CELL SUICIDE THE BIRTH OF A MEGA-MARKET
(FORTUNE Magazine) – For 11 lonely years cell biologist L. David Tomei toiled away in the Columbus labs of Ohio State University, exploring a process known as apoptosis--programmed cell death, in which the body divides dying cells into packets that are then consumed by neighboring cells. Persistence was not unusual for Tomei: Growing up in Buffalo in a family headed by a passionate Italian American father and a stubborn Polish American mother, he had so wanted to be around scientists that he took a job cleaning rat cages at the Roswell Park Cancer Institute. In Columbus, Tomei felt on the verge of discovery, possibly of a novel way to treat cancer. But the rest of the world was unconvinced. Government entities refused to fund his research, and Ohio State fired him in 1992.
Undeterred, the former rat janitor threw his belongings into his 1962 Lincoln Continental, made for San Francisco, and founded a company, LXR Biotechnology, to pursue the promise of apoptosis (the second "p" is silent). Now, three years later, apoptosis looks to be the richest drug vein struck in the two-decade history of biotech. Unlike the one-hit discoveries that buoyed biotech companies in the past, apoptosis research affects a whole range of maladies and drugs. Says Peter F. Drake, an analyst at Vector Securities International in Deerfield, Illinois: "Apoptosis changes the platform of biotech drug development by extending it across a variety of diseases."
Medical scientists around the world are rushing to harness cell suicide to new ways of treating cancer, AIDS, heart disease, and the degeneration of the brain, as in Parkinson's disease. Other possible targets include rheumatoid arthritis, multiple sclerosis, and stroke. Some new drugs are already in clinical trials in human patients, and bold investors are betting on some of the small, publicly traded biotech outfits conducting those trials. That kind of optimism has helped make David Tomei, who took his company public in May 1994, a rich ex-professor.
Apoptosis is a surprise in more ways than one. Scientists had long assumed that all cells die an ugly death. In necrosis, as the more familiar process is called, cells burst like punctured bags, releasing toxic components into the body and causing inflammation (see diagram). Necrosis results from insults such as severe burns or big doses of radiation or toxic chemicals. Apoptosis, on the other hand, is a more gentle process of cell suicide, first described by Australian pathologist John Kerr and two colleagues in 1972. A professor they knew chose the name, which is Greek for the way petals fall from flowers and leaves drift from trees. One scientist likens necrosis to the blow of a sledgehammer and apoptosis to the brush of a feather: There is no inflammation in apoptosis, no triggering of the immune response, no harmful effect on the body.
Why should cells be programmed to die? Cell death is essential, even in fetal development. Nature supplies a lot more cells than an embryo needs. The superfluous cells eliminate themselves; otherwise we would all be monsters with webbed feet, miswired and misshaped brains, and tails--residues of an evolutionary past. Instead, programmed cell death orders an organism's development, reshaping fetal hands and feet from paddles into fingers and toes, eliminating unneeded cells in the growing brain and other organs. Says Walter Eckhart, director of cancer research at the Salk Institute in La Jolla, California: "In this altruistic process, life and death are intertwined: The death of the cell promotes the growth of the organism."
In a healthy adult, apoptosis is business as usual. Our bodies contain more than a trillion cells, as many as there are stars in the Milky Way. Day after day the body must remove and replace hundreds of millions of those cells. The average person, for instance, makes 100 million new white blood cells every day. So 100 million existing cells must die. Otherwise, you get leukemia, characterized by an excess of white blood cells.
Any beach bum has seen the effects of apoptosis in the peeling of skin after sunburn. A skin cell whose genetic blueprint, its DNA, is damaged by ultraviolet radiation is either repaired or, if the damage is too great, recycled via apoptosis. Such control ensures that a mutated cell cannot proliferate; otherwise, skin cancer and other malignant tumors would be much more common.
When apoptosis is interfered with, disease results. Cancer, for example, not only triggers signals for cells to proliferate but also blocks apoptosis. Says Walter A. Blattler, senior vice president for R&D at publicly traded ImmunoGen in Cambridge, Massachusetts: "Cancer cells no longer know how to die."
That's a brand-new insight into the nature of cancer. "It's a revolution," says Allen Oliff, executive director of cancer research at Merck. "Understanding the apoptosis mechanism for killing cancer cells, which has really come about in the past two or three years, has changed how we think about developing cancer drugs."
While cancer blocks apoptosis, AIDS embraces it like a necrophiliac. The latest evidence shows that people develop AIDS when the human immunodeficiency virus (HIV) sets off unregulated and untimely apoptosis in crucial defenders of the immune system known as CD-4 and CD-8 cells. Sending chemical signals that find the cells throughout the body, HIV persuades more and more of them to kill themselves, until AIDS triumphs.
There you have it: Restore programmed cell death in cancer, or block it in AIDS, and you've discovered, potentially, a new method of treating killer diseases. So why, until recently, was apoptosis about as popular among mainstream medical scientists as cold fusion is among conventional physicists?
For one thing, cell death didn't seem all that interesting or important. Lab scientists, for the most part, want the cells in their experimental cultures to live, not die. They literally failed to see apoptosis. "When apoptosis occurs," says Alison Taunton-Rigby, CEO of Cambridge Biotech in Worcester, Massachusetts, "basically, the cells just disintegrate. It happens very fast and leaves no records. So people didn't realize it was happening." Indeed, medical textbooks published as recently as 1992, the year David Tomei lost his job, failed to mention apoptosis.
Then came a dramatic change. In the past few years cancer researchers in Australia, Israel, and the U.S. found that many newly discovered cancer-causing genes do their damage by suppressing apoptosis. Since restoring cell death would undo the work of these genes and, potentially, stop cancer itself, apoptosis moved to the forefront of drug development.
One result of that discovery: Humbled cancer researchers suddenly realized that many of the drugs they had developed to slow cancer didn't work as they had imagined. "Everyone previously thought that cancer therapies killed cells primarily by interfering with their ability to replicate their DNA," says Merck's Oliff. "It turned out that many of the current therapeutics actually do it by inducing apoptosis and have relatively modest impact on DNA synthesis. We're now looking for drugs that directly promote apoptosis."
More than 20 companies have joined the hunt for apoptosis-related drugs, from biotech startups to pharmaceutical powers like Glaxo and Marion Merrell Dow. They aren't deterred by the fact that much remains to be learned. Researchers know the general outline of how apoptosis works, but they are still trying to decipher the molecular details of the process.
Doing that is one of two approaches companies are exploring. Meanwhile, some firms are working to refine existing drugs now known to influence the cell suicide program. Says MIT biologist H. Robert Horvitz: "There's a whole world to be explored for pharmaceutical development. No one has touched it." What could result is medications to cure the major diseases of our time.
CANCER. Today's principal treatments--radiation and chemotherapy--are sharply limited in effectiveness because they indiscriminately kill both cancerous and healthy cells. Cancer patients can die of infections when the treatments destroy so-called stem cells in the bone marrow that give rise to white blood cells to fight off bacteria and viruses.
In an effort to save the healthy cells while killing off the leukemic, Receptagen, a public company based in Edmonds, Washington, and British Columbia, is adapting a therapy that worked spectacularly in the past but was judged too unwieldy for widespread use. Back in the early 1960s, Australian scientists showed that depleting cells of vitamin B12, a vital component in the production of cellular DNA, blocked the growth and proliferation of leukemia. When patients inhaled a mixture of nitrous oxide and oxygen, the gas deactivated their B12. As a result, the leukemic cells died, while those important white blood cells were unaffected.
But there were drawbacks: The patients, all children, had to wear soft plastic bubbles on their heads to breathe the gas, and live four weeks at a stretch in a sterilized hospital chamber. Not surprisingly, the therapy never caught on.
Enter Receptagen, 30 years later. The company has microminiaturized the Aussie therapy. Using man-made antibodies, it blocks the receptors, or docking ports, for vitamin B12 on both healthy and leukemic cells. Result: The leukemic cells commit suicide; the white blood cells just stop growing. Stop the treatment, and the healthy cells start growing again. Receptagen is testing its drug in mice that have been implanted with human immune systems, in preparation for clinical trials in people. This time patients won't need plastic bubbles and an isolation room; Receptagen plans to sell its formula in pills.
A different attack against cancer involves replacing damaged or deleted genes that induce apoptosis. Under particularly close scrutiny is the so-called p53 gene, which plays a crucial role in helping the body repair jumbled DNA but which is either damaged or missing in most cancerous tumors. When present and healthy, p53 acts as a kind of biological proofreader, checking DNA for errors. If the misprints it finds can be fixed, p53 stops cell development and supervises the repair. If the genetic code is scrambled beyond repair, p53 sets off the cell suicide program, thus defending the organism against cancer.
Even when cancer does occur, p53 is still at work within the tumor. A major reason for the paradoxically slow growth of many tumors--and the occasional complete disappearance of a tumor--is high cell loss through natural apoptosis. Usually, though, the "founder cells" of a tumor, those with deficiencies in their suicide programs and high rates of growth, prevail.
Four companies--Onyx Pharmaceuticals of Richmond, California; Canji Inc. of San Diego; and Apoptosis Technology and Mitotix Inc. of Cambridge--are beginning to succeed at drug treatments involving p53. Mitotix, for instance, has found that restoring to cancerous cells a protein made by p53 induces widespread apoptosis. Normal cells appear unaffected. Canji researchers have shown in rats that p53 gene replacement leads cancer cells to commit suicide. Last December the company received contingent approval from the government to treat liver cancer in humans by locally injecting a harmless virus carrying intact p53 genes. Schering-Plough will conduct the clinical tests, scheduled to begin early next year.
Other outfits, including privately held Titan Pharmaceuticals of Menlo Park, California, aren't relying on p53 to launch apoptotic attacks on cancer. Titan subsidiary Ingenex, for example, has developed a drug that goes after a potent cancer-causing gene, called Rb. Preliminary tests show that the drug slows tumors by unlocking the apoptosis mechanism controlled by Rb. Ingenex's sister company, Ansan, is testing a drug derived from butyric acid, a nontoxic natural compound found in milk and cheese. Early results suggest that the compound induces apoptosis in leukemia, melanoma, and lung cancer, and the company hopes to start testing its drug on humans this summer.
Merck is taking yet another approach to using apoptosis to control cancer. The company is homing in on an enzyme that activates a cancer-causing gene called Ras. When the enzyme mutates, it creates a defective protein that sends out repeated signals instructing the cell to proliferate. That kind of uninhibited growth can result in widespread cancer. "It's like a switch that's stuck in the 'on' position, and we've been trying to find ways to prevent that from happening," says Oliff. So far, Merck scientists have learned to turn off the switch in mice, thus allowing the reemergence of apoptosis. Merck hopes to start tests on patients within the next two years.
Some anticancer apoptosis research has already moved into clinical tests. Ligand Pharmaceuticals of San Diego, whose stock is traded on Nasdaq, is giving advanced cancer patients pills or injections that deliver retinoid compounds. Retinoids, synthetic versions of vitamin A, promote apoptosis in cancer cells. (Yes, retinoids are related to Retin-A, the popular skin cream used by teens to combat acne and by adults to smooth wrinkles.)
AIDS AND OTHER VIRAL DISEASES. ImmunoGen's Blattler believes that one of the most alluring markets for drugs that employ apoptosis may be in fighting viral infections. "This is a very big, promising field," he says. "There are few good antiviral drugs today. The drugs are toxic and not very effective because drug designers could not take advantage of the specific way viruses work. But now those mechanisms are becoming clear. The new drugs will have fewer side effects."
One key target, obviously, is AIDS. HIV "succeeds" by overwhelming its victims' immune system, priming the body for infections that often prove fatal. Researchers now know that apoptosis is HIV's secret weapon. The virus uses cell suicide to prematurely destroy white blood cells that would otherwise defend the system.
The virus is so lethal it doesn't even have to enter cells to kill them. Scientists believe that HIV may send chemical signals that stimulate apoptosis in previously uninfected immune system cells.
Once again, Receptagen is refining an existing medication: a drug for people suffering from congestive heart failure that has been on the market in Japan and Europe since the early 1980s. It helps regulate cell activity by switching a particular enzyme on and off. When on, the enzyme helps generate a cell fuel known as ATP. Without sufficient ATP, the white blood cells of HIV patients cannot drum up enough energy to fight off apoptosis signals sent by the virus.
In a recent clinical study, Receptagen gave seven AIDS patients a form of the drug. After a six-week treatment, six of the patients showed an increase in the number of protective white cells. Receptagen is now expanding its clinical trials.
Other antivirus treatments are equally promising. Some companies are taking on herpes and adenoviruses, which cause such maladies as conjunctivitis and colds. These viruses transform cells into viral factories. They insert their DNA into the cells' nuclear machinery and use it to make millions of copies of viral particles.
The body uses apoptosis as a defense mechanism against such viral infections. But, like cancer cells, the viruses neutralize the ubiquitous p53 "proofreader" gene so that it can't initiate cell suicide. Many viruses produce a special protein for the job that locks on to the gene like an anti-car-theft bar that clamps onto your steering wheel.
That kind of clamp is a welcome target for companies looking to use apoptosis against viral infections. Apoptosis Technology, an ImmunoGen subsidiary in Cambridge, is focusing on the cytomegalovirus (CMV), which most people carry but suppress with a healthy immune system. Unregulated CMV can cause extensive tissue damage. Most at risk are AIDS patients, as well as recent recipients of organ transplants, whose immune systems are weakened by drugs taken to prevent transplant rejection. Apoptosis Technology hopes to develop a drug that will unlock the viral clamp on apoptosis, thus destroying CMV-infected cells.
HEART DISEASE. Cardiac cells, like brain cells, are made to last a lifetime. They normally don't divide; when healthy, they keep their suicide programs shut off. Disease and shock, however, can turn on the programs; for example, cells deprived of oxygen after a heart attack release signals that induce apoptosis in cells through part of the organ. Worse yet, when blood flow is restored through balloon angioplasty or the administration of clot-busting drugs, the shock of the renewed flow can kill still more cells.
Using apoptosis blockers, David Tomei's LXR Biotechnology is approaching the treatment of heart attacks in a completely new way. Says Tomei: "We can go in there and, rather than wait for the cells to die, we can deliver drugs to the heart that will block the cell death." His company is trying to do so with rixosane, a drug currently used to protect the hearts of breast cancer patients during chemotherapy. LXR is conducting animal tests to show that its version of rixosane can prevent cell death after a heart attack. Another of the company's drug candidates, LXR15, may extend the lives of organs destined for transplants. Using this insoluble compound derived from soy flour, LXR hopes to preserve hearts for 24 hours, vs. the two or three hours possible now.
AUTOIMMUNE DISEASES. The body teaches a particular type of protective cell to differentiate "self" (normal body cells) from "nonself" (foreign invaders such as bacteria and viruses). But not all of these so-called T-cells learn their lessons well. Autoimmune diseases such as rheumatoid arthritis and multiple sclerosis result when a tiny percentage of uneducated T-cells attack the body's own tissue.
In a landmark discovery in 1991, National Institutes of Health (NIH) scientist Michael Lenardo found that these outlaw cells die via apoptosis when exposed repeatedly to distinctive proteins, called antigens, that such T-cells would normally attack. Explains Leonard Bell, CEO of privately held Alexion Pharmaceuticals in New Haven: "You can intravenously treat a patient with a drug that contains the antigen, and it will delete those T-cells." This is like throwing poisoned meat into the ocean to attract sharks.
Alexion scientists are using the procedure to create a drug that fights childhood diabetes, rheumatoid arthritis, and multiple sclerosis. The company calls the novel antigens it plans to develop "apogens," short for "apoptosis-inducing antigens." Its multiple sclerosis apogen has already succeeded in slaughtering outlaw T-cells in trials done on animals. While Alexion's approach will not reverse damage already done by MS, it could prevent progression of the disease--which is a lot more than any conventional therapy can offer. Clinical trials are planned at NIH early next year. NEURODEGENERATIVE DISORDERS. Apoptosis may help destroy the brain cells of people afflicted by strokes or diseases like Alzheimer's, Huntington's, and Lou Gehrig's. The death of such cells can be devastating, since like the heart, the brain normally creates no new cells to take up the slack.
Scientists at the Marion Merrell Dow Research Institute in Cincinnati are working on drugs that would wipe out what senior scientist Matthew D. Linnik calls "poison pill" enzymes that push brain cells toward suicide. He and his team are focusing first on the acute neuronal death that causes stroke. They hope eventually to apply similar drugs to slower forms of apoptosis, like the chronic degeneration of neurons that takes place in Parkinson's and Alzheimer's diseases.
Katherine Gordon, CEO of privately held Apollo Genetics in Cambridge, is taking a different approach: using estrogen implants to stall apoptosis and keep brain neurons alive. Explains Gordon: "As the brain ages, many hormones become largely depleted. Neurons become more vulnerable to damage and death." She notes one surprising result from a study of older women who took estrogen supplements: The incidence of Alzheimer's was severely reduced. "Our drug will not rejuvenate Alzheimer's patients," says Gordon, "but it should stabilize that rate of decline." Her first drug is for women only, but other anti-Alzheimer's drugs in the pipeline at Apollo Genetics are gender blind.
AGING. No, we're not suggesting that understanding apoptosis is your ticket to the Fountain of Youth. Indeed, most scientists find no direct link between aging and cell suicide. Unlike apoptosis, the aging process does not seem to be controlled by a genetic program we can manipulate.
Nevertheless, a recent experiment at UCLA did extend the lives of middle-aged mice by 25% by blocking apoptosis. Why should we care? Tomei and Philip J. Barr, who heads up LXR's R&D division, point out that one sign of aging is a loss of control over apoptosis. Healthy senior citizens continue to use cell suicide to turn back disease; less healthy elderly let pile up defective cells that a younger organism would have eliminated.
Aging may remain beyond our control--but the close correlation with apoptosis suggests just how much cell suicide functions as the body's quality-control mechanism, and why this sophisticated gene system is the latest, greatest thing in biotechnology.
Of course, wary investors may think they have heard such optimism from this industry before. And if David Tomei's experience is any guide, investing in companies that focus on apoptosis may be another roller coaster ride. When LXR Biotechnology went public, the stock shot up, making Tomei, his CFO brother, Mark, and Barr paper millionaires. But then David Blech, a major industry investor, was forced to restructure his biotech holdings. LXR's stock, like that of many firms known as "Blech companies," plummeted. Suddenly, Tomei's stake was worth less than it was on the day the company went public. The stock has rebounded only slightly since then. Tomei isn't complaining, though--he figures investors will be back as apoptosis drugs move closer to America's medicine chests.