In 1918, the writer Mary McCarthy, then just six years old, boarded a train in Seattle, bound for Minneapolis— and orphanhood. Her parents contracted influenza on the train, and a day after they arrived in Minneapolis her mother died. Her father followed the next day. The flu killed at least 20 million people that year, more than 1 percent of the world’s population, more than even AIDS has killed.
Influenza still claims more than 20,000 lives in the U.S. each year, but it’s only one of many fearsome viruses. HIV and hepatitis B and C cause hundreds of thousands of deaths worldwide, and viruses have been linked to several cancers. Even the virus that causes the common cold can kill infants and the elderly. And hanta and Ebola suggest that new and horrible microbes will arise in the future. This is particularly frightening because, unlike bacterial infections, medicine has never cured a viral illness.
That may be about to change. Last year, Elizabeth Zolowicz and her daughter Jacqueline got the flu. “Both of us were lying in bed with really high fevers, 103 or 104,” Elizabeth recalls. “My son turned on the TV, and there was a little blurb about a study being done for a flu medication. So I called.”
Elizabeth and her daughter had been sick for a day and a half when they took the experimental drug, called a neuraminidase inhibitor, made by pharmaceutical giant Glaxo Wellcome. “Twenty-four hours later, or even less, we were up and walking around,” Elizabeth recalls. Their fevers plummeted, their appetites returned, and their energy rebounded. “It’s a great drug with no side effects,” says Elizabeth, who usually reacts badly to medicine. “I want to see it on the market quick.”
In fact, Relenza, as the drug is called, will probably be in pharmacies in time for next year’s flu season. Glaxo applied for approval by the Food and Drug Administration last month, and the drug is expected to sail through. It cut the duration and severity of the illness by about a third, with hardly more side effects than a placebo. Moreover, test-tube studies show the drug is active against all known strains of influenza— including the mysterious avian flu that arose in Hong Kong last year.
What countless mothers have told their children— that there’s nothing to be done for a viral illness except to rest and drink lots of fluids— is becoming obsolete. The massive research effort against HIV has resulted in 14 approved drugs that target the AIDS virus, slashing death rates in the developed world. But the lay public thinks of HIV as a special case: The powerful protease inhibitors that turned the tide against AIDS were featured on the cover of Newsweek, lavishly photographed like celebrities. But
the only thing special about them is that they paved the way for other antiviral drugs. Indeed, a new protease inhibitor is about to enter human trials, but it doesn’t target HIV. It works against the cold virus. That’s right, there’s a protease inhibitor being developed for the common cold.
Welcome to the age of antivirals. Glaxo’s flu drug is being followed by a similar compound marketed by Roche Labs, and a small company called ViroPharma is expected to win approval within a year for a highly regarded drug that targets enterovirus (the cause of summer flu), ear infections, and viral meningitis, a nasty illness that leads to excruciating, two-week headaches. This drug, called Pleconaril, also appears highly potent against some strains of polio and against almost all variants of rhinovirus, the cause of most colds. Farther back in the pipeline are still other medicines that look promising against rhinovirus, as well as hepatitis B and C, Epstein-Barr, CMV, and even Ebola. Back in 1990, only six drugs targeting viruses other than HIV were in human trials, according to the Pharmaceutical Research and Manufacturers of America. By 1996 there were 25, and this year there were 31.
Impressive as those numbers are, they only hint at the potential. Far more auspicious is that there are now tried-and-true strategies for targeting almost any virus. These strategies aren’t easy— nothing in biology ever is— and there are limitations, such as drug resistance and the tough, wily nature of some viruses, such as HIV, that may never be cured, only held in check. Still, says Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), “as we enter the new millennum, it’s going to be a great era for the development of antiviral drugs.”
Such optimism was echoed by more than a dozen researchers in government, academia, and industry. “When I was a medical student in the late ’60s and early ’70s,” says Stephen Straus, a leading virologist at NIAID, “the people interested in studying antiviral drugs were involved in such esoteric, out-of-the-way, unpromising niches that no one thought their work would amount to anything.” As it turned out, the effort to cure viral illnesss has shed new light on many fundamental areas of biology, thus contributing far beyond the harvest of new treatments.
Viruses, which consist of only a few genes sheathed in protein, exist in a twilight zone between the animate and the inanimate. By themselves they are inert, unable to replicate. But inside a cell they become energetic parasites, exploiting the host’s chemicals to churn out copies of themselves. Viruses are so dependent on cells, explains Catherine Laughlin, a top virologist at NIAID, that “for a long time the dogma was that antivirals weren’t possible, because anything that kills the virus also kills the cell.”
Enter molecular biology, the study of living things at their most elemental level: molecules and atoms. In the last few decades, scientific advances in dozens of fields have allowed biologists to isolate, define, and manipulate the atomic structure of viruses and cells— which, in turn, has enabled them to identify specific viral targets and to design drugs that disable the virus while leaving the host cell largely unharmed.
The first success came from understanding exactly what viruses do: In order to replicate, they commandeer the cell’s building blocks of RNA and DNA. That gave a few pioneering drug designers an idea: Maybe they could create a decoy for these building blocks, one that the virus would use but the cell wouldn’t. The decoy would gum up the viral machinery while leaving the cell unimpaired.
Something even more impressive happened with acyclovir, which fights herpes and was one of the first effective antiviral drugs. Researchers knew the molecular structure of “nucleosides,” the building blocks of RNA and DNA, and so they made thousands of very subtle variations, called analogues. Finally, after testing thousands of these variants, they hit the jackpot: a decoy that operates only in infected cells. Amazingly, one of the virus’s own enzymes activates the drug, which then paralyzes the virus and kills the infected cell.
That was the first so-called “nucleoside analogue,” and discovering it won a Nobel Prize for the lead researchers (one of whom, Gertrude Elion, had almost abandoned science for secretarial school because laboratories rejected her job applications on account of her gender).
The first five HIV drugs, including AZT, were all nucleoside analogues, and this approach is still yielding success. Bristol-Myers Squibb, for example, has a nucleoside analogue in early human trials that appears extremely potent against hepatitis B, a sometimes fatal virus that is linked to liver cancer. But there’s a newer, more powerful strategy for finding antiviral drugs.
Siegfried Reich, director of medicinal chemistry at Agouron Pharmaceuticals, is wearing faded jeans, a shirt open at the collar, and oversized spectacles like people use at 3-D movies. He’s using them to view a picture that, to drug designers, is more exciting than anything Steven Spielberg could ever create: the three-dimensional atomic structure of the protease enzyme of HIV.
Using the same state-of-the-art computer that Hollywood employs to make special effects, Reich can rotate the enzyme to see it from any angle. As he turns the huge molecule (a mostly green entity that, floating on a black background, looks like an asteroid in outer space), it reveals its “active site.” That’s the part of an enzyme that carries out its biochemical function, and in the case of HIV protease, it looks like a tunnel boring all the way through the enzyme. Having an atomic, three-dimensional model of the protein allows scientists to design a compound that plugs the tunnel.
Working the computer like a video game, Reich flies into the cavernous active site. “That’s a water molecule,” he says, freezing the image and magnifying it. “That’s important. It’s pinned down really well— it’s got two hydrogen bonds from the protein, and it donates two.” Agouron designed its drug, called Viracept, to adhere to the two powerful hydrogen bonds donated by the water molecule, thus helping to ensure that the drug would stick securely in the tunnel. They also sculpted their drug so that its physical shape conforms very closely to the contours of the tunnel. The closer the shapes match, the tighter the drug will bind to the enzyme, and the more potent the drug will be.
This is called “structure-based drug design” because it allows pharmaceutical scientists to create drugs that match the atomic structure of almost any viral protein. Pharmaceutical chemists tailor molecules to bind to the shape and chemical properties of the active site, adding, for example, a sulphur molecule here or a few carbon molecules there.
It sounds easy, but it’s not. To obtain the three-dimensional structure of a viral protein, for example, scientists must crystallize it, which allows them to take its picture with X rays. But crystallizing a protein can take years, and some proteins have foiled every effort. Then, some proteins— such as the protease enzyme of hepatitis C— just don’t offer a good binding site, forcing scientists to start all over with a different enzyme.
Even when an effective compound is created in the test tube, “you’re only 10 percent down the road,” says Agouron’s head of research, Michael Varney. He ticks off a few of the properties a drug must possess, over and above potency: It should not be toxic. It should stay in the body long enough that patients don’t have to take it more than a few times a day. It must be simple enough to manufacture cheaply and reliably. Each of these gives drugs a chance to fail. Varney chuckles wryly and says, “These are really, really difficult problems. You realize, the longer you’re in it, how hard it is.”
But it’s worth the effort. The death rate for AIDS has dropped by almost half in the U.S., largely because of protease inhibitors like Agouron’s. And in the first full quarter that Viracept went on the market, Agouron’s sales went from zero to $43.5 million.
Even if the new antivirals were panaceas— and they’re not— they wouldn’t be available where they’re needed most: in the Third World, where respiratory and diarrheal viruses still kill millions of children every year. Only now, four decades after Jonas Salk effectively ended polio in the United States, is it finally being eradicated from Africa and Asia. And the polio vaccine requires only one dose, not many pills over weeks or months.
Even for First World citizens, the drugs have limitations. The neuraminidase inhibitors must be taken within 36 hours after the onset of flu symptoms, or they have little effect. That could be a problem, explains Jacob Lalezari, a San Francisco physician and researcher who has tested Glaxo’s Relenza. “When the flu hits,” he says, “that’s exactly the time you don’t want to go to a doctor’s office. People generally just lie around and get grumpy.”
William Haseltine, a former Harvard virologist who now runs the biotech company Human Genome Sciences Inc., calls microbes like flu, polio, and measles “hit-and-run” viruses. They do their damage very quickly and are usually easy to transmit, because if they don’t keep jumping to other people the immune system will wipe them out. “But there’s a whole second category of viruses that act more slowly,” Haseltine explains. These viruses, which typically cause only low-level disease or, like HIV, no disease at all for years, possess “a hundred tricks to get past the immune system.”
That’s a problem, because antiviral drugs need the immune system, since they don’t actually kill viruses. They merely block replication, relying on the immune system to eradicate the virus from the body and cure the patient. But, explains Straus, “if the virus’s strategy involves long periods of hide-and-seek, where it sits there and does nothing, those are really difficult.” Herpes simplex, for example, lies dormant inside of nerve cells. Every once in a while, for reasons that are not understood, it will begin replicating. But as long as it stays quiet, says Straus, “we don’t have the foggiest idea of how to get that virus out of your system. It might as well be your gene. You’re not born with it, but you acquire it.” To keep such viruses in check, patients would have to take medication for years, perhaps for life, which raises the specter of severe long-term side effects, which many HIV patients are now encountering.
Finally, the viruses won’t just sit there and take it. “No matter what you treat with,” says Richard Colonno, head of drug discovery for infectious diseases at Bristol-Myers Squibb, “you’re going to deal with resistance. Your drugs become obsolete.”
Viruses like HIV, which persist for years even in the face of drugs, have the most opportunity to evolve drug resistance. But many of the hit-and-run viruses are also highly mutable. Both Glaxo and Roche say they haven’t identified a patient who developed viral strains resistant to their new flu drugs— but such strains have been created in the lab, so most researchers believe it’s only a matter of time before they evolve in the real world.
Of course, pharmaceutical companies know all about resistance— and even see a market opportunity in it. “It’s like antibiotics,” says Douglas Richman, a prominent virologist at the University of California at San Diego. “We’re going to be developing drugs for resistant virus, and better drugs. But just like with antibiotics, as fast as we go, we’ll still be behind. Big pharma isn’t going out of business.”
Even with all these caveats, Straus maintains, “I’m an optimist.” In his early days as a researcher, herpes was a life-threatening illness for some people with impaired immune systems. “I watched them die,” Straus recalls. But one of his patients was lucky enough to start acyclovir, which saved her life. She’s been taking that drug for 18 years, and it’s keeping herpes at bay so effectively that the disease is “a non-issue in her life.”
Such dramatic successes fuel Straus’s belief that “we will be able to control classes of diseases that were uncontrollable when most people on the planet were born.” He notes that in this century, medicine and public health have nearly doubled life expectancy for Americans. Though antivirals “won’t do that again,” he says they will extend the life span and improve the quality of life. “What we’ve gotten to,” he says, “is being able to treat not only life-threatening diseases, but merely annoying ones that interfere with everyday life.” The new antivirals will “take some of the wrinkles out of the normal human situation.”
Inevitably, consumers will demand convenience. Certain viruses, like the flu, need to be treated immediately, so pressure might mount for some antivirals to be licensed as over-the-counter drugs, allowing people to buy protease inhibitors for the cold the way they currently buy NyQuil. That would certainly boost pharmaceutical profits, but it could squander the benefits of the new drugs, argues Stuart Levy, a leading expert on antibiotic resistance. Without a doctor’s prescription and guidance, many people would not use the drugs properly, and, says Levy, “this misuse will result in strains resistant to these drugs.”
Agribusiness is what worries Peter Colman, an Australian researcher who played a pivotal role in developing the flu drugs. Poultry get infected by influenza, so will farmers use the new drugs to protect their flocks? Already, massive amounts of antibiotics go to protecting animals and fish from bacteria, but that has greatly accelerated the development of bacterial drug resistance. “It’s important that we reserve antiviral drugs for use in man, as antibiotics should have been,” insists Colman. Harvard virologist Clyde Crumpacker agrees, saying, “We have to regard antiviral drugs as a precious treasure.”
Haseltine is convinced that science can beat resistance, rejecting the consensus that microbes are always one step ahead of our drugs. “They’re not,” he says flatly, pointing out that companies such as his own have uncovered many new targets for viral and bacterial drugs. Whether or not Haseltine’s exceptional optimism is warranted, the development of antiviral drugs marks a seminal achievement, and he situates it in the sweep of medical history.
“Up to now,” Haseltine explains, “we have done best with diseases that originate outside our own bodies. Indeed, the first advance was to recognize that there is a distinction, that tuberculosis, for example, is different from cancer.” Discovering that some diseases are infectious allowed for a host of control measures, from clean water to vaccines to antibiotics. Bacteria proved to be easy targets for drugs because they diverged from humans more than 2 billion years ago, so their biology has become very different from that of human cells. Cancer, on the other hand, is usually caused by our very own cells going awry, so blocking the workings of cancerous cells often means interfering with the normal function of human cells, which explains why cancer chemotherapy is so toxic. Because viruses co-opt our own cells to do so much of their dirty work, they exist in a fascinating middle ground between diseases caused by external agents and diseases caused by our own cells.
That’s why the scientific knowledge of viruses may prove even more important than the immediate therapies. “Designing drugs that interfere with viruses and the cellular processes they co-opt,” explains Straus, “provides us with exactly the tools to resolve genetic diseases and cancers.” If he’s even partly right, that would complete a historical circle, because many of the advances against viruses stem from Richard Nixon’s war on cancer, and its scientists, who believed that cancers were caused by viruses. It turns out that most cancers aren’t viral, but to understand how viruses work, biologists have been forced to learn how our own cells work.
And so viruses, those curious entities that are neither alive nor dead, may well provide the bridge between the greatest medical advances of the past and those of the future.
Research assistance: Meredith Yayanos