Unsolved, Unanswered, Unknown — Cover
Unsolved, Unanswered, Unknown
What makes for a great medical mystery? Seven faculty members share the unsolved cases that keep them up at night — and some of the great questions still unanswered in medicine.
By Heidi Singer
Resisting Our Genetic Destiny
There are kids with autism who can cite every name, address and number in a phone book but have trouble tying their shoes. Sometimes I wonder which is the bigger medical mystery — their amazing memories and motor deficiencies, or everybody else’s memory deficiencies but adeptness at other, perhaps simpler things?
Studying the genetics of autism brings up a very fundamental mystery: Why do some people who have massive genetic irregularities never develop autism (or other disorders), but their children do? This mysterious ability that some people have to resist their genetic destiny is utterly fascinating. Scientists all over the world are now combing through the genomes of healthy people, looking for those rare ones. These miraculous genomes have learned to resist adversity, so maybe they’ll show us the way. Genetic “resiliency” is perhaps the biggest diagnostic mystery of 21st-century science — and potentially the key to solving our most complex medical questions.
Stephen Scherer (MSc ’91, PhD ’95) is Professor of Molecular Genetics and Director, McLaughlin Centre; Senior Scientist, The Hospital for Sick Children.
Where Cancer Doesn’t Tread
Why do our muscles almost never get cancer? This disease is infamous for becoming very invasive, travelling everywhere in the body — but
skeletal muscle is never the place it goes. It’s just this really interesting observation that people have made, and we don’t have an explanation for it. As far as I can tell, nobody has dug down and figured out why, and there might be some important information to use in the fight against cancer. For example, there could be unique proteins in muscle that prevent tumour cells from wanting to put down roots in this type of tissue. Or it could be something fairly simple — muscle is always moving, so maybe it’s difficult for cancer cells to enter this tissue.
Penney Gilbert is an Assistant Professor at the Institute for Biomaterials and Biomedical Engineering.
Solving a 50-Year-Old Mystery
A few years ago, my lab discovered a crucial receptor for respiratory syncytial virus (RSV), which frequently causes the common cold and serious lung infections like pneumonia. Researchers had known about this virus since the ’50s, but we hadn’t made much progress on a treatment because nobody had identified the molecule that allows the virus to bind to the cell. We looked at our quest as a mystery that needed solving — and I believe that mindset helped us.
First we determined the virus sticks to protein, not sugars or lipids. But which one? The cell surface contains thousands of proteins so, we had to narrow it down. We separated cell surface proteins on a gel and got a common “hit” for all the cell types and RSV strains we tested. We identified the protein we thought was responsible for these hits, and after a series of experiments using different techniques, we established the evidence that this unusual molecule was indeed an RSV receptor. The answer wasn’t intuitive, but came from a great deal of trial and error — gumshoe detective work that solved a 50-year-old mystery.
The main lessons were to keep an open mind, expect the unexpected and understand your tools. Basic scientists don’t always see their investigations as mysteries to solve, but I think it helps to look at it this way because in any good mystery the culprit is never the one you suspect at first.
Richard Hegele (MD ’84, PGME ’89) is Vice Dean of Research and Innovation and a Professor in the Department of Laboratory Medicine and Pathobiology.
What’s in a Name?
I marvel at the dire shortage of knowledge, both scientific and humanistic, concerning the disparate causes of, and the cures for mental disorders.
These gaps in knowledge have the unfortunate effect of compounding other mysteries, and they cause fear and dread – which in turn feed superstition, and have led too often to stigma. Consequently, psychiatry has emerged as arguably the most challenging and demanding of medical specialities.
The challenges of the mind and brain and their legion of mysterious afflictions do tend to stimulate our curiosity. Our antennae of critical faculties are set tingling by unexpected notions and unusual connections. Frequently they emerge through random associations from literature and the arts – think of Shakespeare’s metaphorical references to London’s medieval “Bedlam” facility.
Novelist Timothy Findley wrote eloquently and sensitively of psychiatric patients’ experiences and, for the most part, he used the real names of Toronto area hospitals. Not so for the (now former) Clarke Institute of Psychiatry, which he called “The Parkin Institute of the University of Toronto” – after its prominent architects, rather than the sometimes-controversial Psychiatry professor and Medicine Dean C.K. Clarke. Findley’s reason for that enigmatic substitution remains a mystery.
John Court is an assistant professor in the Department of Psychiatry and IMS, based at CAMH, who researches and instructs on the history of psychiatry
The Mystery of the Aging, Failing Brain
Aging, failing brains are normal enough — anyone who lives a long time will probably feel this decline. Of course dementia is far more tragic than “normal” memory loss, but why should we lose any part of the thoughts and memories that make us human? I don’t think it’s a given that our brains should wear out like other parts of our bodies. Why should the aging process wipe out our very identities?
We’ve never solved this mystery, and as a result the medical landscape is littered with failed drugs to treat dementia. But recently, we have started to take a step back to understand the molecular basis of learning and memory. There have been great strides recently in this area. Now the challenge is to understand why and how these processes go wrong in conditions like Alzheimer’s — and then develop treatments to alleviate and perhaps even cure these awful diseases.
Graham Collingridge is Professor and Chair of the Department of Physiology.
A 64-year-old woman was carried into the emergency room one night screaming from abdominal pain. To my surprise, her belly was soft, ruling out most of the obvious causes. Her adult daughter was worried sick, and pushing hard for action. I felt the pressure to get it right. Blood tests showed elevated lactate, which meant somewhere in her body wasn’t getting oxygen. I could order a CT scan, but radiologists always say if you don’t know what you’re looking for, you won’t find it with a scan. Just when I’m trying to figure out my next move, she flips into atrial fibrillation. That’s when I smile — now I know she’s got a blood clot leading to an ischemic bowel.
I put her on blood thinners and send her off to the CT scan. Now that I know what I’m looking for, the scan confirms the diagnosis: it shows several feet of bowel that are deprived of oxygen and swelling up, causing intense pain. An interventional radiologist takes the clot out.
The things that ER physicians see are common occurrences. We solve mysteries mostly through pattern recognition. The first unusual pattern I saw in this case was pain out of proportion. But it wasn’t until her heartbeat went irregular that I thought of a blood clot in the vessels of her intestines. That heartbeat was like a gift from God: it made me realize there was turbulence in the blood stream.
Detectives solve mysteries. But I don’t imagine them becoming emotionally burdened by anxiety from their cases like doctors do with their patients. What if that woman had been close to death and I hadn’t had much time to figure out the problem? Clinicians are never dealing with a sterile medical mystery. Panic and logical thinking never go well together.
Brian Goldman (MD ’80, PGME ’82) is an emergency room physician at Mt. Sinai Hospital, Assistant Professor of Family and Community Medicine and host of the CBC Radio show White Coat, Black Art.
Why Do Children Get Cancer?
As a medical student, I used to think cancer was a disease of old people: your cells get old and don’t divide as well and the DNA gets jumbled. But why do children get cancer? On an emotional level it’s totally unfair; however, there are lessons here that can be applied to many cancers. In children, there’s a fine balance between normal development and cancer. For example, some childhood cancers are caused by two chromosomes breaking and rejoining out of order, resulting in two normal genes being pushed together. These genes are essential for normal development, but putting them next to one another, “out of order” on the chromosome, is enough to push a very controlled process (normal development) to an uncontrolled one (cancer).
We still don’t understand what’s causing those chromosomes to break in the first place. Researchers are studying this question, and we’re hoping that genomic sequencing and high-powered bioinformatics will help us solve this mystery.
Gino Somers (PGME ’04) is an Associate Professor in the Department of Laboratory Medicine and Pathobiology, and the Division Head of Pathology at SickKids.
The Deep Sea of Possibility
The world’s oceans hold medical mysteries overlooked since the beginning of time — I think they hide life forms that could be the next frontier in understanding and curing disease.
The vast majority of this planet’s biological molecules, up to 95 per cent, haven’t been studied well, because we don’t know how to grow them in a lab. But they have all kinds of interesting biological activities. For example, there’s a single-cell organism that puts out a telescopic spike ten times longer than its body — a whole new life form. Scientists are only now starting to pull these fascinating creatures out of the sea, and they’re finding that any crazy thing you can dream up, some species does it. For example, some don’t make DNA transcripts — instead, they stitch together bits of RNA to form the proteins that control our genetic destiny. Who knows how this can be used for gene editing?
Over a billion years, evolution has figured out every way imaginable to play around with biological molecules. To fix what’s wrong in our genes, we need to uncover the mysteries that are already in front of us, or hiding under water.
Andy Fraser is a Professor at the Donnelly Centre for Cellular and Biomolecular Research and the Department of Molecular Genetics.