Research associate Wen Wei Zhang and Dr. Greg Matlashewski PHOTO: OWEN EGAN

On the trail of killer infections

DANIEL McCABE | When a woman contracts the human papillomavirus (HPV), a molecular battle is soon waged in her body -- a battle that could put her life in jeopardy depending on which side prevails. HPV's arch-enemy is the p53 tumour suppresser gene. The gene acts as a cellular watchdog of sorts -- once it spots the presence of HPV in a cell, or, if the cell develops cancerous properties, p53 programs that cell to destroy itself, along with the virus. For its part, once HPV invades a cell, "it has to get rid of p53 in order to survive," explains Dr. Greg Matlashewski from the Institute of Parasitology at the Macdonald Campus. "It's a very interesting and intimate relationship. The outcome of that interaction plays a large role in determining if there will be a persistent viral infection." If that occurs, if HPV infection isn't stamped out by p53, the risk of the woman infected contracting cervical cancer increases substantially. Cervical cancer affects 500,000 women world-wide each year and it's the second leading cause of cancer death among women. It's a disease that usually strikes women in developing countries. Almost all cases of cervical cancer are caused by HPV infection. As it happens, there are two forms of p53, HPV's nemesis, in the general population. What Matlashewski and his collaborators have discovered is that one form of p53 (Pro form) is more resistant to HPV than the p53Arg form. "Depending on what form of p53 you have, it could indicate whether you're more susceptible to the virus and therefore more at risk for the development of cervical cancer," he says. The research was recently published in Nature. According to Matlashewski, women who carry two copies of the less effective p53Arg form may be seven times as likely to develop HPV associated cervical cancer. While he stresses that more research is necessary to better understand how HPV works, the finding does point towards the less resilient form of p53Arg as a potential genetic marker for susceptibility to cervical cancer. In collaboration with Dr. Eduardo Franco from the Department of Oncology, he plans to conduct future studies in Brazil, which has among the highest levels of cervical cancer in the world. If doctors can detect precancerous cells in their patients at an early enough stage, virtually all cases of cervical cancer are preventable. Matlashewski's results could help identify the women who are at the greatest risk for cervical cancer and their cases could then be followed closely by the patients' gynecologists. He certainly isn't the only one who thinks that his research could have immense impact. Digene, a large U.S. medical firm, has obtained a world-wide license from McGill, in a deal brokered by the University's Office for Technology Transfer, to commercialize p53Arg as a potential genetic marker for HPV-associated disease. The deal, with McGill and Matlashewski's research partners at the International Centre for Genetic Engineering and Biotechnology in Italy, will pay McGill an up-front fee. If Digene's efforts with p53Arg prove to be profitable, McGill will also earn royalties on product sales. In a news release, Digene's vice president of research and scientific director Attila Lorincz states, "We believe the p53Arg gene will be a strong complement to our existing product line for cancer screening." Matlashewski says the deal with Digene makes sense since, in terms of looking at ways to diagnose cervical cancer, "Digene is far ahead of everyone else in this area." Matlashewski's work on p53Arg and HPV predate his arrival at McGill 12 years ago. He was part of the British team that first managed to successfully clone the human p53 gene. While Matlashewski's work on HPV continues, it isn't the only focus of his lab. In fact he's preparing for a two-prong assault on another deadly disease -- leishmania. If you've never heard of it, you can't be blamed -- the parasitic infection is rarely seen in North America or in Europe. It is, however, a major problem in many countries of the developing world. "It's very widespread. It's present in 90 countries," says Matlashewski. The infection, spread by mosquito bites, causes skin lesions not unlike those caused by leprosy and the visceral form of the disease is often fatal. "It's an ancient disease," says Matlashewski. "There is pottery from the Inca period that shows the faces of people who've been infected. It's killed thousands of people each year for probably thousands of years." Matlashewski's work on leishmania has uncovered many details about how the infection works. It impairs a crucial protein pathway's ability to defend the body against infection -- opening the door for higher levels of infection. Matlashewski is an advisor to the World Health Organization (WHO) on the subject of leishmania and genetically engineered vaccines. He has WHO support to begin clinical work in 1999 on a new drug that could effectively attack the disease. The study will take place in Peru -- a country that has been hit hard by the infection -- and Matlashewski will be working with Dr. Brian Ward from McGill's tropical medicine department. "It is a very exciting time," says Matlashewski. "We have a real chance of alleviating a great deal of suffering caused by this infection." On another front, he is also trying to develop a vaccine for leishmania. The idea is to genetically engineer different forms of leishmania and to get a better sense of how the infection's genes function. Then the dangerous genetic portions can be sliced away from the leishmania genome and a live, attenuated vaccine (along the lines of several viral vaccines) can be developed. As is the case with the measles virus administered through a vaccine, the body's defence system would beat down the toothless form of leishmania and build up immunity to it for the future. Both of the diseases that preoccupy Matlashewski are conditions that are far more prevalent in the developing world than they are in countries with more advanced medical systems. Leishmania is a type of disease that pharmaceutical companies sometimes shy away from -- research costs big bucks and companies are far more likely to recoup their investments by working on illnesses in countries where the population can afford to pay for expensive drug treatments. "That's why it's so important that a place like the Institute of Parasitology exists," says Matlashewski. "There are other people here who are also looking into infectious diseases that affect developing countries and we're unique in that respect. There aren't very many places like this in the world. If it wasn't for the work going on in university settings like this, these sorts of diseases wouldn't be receiving much attention at all."