread back into the developing world.

Indeed, it's now evident that despite the remarkable innovations of drug-making scientists, the fires of HIV will burn world-wide until major advances are made in prevention and, most especially, the discovery of a truly protective vaccine.

Only recently have some of the developing nations embraced large public-health education programs to teach people how the virus spreads and how best to avoid it. But even there, the countries must counter deeply ingrained sexual behaviors and entrenched cultural traditions that have helped spur the spread of disease.

And while several experimental vaccines are being tested in the U.S. and overseas, many researchers agree that modern science still hasn't figured out how to stimulate an immune response powerful enough to overwhelm an HIV infection. "I am absolutely convinced we will figure out how to eradicate existing infections and, more important, how to protect people with a vaccine," says Dr. Ho of New York's Aaron Diamond AIDS Research Center. "But there is simply no way to predict right now when that will happen."

Infectious Diseases

It's the accepted gospel these days among infectious-disease experts that the bugs will always find a way to outsmart the drugs.

Despite all the advances medical science has made over the past five decades in creating powerful antibiotics and other medicines against bacteria, viruses and other disease-causing microbes, mankind continues to be plagued by persistently pervasive germs that cause illness and death -- often by outwitting even the most aggressive efforts to keep them at bay. Indeed, in recent years, largely as a result of the aggressive use of existing antibiotics, there is a rising epidemic in the U.S. and other developing nations of drug-resistant bacterial and viral infections.

As a result, drug-making scientists are now engaged in one of the most active efforts ever to design new ways to treat infectious diseases.

"Antibiotic resistance is something everybody predicted, but we've been surprised, nonetheless, by the size of the global problem that's been emerging in the past decade," says John Bartlett, an infectious-disease specialist at Johns Hopkins University in Baltimore. "It's clear we have to create better medicines and better manage our use of existing drugs."

Dr. Bartlett and others say the rise in resistant bacteria is due largely to two developments expected to continue to grow in coming years. One is the increasing use of new and powerful drugs in the U.S. and elsewhere. Under attack from these drugs, bacteria often mutate into forms never seen before that are invulnerable to existing treatments. Such resistant strains are commonly the cause of hard-to-treat ear infections in the U.S. that now account for more than 20 million doctor visits a year. These infections require use of expensive and potent drugs -- which merely increases the likelihood that the bugs will seek out even newer and more troubling versions. Public-health experts also report rising numbers of drug-resistant pneumonias and skin and blood infections. Another troubling trend is the rise of resistant bacteria in hospital intensive-care units, where doctors are treating an increasing number of frail and elderly people for illnesses, such as cancer and heart disease, that in the past simply killed people outright. These people often have weakened immune systems that provide fertile environments for bacteria that don't otherwise thrive in healthier people.

Again, under pressure from existing drugs, these organisms often mutate into dangerous infectious agents that are easily spread by health-care workers or on equipment that isn't vigilantly sterilized. That's why about 20% to 30% of serious infections acquired by patients while in hospitals aren't susceptible to existing medicines. Treating these and other serious hospital-acquired infections may add $5 billion a year to the nation's health bills, according to government studies.

"There was a time, back in the early to mid-1980s, when many experts in this field believed we had infectious diseases under control," says Gary Tarpley, head of drug discovery at Pharmacia & Upjohn. "We now know we have a great deal more to do."

Dr. Tarpley's company and a host of others are testing a slew of new antibiotics designed to attack bacteria in ways that differ from existing drugs. At a recent scientific conference on infectious diseases, scientists presented dozens of reports of new drugs or newer versions of older medicines that companies began developing several years ago as concerns about resistance began to grow.

Companies such as Philadelphia-based SmithKline Beecham PLC, Pharmacia & Upjohn, Merck and Pfizer are just now beginning to explore new ways to fight off germs by using knowledge gleaned from the same gene-hunting technologies that are allowing researchers to decode the human genome.

"One of the most promising areas right now involves deciphering the genetic code of microbes and looking at their structure for new ways of attacking the microbes," says Marty Rosenberg, a research executive at SmithKline Beecham.

In the past few years, scientists have begun unraveling the genetic makeup of germs, such as the ones that cause syphilis, malaria and tuberculosis, as well as common bacteria that are causing such widespread problems in hospitals. "If we find new drugs, and we are pretty optimistic we will," says Dr. Rosenberg, "it will come from these new efforts. There is a great deal of incentive for the drug companies to fund this effort."

Diabetes

Diabetes researchers are hopeful that fresh knowledge about how the immune system works will help them reach a long-sought goal: the ability to transplant insulin-producing islet cells into the pancreas.

For patients with type I diabetes, who lack the ability to produce insulin, an islet-cell transplant would be tantamount to a cure. They wouldn't need frequent injections of insulin to maintain blood-sugar levels. But because human islet cells are difficult to harvest, and because the potential supply of human cells would never meet the demand, transplant research has focused on pig islet cells. The human immune system is especially vigilant against tissue from other species and has frustrated scientists working with diabetes.

Recent advances, however, have led to optimism that rejection can be overcome, and human experiments are expected to begin soon. "Everybody has their fingers crossed," says Richard Kahn, chief scientific and medical officer for the American Diabetes Association in Alexandria, Va. "It would be like having a new pancreas. You would be producing your own insulin."

Meantime, a new generation of drugs is reaching the market geared to those with the type II version of the disease, whose ability to use insulin to process sugars is impaired. The drugs, known as thiazolidinediones, or TZDs, act on a receptor that helps overcome resistance to insulin and restore its effectiveness. Though Warner-Lambert's TZD, Rezulin, has been hurt by evidence of liver side effects, scientists hope that competing TZDs, including SmithKline Beecham's recently approved Avandia, will prove less troublesome.

Other research is aimed at understanding more about what promotes or blocks the action of a receptor for insulin in the hope that new drugs might then be designed to make it work better. In addition, growing understanding of the brain's role in metabolism, diet and obesity -- one of the most important risk factors for diabetes -- is expected to lead to new treatments.

But what might yield the most benefit is new research into ways to help diabetics follow strict diets and other regimens that studies show are crucial to controlling the disease. "A major barrier to effective treatment is changing patient behavior," says Dr. Kahn. "We know so little about what tricks you can use to change it."

Making progress against diabetes is taking on new urgency amid surveys showing that Americans on average are getting fatter and more sedentary. Some 16 million Americans are diabetic and at risk of the disease's devastating late-stage complications: amputations, kidney disease and blindness. Of particular worry is a recent rise in type II diabetes among adolescents, reflecting an increase in the number of "fat, sedentary kids," says Dr. Kahn. "It's frightening."

Stroke

Researchers at the University of Pittsburgh recently began a novel experiment to implant stem cells -- which give rise to all the body's kinds of cells -- in the brains of stroke patients in a bid to coax growth of new nerve cells and improve patients' chances of recovery.

While initial reports are encouraging, it is likely to be several years before scientists know whether such sci-fi techniques will translate into real medicine that helps patients recover from the nation's leading cause of disability. For now, however, the 750,000 Americans who suffer strokes each year already have the most important piece of medical technology available: the telephone, for dialing 911.

Current clot-busting remedies are critically dependent upon a patient arriving at the hospital within three hours of the onset of symptoms -- and only about 2% of stroke victims make it to the emergency room in time. At least three drug companies are in the final stages of testing new compounds intended to enable the brain to withstand longer periods of decreased blood flow, but this is a difficult problem. Earlier versions of these so-called neuroprotective agents proved disappointing when tested for effectiveness beyond six hours after a stroke begins.

Even with the new agents, "the time window may be measured in maybe three to six hours," says Mark Alberts, a neurologist and director of the stroke acute-care unit at Duke University Medical Center in Durham, N.C.

This underscores one of the big challenges stroke poses for scientists and drug companies seeking to develop advanced treatments: Patients and their families must be aware of what the symptoms are (sudden weakness or numbness in the face, arm or leg; sudden dimming or loss of vision; slurring of speech; unexplained severe headache; unexplained dizziness) and call for help immediately when they occur. And then rescue squads and emergency rooms must be prepared to respond as urgently as they do for heart attacks.

Another challenge is to juggle the need to keep blood running thin in patients at high risk of an ischemic stroke -- caused by a blood clot -- without increasing the chances of bleeding in the brain. For people who have already had symptoms, such as minor strokes called transient ischemic events, researchers are looking at combining various anticlotting drugs to come up with the most effective recipe, Dr. Alberts says.

On another front, some doctors believe that stents -- tiny metal scaffolds widely used to prop open coronary arteries -- might be effective in preventing strokes. The National Institutes of Health is poised to begin a study comparing stents with a surgical procedure called carotid endarterectomy that is widely used to clear obstructions in the carotid artery in people at high risk to prevent a stroke from occurring.
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