Diseases
No one knew SARS was coming. But when it did late in 2002, scientists around the world had some very fast work to do – first, in identifying just what this new disease was, then in figuring out what to do about it.
This is the nature of infectious diseases, whether something as benign as the common cold or as deadly as HIV/AIDS – they change. Out of seemingly nowhere, a new disease will arise. Or an old one, such as tuberculosis, will make a “comeback.” Or, through overuse of medications by humans, a disease will become drug-resistant, causing scientists to fight a whole new battle.
The combined forces of U of T and the hospitals affiliated with the university involve the cutting-edge work of hundreds of scientists in this never-ending challenge. In this issue of Edge, we profile seven of them.
Are our bodies equipped with secret weapon to fight AIDS? Quite possibly, says Kelly MacDonald.
Director of HIV Research Program at U of T’s Faculty of Medicine and the Ontario HIV Treatment Network (OHTN) for over 10 years and has spent the last seven developing a novel target that originates in our own cells.
The story begin over a decade ago. When AIDS was spreading across Africa, MacDonald travelled to Kenya to help conduct an epidemiological study on sex trade workers in order to understand risk factors for transmission.
The team discovered that, while most sex trade workers were at a very high risk of infection, some of them seemed to be immune to the disease. When further epidemiological studies yielded no clues, MacDonald and her team turned to basic science.
“What we discovered was that certain types of a genetic marker known as human leukocyte antigen (HLA) were associated with reduced risk of infection,” says MacDonald whose work is funded by the Canadian Institutes of Health Research (CIHR), the National Institutes of Health (NIH), the Canadian Vaccine Network and the OHTN.
Found in virtually all human cells. HLAs essentially “show” the immune system where a virus is so that the body can fight it. This process works well for many viruses, but because HIV mutates so quickly the body can’t recognize it long enough to kill it.
So MacDonald’s team began studying the HLAs found int he group that seemed to be immune to the virus. Meanwhile, studies conducted by other researchers yielded important information: when HIV is transmitted, it carries some of the HLA from the last person it was in.
Applying this information, MacDonald and her collaborators showed that sex workers with a less common type of HLA have a lower risk of acquiring HIV, suggesting that the immune system may be able to neutralize the virus by recognizing and attaching the foreign HLA rather than highly mutable viral proteins.
Armed with information, MacDonald and her colleagues did the unthinkable: they began to create a vaccine based on HLA instead of on the virus itself. “This was basically heresy because everyone thinks about making a vaccine from whatever the pathogen is,” admits MacDonald. “But in the case of a virus that ‘steals’ HLA, this was a better idea.”
MacDonald says that the benefit of this vaccine, which is currently being tested in monkeys, is that HLA itself does not mutate, so it is much easier for our bodies to recognize and fight off foreign HLA — which floats along with the HIV virus — than it is to recognize and kill a rapidly-mutating virus.
If successful, what will this new vaccine mean for the battle against AIDS?
“Realistically, I think we’ll discover that our vaccine provides partial protection, which is great,” says MacDonald, “but it may not be the ‘whole enchilada.’ The lesson we have learned thus far is that HIV is a wily virus and it will likely take many types of immune response to contain it.”
– Althea Blackburn-Evans
“Malaria? We’ve beaten that one, haven’t we?”
Kevin Kain smiles at the question and quickly deflates preconceived notions with hard facts:
As a single agent, malaria is the most common cause of death in children globally.
500 million people contract malaria annually. Two to three million of them — mostly African children — will die from the disease.
Malaria often interacts with tuberculosis and HIV. There is evidence that drugs brought to sub-Saharan Africa to treat HIV may make malaria worse — and vice-versa, as malaria in an HIV-positive person makes the HIV even more debilitating.
The mosquitoes that spread malaria are finding new homes — as global warming heats up more temperate regions, even Canada is not immune to the spread of diseases that emanate in the developing world.
“Malaria has been on earth of millions of years,” says Kain, professor of medicine at U of T, a senior scientist at the Toronto General Hospital Research Institute, and a Canada Research Chair in Molecular Parisitology (he also receives funding from CIHR, the Heart and Stroke Foundation, Ontario HIV Trials Network and The Physicians’ Services Incorporated Foundation). “Malaria makes many viruses look puny. It has about 6,000 genes instead of seven or eight, and it thumbs its nose at your immune responses to get rid of it.”
Despite malaraia’s toughness, Kain feels that humans’ ability to co-evolve with malaria over time may well be a clue as to how to combat the disease more effectively. “We have been plagued by infectious diseases like malaria but we have also survived them. Why? Evolution is yelling something at us and we need to understand it.”
To this end, Kain and his team have discovered that macrophage cells — key components in the human innate immune resonse — are equipped with malaria receptors and can attract and “eat” parasites. They also help to modulate the inflammatory response that sometimes causes death in malaria patients. Further investigation turned up an unsuspected parallel with diabetes. He is now preparing to launch clinical trials using a common diabetes drug that has been shown to control malaria in mice.
But Kain isn’t interested solely in malaria. “Human activity often drives the emergence of new disease. The move we harm our natural environment, by, for example, clearing rainforests, the more possibilities we create to enable unknown diseases to rise and others to strength. So we need to talk thematically about what we’re doing as a species to cause these consequences.”
– Paul Fraumeni
We’re overdue for a pandemic, say Allison McGeer and Donald Low.
“It’s really just a question of how bad it’s going to be,” adds McGeer, professor in laboratory medicine and pathology at U of T and director of infection control at Mount Sinai Hospital. “SARS was just a practice run. Influenza is still the biggest threat and the single largest cause of infectious disease deaths in the developed world.”
During the SARS outbreaks in Toronto, McGeer and Low — head of the microbiology division in laboratory medicine and pathobiology at U of T and microbiologist-in-chief at Mount Sinai Hospital and University Health Network — were two of the principal researchers tracking SARS and helping hospitals contain the disease.
Since 1992, Low and McGeer — whose work is funded by the Canadian Bacterial Diseases Network, CIHR, NIH, Pfizer and Bayer Healthcare — have been spearheading a longitudinal, population-based study on Group A strep infections in collaboration with scientists from the U.S. and Sweden. For the past 10 years, they have also run a Canada-wide surveillance program to spot trends in antibiotic resistance.
Despite advances in medical research and technology, however, perhaps the biggest challenge facing infectious disease researchers today is how much we still don’t know. By nature, bacteria and viruses have a huge evolutionary advantage over human beings — the average generation period for bacteria is some 20 minutes compared to 30 years for humans. Couple with that the fact that our understanding of immunology and how the body controls viral infections is still rather limited.
“From an evolutionary point of view, to think that we’re ever going to beat them is unrealistic,” says Low. “Probably one of our largest barriers is utilization and reducing transmission. Any time you develop a new drug, it’s foolhardy to think that resistance isn’t going to develop. So then you have to deal with then ext thing, which is minimizing how quickly resistance develops and, once it does develop, how it transmits to other people.”
McGeer believes the public’s greatest interest in infectious diseases is due to substantially to timing. “By 1980, we had made so much progress with childhood vaccines, smallpox eradication and antibiotics that we thought everything was fixed. We thought we’d won the war so we stopped paying attention. Unfortunately, we’d just won a few battles. Our mistake.”
– Janet Wong
Jun Liu has a short answer for why bacterial infections are increasingly hard to battle: our weapons are overused.
The problem, he says, is that antibiotics — our best strategy for attacking bacteria — are over prescribed by doctors and often abused by patients, so much so that infectious diseases have become alarmingly drug-resistant.
Bacteria are very smart, explains Liu, and can mutate or develop mechanisms to render antibiotics useless. “It’s a race in terms of how fast we can develop new drugs, and how quickly the bacteria evolve and develop a resistance to them.”
An assistant professor of medical genetics and microbiology, Liu specializes in tuberculosis, a disease that still kills about two million people a year. While developing countries are the hardest hit, Liu says that most of us will become infected with TB in our lifetime even if we never develop symptoms — and one-third of us will become carriers.
Liu’s time is split between searching for new drug targets to battle the dramatic increase in antibiotic-resistant strains of TB and developing a new vaccine to halt its spread.
Transmitted by coughing, sneezing or even during casual conversation, TB is one of the most highly contagious diseases, which makes direct study a dicey proposition. “Until now, we haven’t had a proper containment laboratory, so we’ve had to study similar but less virulent organisms and then draw indirect conclusions,” says Liu. But that is about to change. In a few months, thanks to support from the Canada Foundation for Innovation, the Ontario Innovation Trust and CIHR, Liu will be able to work directly with TB organism in a new Level 3 containment facility housed in the Faculty of Medicine. Reserved for the study of highly contagious diseases such as HIV and TB, the lab will be the only certified facility of its kind in Ontario.
But Liu insists his efforts will be futile unless the bigger picture is addressed. “Scientists cannot win this battle alone. We need to encourage government and public health agencies to implement policies that will minimize the misuse of antibiotics.”
– Althea Blackburn-Evans
You can’t effectively fight an infectious disease until you can recognize it. This may sound simple, but it decidedly is not. SARS, says Andrew Simor, was a perfect example.
“With SARS, we learned that the greatest risk is the unrecognized case. Once we could identify a patient as having SARS, the prevention and control measures were extremely effective. But the vast majority of spread occurred from unrecognized cases.”
One of the key figures explaining SARS in the daily news during the Toronto outbreaks, Simor is an internationally respected professor of laboratory medicine and pathobiology at U of T, head of the department of microbiology and an infectious disease specialist at Sunnybrook & Women’s College Health Sciences Centre.
With the corona virus now confirmed as the biological cause of SARS, Simor says research needs to focus on effective detection. “One of the challenges with SARS is the lack of an ideal test that can quickly help sort out whether you are dealing with SARS. This has huge implications for treatment and prevention.”
With funding from the Orly Watkin Fund for Meningitis Research and the Ontario Association of Medical Laboratories, Simor has been working on improving diagnostic detection for infectious diseases for years. Among his most important work is experimentation with a revolutionary diagnostic test called the polymerase chain reaction (PCR). Invented by Nobel laureate Kary Mullis in the 1980s, PCR involves extracting the DNA of the organism causing the disease and then multiplying it, making it much easier for laboratories to characterize the true nature of the infection.
Simor and his team have used PCR successfully in the diagnosis of bacterial meningitis, a severe life-threatening infection, and necrotizing fasciitis (commonly known as “flesh-eating disease”). “Conventional methods take 24 to 72 hours to diagnose bacterial meningitis. Many tests are negative because the patients are already on antibiotics. With PCR, we can diagnose it within two hours of seeing a specimen in the lab. And PCR is proving to be highly sensitive and very accurate.”
PCR also has important public health benefits, Simor feels. “With meningitis or flesh-eating disease, public health officials want to know who has been in close contact with the patient. Once we know the organism, we can prescribe treatment. And that is crucial in halting the spread of any infection among a wider population.”
– Paul Fraumeni
Most of us are living with it, but few of us will ever know it.
Epstein-Barr virus (EBV), which infects 90% of the world’s population, is a type of herpes virus that is transmitted through saliva and then moves about quietly in our systems for the rest of our lives. In cases where the first infectious mononucleosis — better know as “mono” or the “kissing disease.”
While EBV has a unique ability to take cells which normally aren’t supposed to divide and makes them divide repeatedly, a process called immortalization,” explains Lori Frappier, a professor of medical genetics and microbiology. “And cell immortalization is the first toward cancer.”
So far, EBV has been linked to Hodgkin’s disease (a cancer of the lymphatic system), Burkett’s lymphoma (a childhood blood tumour) and nasopharyngeal carcinoma (a tumour of the nasal passages and throat). It also frequently induces cancerous tumours in AIDS and organ transplant patients.
Frappier’s research focuses on a particular protein, called EBNA1, which is crucial to EBV’s longevity. “EBNA1 is responsible for maintaining the EBV genome in infected cells and also manages to hide from the immune system so that your body doesn’t fight these cells. As a result, viral infection is maintained at a low level for life.”
Studying this protein yields all kinds of information, says Frappier, who was one of first Premier’s Research Excellence Award winners and whose current work is funded by the National Cancer Institute of Canada and CIHR. “It helps us understand how viruses persist, and it also tells us more about how cells work, because viruses are very good at picking out the important cellular regulatory proteins and altering their function to use them for their own purposes.”
Getting a better understanding of cells may also provide clues about controlling cell division and tumour development — which could prove to be a boon for cancer researchers. But understanding how viruses interact with cells is an arduous process, she says, one that could take years to complete.
“Now that we have found a number of cellular proteins that EBNA1 interacts with, we need to find out what they do for the cell and why EBNA1 targets them.”
– Althea Blackburn-Evans