When Bad Bugs Go Good

By Alice Park

Like a seasoned burglar, the virus circles a human cell looking for the easiest point of entry. Within seconds, it has broken into its target, located the nucleus and deftly slipped its genetic material into the cell's DNA. Now whenever the cell divides to copy itself, it also makes copies of the interloper. Soon those multiplying viruses have hijacked not just that cell but also all its neighbors, turning them into one massive virus factory. When the cells can no longer make the proteins they need to survive, they start, one by one, to die.

And that's exactly what Dr. Stephen Russell was hoping for. A cancer specialist at the Mayo Clinic, Russell does everything he can to aid and abet those viral bandits. He arms them with detailed instructions for finding their target cells and outfits them with specially designed protein keys to speed up entry. As far as he's concerned, those viruses are the good guys, since the cells they are attacking and destroying are cancer cells in a fast-growing tumor.

In labs like this around the world, bad bugs are undergoing the ultimate rehabilitation, being transformed from life-threatening viruses and bacteria into lifesaving therapeutic agents. Using the tools of molecular biology, researchers like Russell are disguising and manipulating common microbes so that they will do good instead of harm. After all, nothing is better than a virus at evading the body's immune defenses and breaking into a cell. And nothing is better than a bacterium at producing deadly toxins that destroy a cell from the inside. "We can make a good anticancer agent," says Russell, "by harnessing and channeling these destructive powers."

The bad-bug--good-bug strategy was championed by doctors treating allergies and infectious diseases. The idea was to expose patients to small quantities of partly disabled microbes to jump-start their immune system. But cancer researchers have taken the approach one step further, turning microbes into tiny Trojan horses that can sneak into tumor cells and destroy them from within. "There is a good probability that microbe approaches will be part of the arsenal of the future," says Kenneth Kinzler, a cancer researcher at Johns Hopkins Hospital's Kimmel Cancer Center who is working with the clostridium bacterium. "We're betting on it."

Until quite recently, that wouldn't have been a smart bet. The idea of harnessing microbes to do a doctor's bidding flourished briefly in the 1960s, during the early days of the genetic revolution. Scientists sketched out grand plans for treating disease by adding or removing genes taken from bacteria or viruses. Because they were so good at penetrating cells, infectious agents seemed the ideal vehicles for delivering drugs. Some cancer patients were treated with experimentally modified viruses, and a few even saw their tumors shrink. Too often, however, scientists lost control of their microbial partners. "It wasn't possible at the time to engineer them to make them more specific," recalls Russell. "When they did work, there was a price to pay. The tumors were cured, but the patient died."

Forty years later, scientists know a lot more about genes and proteins and how to target microbes so that they home in on one particular kind of cell--a cancer of the ovary, for example, or a tumor in the throat. They have also learned to affix molecular tracking devices to a microbe to ensure that when let loose in the body, it doesn't deviate from its therapeutic mission.

The ideal microbial ally, say scientists, is one that already infects humans and yet can be easily controlled with antibiotics or antiviral medications should something go awry. For his research, Russell likes the measles virus, in particular, the modified strain of the virus used for more than five decades in the measles vaccine. That weakened form has a special fondness for tumors, lured there by a protein expressed in copious quantities on the surface of malignant cells. As part of an ongoing trial in ovarian-cancer patients, Russell's colleague Dr. Eva Galanis constructed a measles virus that could also churn out a protein that can be picked up in the blood, allowing the investigators to measure how well the virus is working. The final results of their trial won't be available for another year or so, but the strategy appears to be working. Russell and Galanis are also targeting brain tumors and have designed a measles virus that recognizes a mutation often found in brain-tumor cells but never in normal ones.

Of course, a virus has to reach its target to destroy it, and that means surviving the defensive armies of a formidable opponent: the immune system. "Blood is a pretty hostile environment for the viruses," notes Russell. "The name of the game is to dodge the immune defenses for a few hours and give the viruses enough time before the immune system gets in and stops them." His group is perfecting two approaches: 1) temporarily distracting the immune system with drugs that suppress it and 2) cloaking the virus in a protective protein coat that renders it invisible to immune cells.

Other bug-based therapies for cancer take advantage of the body's natural response to invaders. To this end, scientists at the Texas Medical Center have enlisted the aid of the Epstein-Barr virus (EBV). More than 95% of the population is infected with EBV, a usually benign microbe that sequesters itself in the immune system's B cells. Like any other cellbound virus, EBV doesn't remain dormant for long, dividing furiously and emerging in runaway viral mobs. But unlike most other viruses, EBV is quickly eliminated by the vigilant immune system's killer T cells.

The Texas scientists wondered whether they could take advantage of that existing defense system and use the transformed B cells as cancer alarm bells. By customizing EBV-infected B cells with proteins specific to certain cancers, they could grow killer T cells in the lab that are trained to fight those specialized B cells. The T cells would then be able to find and destroy malignant cells as if they were just another cell infected with a virus.

To make that work, the researchers needed huge quantities of EBV. That wasn't a problem, since the infected cells grow abundantly in culture. "You can get bucketloads of them," says Cliona Rooney, an immunovirologist at the Texas Medical Center. Rooney's group modified EBV-infected cells to wear a protein that is shared by three different types of cancer--a devastating form of throat cancer as well as Hodgkin's disease and non-Hodgkin's lymphoma, both cancers of the lymph system. Using separate culture dishes of those cells for each patient, she added T cells extracted from each patient's blood and selected just the ones that homed in on the viral and cancer proteins. Those specialized T cells were then injected back into patients, giving their defenses a boost of reinforcements. "We have seen some remissions in all three groups of patients," Rooney reports. "We are working on ways to make our approach more potent and useful for other types of cancer."

Viruses are not the only microbes being rehabilitated for good works. Following the lead of the millions of Botox devotees who regularly benefit from injections of one of the world's deadliest toxins--botulinum--scientists at Johns Hopkins were inspired to look more closely at the botulinum-producing clostridium family. They matched one of the bacterium's unique features--it flourishes under low-oxygen conditions--with one of a malignant tumor's most vexing characteristics: it continues to divide extremely well with little or no oxygen. "The trick to using bacteria or viruses therapeutically is to have them exploit something unique to the cancer cell," says Kinzler, who is co-directing the studies. Kinzler and his colleague Bert Vogelstein have altered the clostridium to replicate only in the oxygen-starved depths of a tumor. Once there, the bacterium's natural toxins are released and quickly eat through the malignant growth. So far, the scientists have tested their therapy only in mice, but the results have been impressive.

Meanwhile, scientists at Vion Pharmaceuticals in New Haven, Conn., have been experimenting with another bacterium, salmonella, and another way of destroying a tumor from the inside out. Salmonella is a familiar but unwelcome interloper in kitchens and at picnics, thriving in uncooked meats and other food products such as eggs. Once in the blood, its surface coat can trigger septic shock, a hyperaggressive immune response that can lead to liver and kidney failure and a dangerous drop in blood pressure. Confined to a tumor, however, the bacterium could be a potent cancer killer. Like the measles virus, salmonella zeroes in naturally on tumor cells. "If an animal has a tumor, that tumor is salmonella's favorite place to go," says David Bermudes, director of microbiology at Vion. With a simple change in the bacterium's genome, the Vion team and Yale scientists were able to give salmonella the ability to convert a powerful compound found naturally in the body into a toxic chemotherapy agent. In a small pilot study conducted at the Mary Crowley Medical Research Center in Dallas, 2 of 3 patients given the modified salmonella showed signs that the chemotherapy agent was active. "It's a proof of principle that the strategy is working," says Bermudes. While his team seeks a partner to continue these studies, Vion is sufficiently convinced of the promise of bacteria-based therapies that it holds patents on potential cancer treatments from three more bacteria: listeria, streptococcus and shigella.

We may need all those microbes if the bad-bug approach turns out to be as successful as early trials suggest. Like AIDS cocktails and cancer chemotherapies, microbe-based therapies may require a multidrug approach. For example, combining the modified clostridium bacterium, which attacks a tumor at its anaerobic core, with the altered measles virus, which destroys the periphery of the tumor, could be a potent new way to fight cancer. Add some radiation or chemotherapy to mop up any lingering cancer cells, and doctors could find themselves closing in on a cure.