Medicine Versus Microbes

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By Patricia Nicholson

Dr. Michel Bergeron has a formidable adversary. As founder and director of the Infectious Disease Research Centre (IDRC) at Laval University in Quebec City, he’s up against the world’s number 1 killer. Infectious diseases, Bergeron says, account for about one-third of worldwide mortality. That’s 17 million deaths every year from bacteria, viruses, fungi and parasites.

Bergeron attended medical school at Laval, then completed his specialty in internal medicine at McGill University and the Montreal General Hospital. From there, he went to Massachusetts in the early 1970s, where he worked with world authorities on infectious disease and microbiology: Dr. Salvador Luria — a Nobel Prize winner for his work on the replication mechanism and genetic structure of viruses — at MIT (Cambridge, MA); and Dr. Louis Weinstein, PhD — a pioneer in infectious diseases who was one of the first doctors to warn against over-prescribing antibiotics — at Tufts University (Boston, MA). He returned to Laval University in 1974.

“I came here and there was no one in infectious disease, so I started alone and I’ve built up slowly,” Bergeron says. “My objective was to build a team that could cover many of the aspects of infectious diseases so that people could interact.”

The IDRC is now the biggest such centre in Canada, and enjoys an excellent reputation at home and abroad. Bergeron heads a 250-person multidisciplinary team, with expertise in chemistry, physics, microbiology, molecular biology, genomics, proteomics and even plant biology. The centre is also active in clinical trials, for both its own discoveries and for drug companies.

The IDRC’s research falls under three main categories: prevention, diagnosis and treatment.

Preventive Medicine

“Prevention is very important for me because I believe prevention is the solution of the future,” Bergeron says, explaining that it is often cheaper and easier to prevent disease than to treat it.

In order to prevent infection, one must understand how it works. One of Bergeron’s critical areas of study is microbe versus host interaction.

“On the one side you get the microbe, on the other side you get the host,” he says. “Disequilibrium between the two is what causes disease. So in our lab we have experts that work on both sides.”

Some of the key microbes that Bergeron’s team is investigating are viruses, including HIV, herpes and respiratory viruses that cause flu and pneumonia. But the centre is also working on parasites.

“One parasite that causes infection in 15 million people in the world is leishmania,” Bergeron says. He describes leishmania as a beautiful model for the study of malaria and other diseases that infect over a billion people worldwide. “That’s why we work with it, because it’s hard to work with malaria because there are no animal models.”

By better understanding how a microbe invades and how a host defends itself, Bergeron is developing what he calls preventative tools, such as vaccines. Some of the vaccines the centre is currently working on include HIV, hepatitis and leishmania.

HIV is a challenging virus to vaccinate against, Bergeron says, because it is difficult to develop antibodies that can kill HIV. So his team’s strategy is to boost the immunity of the host.

“We modify the HIV virus and we combine it with protein from other agents. And what we’re using are plant viruses,” he says. “We’re combining it with protein of the papaya virus.”

This is a unique approach, as is another pathway that Bergeron’s team is investigating: combining HIV with part of the leishmania parasite.

“I believe this approach will work out because it’s a logical approach that’s never been taken,” Bergeron says. “Leishmania goes into white blood cells. So we’re using a leishmania that doesn’t cause disease in humans, but can stimulate immunity, can stimulate your antibodies. So by combining both — part of the protein of the HIV virus and leishmania or the HIV virus with papaya, for example — we’ve shown it can boost immunity. We don’t have a vaccine yet. But it’s a very interesting and original pathway we’re taking right now.”

Protective Measures

The IDRC’s preventive medicine is not limited to vaccine development.

“There are different ways to prevent disease. Vaccine is one way. One other way is to give people the possibility to protect themselves,” Bergeron says. “What I’ve developed in my lab, in the last 10 years, is a way to protect women against STDs. I’ve developed a microbicide which I call the Invisible Condom™.”

The platform technology is a thermo-reversible polymer gel that is a liquid at room temperature, and at body temperature becomes a gel that is very adherent to mucosa. It is the basis of one of two companies that have spun off from the IDRC’s research: Gealth Prévention Inc. (St-Foy, QC).

“It kills microbes and it’s (also) a spermicide,” says Josée Fortin, president of Gealth. “So women would be protected against STDs including HIV, and also unwanted pregnancy.”

Gealth drew its name from a combination of the words “gel” and “health,” and from its goal of targeting prevention rather than treatment.

“Our Invisible Condom offers both physical and chemical barriers. The physical is because it covers the entire vagina, so it blocks the microbes. And the chemical barriers will kill the microbes, and sperm as well,” Fortin explains. “Moreover, it’s colourless, odourless and tasteless, and it’s totally imperceptible to the partner.”

Gealth and the IDRC, with input from engineers and designers, created a novel applicator for the gel to ensure effective delivery.

The product has proven highly effective in animal models and has already completed a small Phase I clinical trial at the IDRC.

A much larger trial will begin within the next few months. That study will take place in Africa, and will involve up to 5,000 women from high-risk populations.

Fortin says she is optimistic about launching the Invisible Condom by 2007.

Definitive Diagnoses

For Bergeron, diagnostics are an important area of prevention. As a clinician, he quickly realized that one of the biggest problems in treating infectious disease is the difficulty in determining which microbe is causing the problem. Several different bacteria can cause similar symptoms, and those symptoms are again similar to those caused by some viruses, which are untreatable with antibiotics. It usually takes two days or longer to get culture results, so the doctor must often take action without those results.

“Even though sometimes you’re pretty sure of your diagnosis, until you get the culture you’re not sure,” Bergeron says. “So what am I going to do? I’m going to give you a broad-spectrum antibiotic.”

Widespread use of broad-spectrum antibiotics has contributed to the rise of bacteria that are highly resistant to antibiotics.

“What happens with that is I’m helping the microbe become resistant, because the microbe has to defend itself. And since microbes have survived for 3.8 billion years, they can adapt to anything,” Bergeron says. “That’s the reason why I have developed very rapid diagnostic tests — the most rapid in the world.”

Bergeron has developed a DNA-based diagnostic platform capable of detecting any microbe in less than one hour.

“Any virus, any bacterium, any fungus, or any parasite,” he says. “But we’re starting mainly with bacteria and viruses because they are the most common — or they are the most common here. But we’re working also on parasites.”

The rapid diagnostic tests are being marketed by the IDRC’s second spinoff company, Infectio Diagnostic Inc. (IDI) (St-Foy, QC). IDI’s first product — IDI Strep B™ — hit the market last month. The kit diagnoses Group B Streptococcus in pregnant women, and is intended to prevent neonatal infection which can cause severe diseases in newborns, including meningitis, pneumonia and septicemia, and can lead to permanent deafness, blindness or mental disability.

“The beginning of the story was the vision of Michel Bergeron about the interest in the future of the real-time diagnostics in infectious diseases,” says Jean-Pierre Gayral, PhD, vice-president of Product Development for IDI and the company’s interim president and CEO. That vision was to help physicians make more relevant treatment decisions by providing faster diagnoses.

All of IDI’s tests are DNA-based, using real-time PCR identification methods. IDI has a strategic alliance with Sunnyvale, Calif.-based Cepheid, and uses Cepheid’s SmartCycler™ instrumentation in its ready-to-use kits.

IDI intends to have another diagnostic product — for methicillin-resistant Staphylococcus aureus (MRSA) — on the market by the end of 2003.

“MRSA … is one of the most harmful pathogens regarding resistance to antibiotics. Here, the first application we target is to screen patients who are carriers of MRSA. You know these bacteria may disseminate very quickly into the hospital environment, and even in the community, nursing homes and so on,” Gayral says. “So the trick here is to be able to detect carriers very quickly in order to regulate them before they contaminate other people in the hospital environment. We have developed a test that enables one to do the detection in one hour from a nasal swab. The current methods take an average of two to three days to do the same test.”

The company expects to launch its third product, for diagnosing vancomycin-resistant Enterococcus (VRE), in the second half of 2004.

Cultural Revolution

Bergeron has been working on the IDI technology since 1985, and is very proud to see the platform’s first product launched.

“We’re very pleased because it’s the premier in the world,” he says. “Companies in Canada, usually they sell their things to big companies. But us, we did it from scratch to the patient. I’m pleased about that.”

The results of IDI’s technology, Bergeron says, will be revolutionary.

“We’re developing a series of tests to replace what I call Pasteur microbiology. In 1875, Louis Pasteur started the revolution of microbiology: the culture. And even today, in 2003, we’re using the same techniques. It has been automated, but it’s the same basic principle,” Bergeron says. “So what I’m doing, and what Infectio Diagnostic is doing to the test we developed in my laboratory, is to replace Pasteur microbiology with this new DNA-based microbiology. That’s why it is a revolution.”

Bergeron says such diagnostic tools will have an incredible impact in areas such as disease prevention and also in antimicrobial resistance — an area that Bergeron has been researching for 20 years, trying to understand the different mechanisms by which microbes become resistant. A whole research team at IDRC is devoted to antimicrobial resistance.

Other applications for rapid diagnostics include bioterrorism response. The Department of National Defence’s Chemical, Biological, Radiological and Nuclear (CBRN) Research and Technology Initiative (CRTI) has shown interest in the platform’s potential to identify anthrax in 35 to 40 minutes.

Therapeutic Approaches

The third research area that Bergeron’s group is pursuing is treatment. The centre is developing new therapeutic tools, including new antibiotics. This is another field in which research into microbe versus host interaction is crucial.

“By understanding how the microbe invades and how the host responds, we can find new targets on the bacteria,” Bergeron says. When the pneumonia-causing bacterium Pneumococcus enters the lung, for example, it produces the enzyme betalactamase, which attacks betalactine antibiotics such as penicillin and cephalosporin.

“We’re making antibiotics that will become resistant to this enzyme,” Bergeron says. “By better understanding the tools, or the arms, or the guns that the microbes are using against you, you can defend yourself by producing other guns that are more effective.”

Another therapeutic tool under development is drug targeting for infections such as HIV.

“What we’re developing here in my lab is a system of drug delivery. We’re putting drugs into carriers,” Bergeron says. In HIV infection, the reservoirs of the virus are in the lymph nodes. “The virus goes into these reservoirs and that’s why it’s hard to treat HIV, because it sticks in the reservoirs and contaminates the body. So what we’re doing, we’re targeting these reservoir lymph nodes. We’re using carriers, so instead of taking the pill that you take and it goes into all of your body, it will go directly where the HIV is. We call that drug targeting.”

When the IDRC commemorates its 30th anniversary next year, it will have plenty to celebrate. Although in some ways the centre’s job has become more challenging since its inception — the rise of HIV and AIDS, and of highly resistant superbugs are just two threats that have emerged during the IDRC’s lifetime — Bergeron’s team keeps breaking new ground in its fight against tiny but deadly adversaries.