The cause of multiple sclerosis: we’re getting closer

My feature on the state of research into MS causes (published Dec. 1, 2016, in Nature Outlook) had a long and complex genesis, which is also true of the disease I wrote about.

I have long been interested in how diseases happen, from my days writing about research for my column in the Canadian Medical Association Journal (CMAJ). I covered a whole variety of health issues, of course, but the ones that were of most concern  the ones that could wipe out populations and cultures were diseases.

A few years ago at the Canadian Science Writers Association conference, Dr. Brian Goldman presented a news clip on an experimental treatment for MS touted by Paolo Zamboni, which he (suspiciously) called “liberation therapy” based on a theory that MS is caused by chronic cerebrospinal venous insufficiency. Or let’s just say veins blocked by metal buildup. Goldman was critical of the glowing media descriptions of the treatment, as they were not evidence-based.

I was sitting at the same table with Dr. Goldman at lunch, and our gang of science writers debated the ethics of this type of coverage. I recall I said, “Of course, we don’t know what causes MS.” Because that was the understanding at the time.

That discussion stuck with me, especially as I met more people with MS over the past few years. Then, in reporting for CMAJ, I covered two research stories on discoveries relevant to the cause of MS. I starting following the references in one of the articles to other research, and I soon learned that the evidence was mounting for several causal factors. Some researchers were looking into whether these factors were linked. In fact, right now there’s a new article every month on these factors.

But I had seen nothing (and I looked) in the media about the good, solid, research that had been slowly amassing over years about Epstein-Barr virus and vitamin D, in particular.

I pitched an idea for a feature on this research at this year’s Canadian Science Writers Association conference as part of a “Dragon’s Den” pitch session to a panel of four editors. And long story short I was eventually asked to write it for Nature Outlook.

Why I included the Elmvale Acres Ottawa cluster

I was in the midst of my research on MS causes, and I was particularly interested in the paper from Winnipeg researchers showing clusters of incident cases of MS in that city. As the authors of this paper told me, clusters are an important clue into causation. They can indicate genetic differences, especially in a multicultural city like Winnipeg, or environmental factors. I was fascinated because the clustering in Winnipeg (unfortunately, for copyright reasons, I couldn’t reproduce the study’s maps, which are worth a thousand words) looked like maps of disease outbreaks. That doesn’t mean they are it is just a possibility worth exploring.

I had wanted to get the human angle on this research, to show that this research is about real people, not just dots on a map. I was even thinking of calling the MS society in Winnipeg to contact patients in the affected neighbourhoods. At this point, several of my friends who knew I was working on the article called or emailed to say there was a CBC story on a cluster right in my city – Ottawa.

I contacted the man at the centre of the CBC story, Jacques Dutrisac. Now, I have some graduate courses in statistics and I’ve read plenty of biostatistics. I know that disease clusters often occur by chance alone. There’s also a well-known perceptual effect that once you have a problem you tend to see it all around you. Careful and complex statistical methods like those used in the Winnipeg paper are needed to determine “true” clustering.

So, to be honest, I called Dutrisac prepared for the possibility that the cluster in the Elmvale Acres neighbourhood of Ottawa might be by chance alone. Dutrisac is a wonderful raconteur and sleuth. Not only had he kept track of all of his former friends and neighbours with MS, he had their names, locations, schools, ages, and ethnic background. He was telling me about one after the other, and I was taking notes. After our chat, I made a table of all 14 people with MS (at that point another neighbour with MS has come to light as a result of the publicity around the cluster). The prevalence of MS in Canada (where it is highest in the world) is 291 per 100,000 or a little under 3 per 1000. In an area of less than 1000 people, the rate was at least five times higher than the national average. When I looked at the fact that the people affected not only lived in a kilometre-radius area, but were all about the same age in fact, most exactly the same age as Dutrisac –, went to the same schools and were two-thirds francophone… well… that can’t possibly be by chance.

So I feel that I’m being responsible as a journalist in covering a cluster that has not yet been studied, but should be.




Sale of Canadian medical journals to predatory publisher a signpost of the death of the society journal

Over the last week, I’ve spent some time covering the sale of Canadian medical journal publishers Pulsus Group and Andrew John Publishing to OMICS International, a publisher in Hyderabad, India, that has engaged in many “predatory” journal practices (see blog posts passim ad nauseum).

But is there anything more to this story than just a decision that has left 16 Canadian journals scrambling to find a new publisher? OK, it’s rough for the journals involved, but a tempest in a teapot in the big scheme of things.

I think there is. This is just one signpost one really bad stretch of washboard on the road to the grave for the society journal.

Richard Smith, former editor of BMJ, was accused of hyperbole when he announced the death throes of national medical journals in his blog back in March. He was talking about the recent firing of the editor-in-chief of the Canadian Medical Association Journal in particular, but commented that journals are disappearing in any case, and that in trying to find solutions for their journals medical associations are rearranging the deck chairs on the Titanic.

In work I have done for society journals in the last six years that I’ve been consulting, I have said, “These are tough times for journals.” To keep journals afloat, societies have had to re-evaluate the journal’s role, cut its costs, and increasingly give it to another established publisher to publish.

There are several reasons for this. First, journals have become more complex and expensive to run, as there usually needs to be a print version and an online version (the death of print being exaggerated). Modern digital publishing is not in a society’s core competency. Furthermore, it is much more expensive for a society to develop all of the publishing expertise in order to run a journal or two than for a big publisher just to add a journal to its publishing mill (and let me tell you, some of them are a real mill churning out thousands of articles).

The traditional forms of revenue subscriptions from academic libraries, ads from drug companies, member dues are all down. Journals find funds increasingly from their society’s coffers, creating bad feelings as the society’s Board of Directors inevitably questions why the society is publishing a journal but then grudgingly  agrees to keep it going.

Even for the publishers, there’s no money in it any more. Andrew John and Pulsus Group were respected small commercial publishers that did a good job for their journals. But they couldn’t find buyers who wants a bunch of very niche Canadian medical titles ? One of the societies I talked to said it was too bad that their journal would have to be published outside of Canada, as more and more Canadian journals are. But the large Canadian publishers can’t take on journals unless they are a sure bet or the society agrees to pay the costs under a contract publishing arrangement.

Into this morass stepped two x factors: the fact that Canadian publishers agreed to sell to a questionable publisher and that predatory publishers have started buying legitimate journals in order to buy credibility. The general reaction to these developments was, whoa, where did that come from? But this out-of-the-blue story came about because of the slow, creeping quicksand that journals are in.

So how long will these small society journals be able to continue? I suspect that we may lose a few as a result of the OMICS situation. Others will find a home with a legitimate foreign publisher. Many will move to own their title and copyright or add a “right of first refusal” to their publishing contracts to prevent being eaten by a predator.

But in the coming years more and more titles will disappear. Only a radical rethink of traditional society journals can save them, and I haven’t seen anything suggested that is radical enough. This is immensely sad. It’s an industry that I’ve spent most of my career in. We cannot put our heads in the sand, though. We have to look forward to Richard Smith’s “post-journal world” and see what joys it holds.


BC provincial government site publishes unsupported lifestyle advice on hot flashes

At the risk of being a one-note Johnny, I am very concerned when lifestyle advice to menopausal women from normally credible, reputable sources is unsupported by evidence, at best, or is basically old-wives’ tales, at worst. If other health information were based on such equivocal and weak evidence, it would not be considered acceptable.

The Globe and Mail recently published a lifestyle article on hormone therapy for hot flashes, which I read with interest. It mentioned that HealthLink BC, a patient health information site run by the government of British Columbia, was recommending lifestyle advice that my own literature review indicates is unsupported. By contrast, its advice on medical therapy is generally referenced and based on evidence.

This is what HealthLinkBC says:

  • Avoid using tobacco or drinking a lot of alcohol. They tend to make hot flashes worse.

The evidence on both of these is equivocal (see my previous post). There is some limited evidence from well-designed observational studies that never smoking and quitting smoking are associated with fewer hot flashes. The evidence on alcohol is mixed, with some studies showing alcohol decreases hot flashes.

  • Manage stress. Stress can make hot flashes worse.

Well, there is evidence showing that being happy and contented actually increases hot flashes and stress decreases them. There is little good evidence about effects of stress.

  • Exercise regularly, and eat a healthy diet.

As I indicated in my earlier post, the evidence on exercise is mixed and shows only modest changes. There is evidence that obesity (but not healthy weight) is associated with hot flashes, so losing weight is advisable as a way to decrease hot flashes only if you are obese.

  • Try rhythmic breathing exercises. This is called paced respiration. It can help you meditate and relax, and it may reduce your hot flashes.

OK, the first randomized controlled trial on this recently reported. There was a modest (less than 20%) decrease in hot flashes in the group that used this paced respiration method in which you slow your resting breathing rate (kind of conflicts with the exercise advice). But (get this) the control group, which listened to music instead, had a 44% decrease in hot flashes. Keeping in mind that placebo effect is huge in hot flashes, we should all be listening to music rather than breathing slowly.

  • Drink cold liquids rather than hot ones.

Hot liquids (and anything hot) can bring on a hot flash, but there is no evidence that they increase the overall frequency or severity of hot flashes.

  • Eat smaller, more frequent meals. Digesting a lot of food can make you feel hotter.

No evidence. Also, while the immediate trigger of a hot flash may be warm ambient temperature and other heat sources, the problem is not that women affected are overly hot. Menopausal women in Canada have hot flashes in minus 20 degree Celsius weather. Hot flashes do not feel like being hot from ambient temperature or exercise, and body temperature before a hot flash is normal and then actually rises measurably during the hot flash.

  • Stay cool
  • Keep your area cool. Use a fan.
  • Dress in layers. Then you can remove clothes as needed.
  • Wear natural fabrics, such as cotton and silk.
  • Sleep with fewer blankets.

Staying cool does help prevent the immediate onset of hot flashes and helps women recover from them quickly when they occur. However, from personal experience, I’m not sure it reduces the overall frequency.

No evidence.

From HealthLinkBC’s medical therapy section:

  • Black cohosh may reduce or prevent hot flashes, depression, and anxiety.

There is a reference for the paragraph containing this statement to a Health Canada page on traditional herbal use of black cohosh, which includes menopausal symptoms. There is no reference to the medical literature, which has plenty on black cohosh. There have been some small randomized controlled trials (around 300 patients) showing benefit of black cohosh in hot flashes and published in a respected, peer-reviewed journal (Obstetrics and Gynecology). However, a Cochrane systematic review pooling data from 16 randomized controlled trials involving more than 2000 women with menopausal symptoms found “insufficient evidence to support the use of black cohosh for menopausal symptoms.” However, since some studies found some benefit, the review called for more research on this traditional herbal remedy.

I find a lot of information for patients tries to get around the fact that the evidence is poor by using words like “may” or “might.” As in, “black cohost may reduce or prevent hot flashes.” Or it may not. I suspect many patient-readers looking for something to try are not going to pick up on the subtle distinction of a remedy that may or will provide some benefit. And this is concerning, as many herbal remedies are not risk-free. Black cohosh has been linked with liver-damage events in people who have taken it, although a meta-analysis of black cohosh studies found no evidence of liver problems. Black cohosh may or may not have risky side effects.

But why not just be upfront with readers about the state of the research evidence on various lifestyle advice and herbal remedies? And why tell women something is going to help when it isn’t? I also find that a lot of patient advice is good, general health advice. But it’s like health authorities are trying to trick readers into following advice by selling it as something that’s going to help with a particular problem.

There are lots of good reasons to eat properly, quit smoking and limit alcohol. Like heart disease, cancer and diabetes. Don’t tell women healthy living will help their hot flashes when it won’t.

Why do hot flashes remain a medical mystery?

It’s 3:05 in the afternoon, and I’m working at my desk when I start to get an uncomfortable prickly heat sensation. Within 30 seconds, my body temperature goes from its normal range (35.8 to 36.4 degrees Celsius) up to 36.8 degrees. My face reddens, my pulse increases from my normal 53 beats per minute to 59. I’m breathing faster and harder, and sometimes I even feel breathless. I may have to stop what I’m doing because of a sudden lack of energy. I may feel light-headed and even nauseated. At about 40 seconds in, the heat starts to subside as I break into a sweat. My skin from my scalp to my ankles is bathed in perspiration. By one and half minutes, it’s all over. But if the room is cool, the sweat may leave me feeling clammy and chilled.

Hot flashes happen day and night. On a good day, I might have about 12 hot flashes that cause only a light sweat. On a bad day, I can have more than 30 hot flashes and be so drenched in sweat that I need to change clothes and take extra showers. I’m lucky that I usually sleep through the night sweats or awaken only momentarily – many women suffer insomnia because of night sweats.

I am one member of the first generation of women to go through menopause without hormone replacement therapy (HRT), which was used to help women from the World War II to the baby boom generations avoid menopausal symptoms. Widespread use of HRT stopped after studies showed it raised the risk of some types of cancer as well as heart disease. Nevertheless, some women I know who are really suffering with symptoms are taking bioidentical hormones for a few years; it works well for some women and less well for others.

Estimates say 70% to 80% of menopausal women will have hot flashes (rates vary by country), and a recent study says they last seven and a half years on average, much longer than previously thought.

While this is mainly a women’s problem, some men also experience hot flashes as their hormone levels drop during “andropause.” My father had them during a therapy for prostate cancer that lowered his androgen hormone levels.

So, this is an almost-universal natural process. You would think that we would understand why it happens. But here’s the thing – medical knowledge really does not know why menopause causes hot flashes. For example, the Mayo Clinic website states: “The exact cause of hot flashes isn’t known.” Most medical sources explain that your estrogen level drops and then you have vasomotor symptoms, but stop short of explaining the mechanism leading from one to another. Because they don’t know.

There are a few teams working on research into the mechanism, and I’m eager to hear from them, because maybe research could shed a little light on how to cope with them.

Because there’s another ugly little fact: most of the advice well-intentioned health care professionals give to menopausal women about hot flashes has little evidence to back it up. And some of it is completely wrong.

Here is typical advice, from WebMD.

“To prevent hot flashes, avoid these triggers:

  • Stress
  • Caffeine
  • Alcohol
  • Spicy foods
  • Tight clothing
  • Heat
  • Cigarette smoke

Other things you can do to keep hot flashes at bay include:

  • Stay cool. Keep your bedroom cool at night. Use fans during the day. Wear light layers of clothes with natural fibers such as cotton.
  • Try deep, slow abdominal breathing (six to eight breaths per minute). Practice deep breathing for 15 minutes in the morning, 15 minutes in the evening and at the onset of hot flashes.
  • Exercise daily. Walking, swimming, dancing, and bicycling are all good choices.
  • Try chill pillows. Cooler pillows to lay your head on at night might be helpful.”

Let’s start with caffeine. While a 2005 study found some evidence that caffeine triggers hot flashes, a 2010 study found only a small effect of caffeine on hot flashes (this study included caffeinated sodas and cocoa). However, a very well-conducted 2011 study found that “women who drank more coffee had less severe [hot flashes] than the ones who drank less coffee.” I’m not seeing a lot of reasons to avoid caffeine, and coffee may actually help (in fact, I find that it provides short-term relief).

Which brings me to alcohol. The 2010 study found only a small effect of alcohol on hot flashes, and the 2011 study found no effect of alcohol drinking. A study just out showed that drinking alcohol during menopause actually decreased the chance of having hot flashes at all, as well as their severity. Alcohol is associated with health and social problems, so I wouldn’t start or increase drinking because of hot flashes, but there is no evidence that you should avoid alcohol if you are currently a moderate drinker.

Deep, slow abdominal breathing: This is a new approach being tested; results are not yet available. It may help cope with a hot flash. The jury is out on whether it could prevent hot flashes or make them less severe.

Anything that heats you up: Warm clothing, warm weather, warm beverages, warm food… basically anything warm can bring on a hot flash. One of my friends can get a hot flash walking by a hot stove. Keeping the room cool, turning on a fan or air conditioner, sleeping with fewer covers, etc. can all prevent hot flashes or make them less severe. But not entirely. You are still going to get them.

Tight clothing: I could find absolutely no evidence for this. The fact that women loosen or take off their clothes during hot flashes is just to get cool.

Spicy food: I found one study that came out in 2013 showing that a diet with regular hot spicy food intake increased hot flashes. The odd spicy dish might bring on a hot flash just because it warms you, but I wouldn’t cut out spicy food if it’s not a big part of your diet.

Cigarette smoke: I found mention of one study that found second-hand smoke increases hot flashes in non-smokers. More important is the evidence on smoking, which is conflicting. Observational studies have shown a negative effect of smoking, but that could be due to other positive health behaviour among non-smokers. The 2011 study, which had a strong design to detect triggers, found no effect of smoking. A new study shows that quitting smoking has a positive effect on hot flashes, making them less frequent and less severe, and that hot flashes were worse among women who had smoked than among non-smokers. Quitting smoking is a good idea for many reasons, and there is some limited evidence that it helps with hot flashes.

Obesity: Many studies have shown that obesity is a risk factor for hot flashes, so losing weight will help those who are really overweight. Women with a healthy weight should not try to lose weight to help with hot flashes – there’s no evidence for this. Furthermore, one study found that fasting (empty stomach) worsened hot flashes, and glucose improved them, so make sure you are not going hungry.

Stress: A 2005 study found that feeling happy and in control actually increased hot flashes, and stress decreased them. A small controlled study conducted in Japan and published in 2008 showed that doing a difficult mental task increased hot flashes on the spot. A recent study found that greater perceived stress and more depression and anxiety symptoms when hot flashes started were associated with more years of hot flashes. However, these stress symptoms may be an effect rather than a cause, and depression and anxiety are also symptoms of menopause itself. Limiting stress is a good idea for lots of reasons, but it’s unclear whether it helps with hot flashes. And I’m not going to stop doing difficult mental tasks because they might cause hot flashes.

Exercise: A very good randomized controlled trial published this year showed that exercise had no effect on hot flashes. A previous study showed that exercise actually worsened hot flashes, unless it was intensive exercise, in which case it improved them. Exercise is good for your general health, and there are lots of reasons to get exercise, but it probably won’t help with hot flashes.

The problem with trying to study hot flashes is that there are strong placebo effects – basically, if you think something might help, it probably will, but it seems to be mind over matter. And hot flash frequency and severity change often during menopause, sometimes day to day, so it’s difficult to say that doing any particular thing affected hot flashes. That’s why anecdotal reports from women that something improved their hot flash experience are unfortunately unreliable. The lifestyle advice has very little evidence behind it, except for losing weight if you are obese and for quitting smoking. Help for hot flashes will come from basic research into what causes them – I’m waiting for that news.

Fun science argot for the summer

As a science writer and editor, I see a lot of terms. Terms you don’t see elsewhere. Usually they just make me furrow my brow, but sometimes they make me laugh out loud. For your summer enjoyment, here are some of my favourites.

You know those animals all over conservation websites? Pandas, condors, and lions and tigers and bears oh my. Biologists call these charismatic megafauna. The first time I heard this, I nearly fell out my chair laughing. Of course, using charismatic megafauna to promote animal welfare is controversial, as the cuteness of an animal may trump its ecological value and lead to poor conservation decisions. Who wants to save leeches? They fulfil an important role, but charismatic they ain’t.

Recent reading on transportation accidents revealed a vocabulary most of us would never understand. For example, if an airplane leaves the runway in an unplanned kind of way, this is called an excursion. It’s just taking a little trip. Also, if an airplane hits the ground in a similar unanticipated situation, this is called a collision with terrain. Rather than another word the rest of us might use.

I work on a journal about seabirds, and that’s a treasure trove of argot. Today I’ll just mention an article in which the authors needed to categorize birds by how they were flying, so they called them gliders, glide-flappers, flap-gliders, and flappers. It was just a colourful way of capturing how much flapping and gliding they were doing, but I couldn’t keep a straight face.

Remember Superstorm Sandy? That was technically a mesoscale convective complex. If that phrase wasn’t in context, I wouldn’t even know what discipline it was in — geology? psychiatry?

Some of the most popular articles published in the Canadian Journal of Physics were on the motion of rapidly rotating sliding cylinders. Which is funny enough on its own, and gets even better when you realize the authors are talking about curling rocks.

Small fly species discovered in 1993 were named Heerz tooya and Heerz lukenatcha. You can’t make this stuff up.

Over in chemistry, I laugh every time the molecule Buckminsterfullerene is mentioned. This molecule was discovered in 1985, when futurist Buckminster Fuller and his geodesic dome — to which the molecule bears a striking resemblance — were still in vogue.

Those are just a few. If you have others, please write in and I’ll post the best ones.

Does anyone know what a meme really is any more? Or, 3 misused scientific theories that will astound you

As a science communicator, I get annoyed when scientific concepts are misused. And especially if they are used wrong and overused. And double especially if they are misused, overused, and used in a way that discredits the term’s inventor.

Which brings me to memes. First of all, what a meme is not: a photo with a caption uploaded to Facebook. Seeing it used to mean any trivial fad that zooms around social media for a while — or, even worse, the actual concrete image or text that gets shared and liked 438,962 times — just makes me bang my head against my desk.

A quick recap of what memes really are: the term was coined by British geneticist and atheist Richard Dawkins in his 1976 book The Selfish Gene. It is arguable that he was just looking for a metaphor for the self-replicating nature of genes, but he hit on something that had not previously been so well expressed. He noted that “cultural entities” can be self-replicating, like genes, moving quickly through populations and having marked effects on human behaviour and culture. While some of these can seem trivial — popular songs, fashions — many are ideas or skills that take hold and change the way people do things. Furthermore, there are arguments that some of the most popular things in culture, including music and clothing, become popular because they in fact reflect or signify underlying shifts in the zeitgeist. Cultural theorists have seized on the meme concept to explore how culture changes and why — questions in anthropology and sociology. Understanding memes could help explain social movements that are positive (the Arab Spring) or negative (anti-vaccination beliefs in North America).

The misinterpretation of the meme is the latest, but hardly the worst, example of mangled scientific theories. In fact, how scientific ideas become twisted and watered down even as they become popular is probably something those meme theorists should study. I have two other examples from the history of scientific ideas to help the academics get started.

Paradigms lost

I have heard paradigm shift used to mean a radical change in one’s personal or professional life (this one from a self-improvement course) or a significant social change (from one of my public policy professors). Neither was what Thomas Kuhn meant when he coined the term in The Structure of Scientific Revolutions in 1962. Just for the record, he meant what happened when a scientific model (paradigm) shared by the scientific community had to be completely jettisoned and replaced when an anomaly was found that did not fit the model. But as soon as the idea was released, it was applied in many contexts that Kuhn clearly did not foresee. Almost any change was dubbed a “paradigm shift” just to make it sound more significant. It came to mean a “sea change” (which is not what Shakespeare meant in The Tempest either, but that’s another subject for another blog). I would use the term if a widely held model was completely upended in any field — not just science. But it does not mean an unexpected election outcome or someone’s decision to walk away from his or her job.

Origin of the Specious

After Darwin’s On the Origin of Species appeared in 1859, its concepts of “survival of the fittest” and “natural selection” were swiftly misapplied to justify mistreatment of one social group by another on the basis that it was “natural” for weak people to be crushed underfoot and for strong people to do the crushing. This was used to justify unbridled capitalism, eugenics, racism and so on — a trend later called “social Darwinism.” Never mind that Darwin was referring to a strictly biological process that often required hundreds of years of adaptation. This one is easy to see in hindsight, but ask yourself how often today we take it for granted that there are social losers and winners and that the decisions affecting people are “just business decisions.” Maybe the social Darwinism meme was more lasting than we care to admit.

Maple just one of the plants that can fight bacteria

When the story came across my desk, it sounded too sweet to be true: our iconic Canadian elixir can actually help antibiotics vanquish resistant bacteria. Researchers at McGill University in Montreal have found that some of the chemicals in maple syrup — a phenolic fraction — can help antibiotics in two ways: by breaking down biofilms that many bacteria build to protect themselves and by stopping the action of “pumps” inside bacteria that flush antibiotics out of the bacteria. The maple syrup extract also affects the genes that make bacteria infective.

But this type of ability is not that unusual in plants. I have had the pleasure of working with a researcher in Mexico, Dr. Francisco Espinosa García, as well as students in his lab, who study “chemical ecology” – the chemicals produced by plants and animals that affect their interactions. For example, one of his students had an interesting paper on how tomatoes adapt genetically to produce a chemical that repels the tomato’s most common pest. Plants have complex chemical “immune systems” that fight off pests and infections. It is no wonder that these chemicals are often antibacterial.

Back 10 years ago, the Canadian Journal of Microbiology published a very interesting article from researchers in Brazil, where a methanolic pomegranate extract has been used as a folk remedy for infections. The researchers found that the extract worked synergistically with various antibiotics against many strains of methicillin-resistant Staphylococcus aureus (MRSA), one of the most feared infections today. There were some problems with the research – the antibiotics tested were older drugs no longer available in many industrialized countries and the tests were in a lab, not in people – but the principle was there.

As I mentioned in my previous post, the answer to antibiotic resistance may not involve going to the ends of the earth, but looking at the natural processes all around us to discover ways to combat pathogens with pomegranates, tomatoes and maple syrup.

A new pipeline for antibiotics

When I was hired at the Canadian Medical Association Journal in 1991, it was because there were so many ads for drugs that they needed people to edit copy to keep the ads from bumping into each other. I joked that Prozac was paying my salary.

It turns out that was the crest of a wave of innovative drug discovery. Releases of novel drugs are less common today. Many of the new drugs are “biologics” engineered from DNA or proteins, many of which are for chronic conditions and diseases. And a lot of new drugs are so-called “me too” drugs, similar to other recently released drugs so that the manufacturer can grab some of the market. In this picture, there has been little new for pathogenic illnesses since the protease inhibitors revolutionized HIV treatment. It’s as if everyone has figured all the antibiotics have been found.

I recently covered the discovery of a new antibiotic for CMAJ. Several other media outlets had the story as well — it had been published in Nature. But I quickly realized that the particular antibiotic wasn’t the story. There had been some excellent features recently on “antibiotic hunters” who were scuba-diving in Greenland to find new antibiotics. Literally going to the ends of the earth. The reason for the extreme measures is that sources of antibiotics nearer to the lab had been “overmined” in the words of several researchers. The real story is that several research teams have figured out new ways to find antibiotics from old sources. There are lots of antibiotics all around us: we just didn’t know how to “tame” them, as the researchers call it. Some of the newly discovered antibiotics are coming from people’s back yards!

A lot has been made of the use of these novel antibiotics to overcome resistance, as this is a major problem in infection control. Bacteria and viruses adapt genetically very quickly, doing a kind of DNA juggling that other organisms can’t even do, swapping genes with other bacteria and reorganizing their own DNA. How can lengthy drug development cycles keep up with these fleet pathogens?

Yes, resisting resistance is one benefit of novel antibiotics. However, I think the molecules and pathways now being studied will go much farther than addressing resistance. If researchers can find thousands of potential antibiotics, some of them may be active against viruses — for which we still have very little –, cancer, and many chronic diseases for which we do not know the cause but which may be pathogenic. In fact, in a generation or two we may think of drugs in an entirely new way, as capable of curing illnesses minor and grave that today are accepted as incurable. A century from now, medicine may be as far ahead from today as it is today from our grandparents’ day.

Good news: Ebola has peaked

Deep within the newspaper today, a spark of good news: new Ebola treatment centres in Liberia are sitting 80% empty. Because Ebola is declining. Hurray. Health officials caution there are still hotspots and there may be another rise, but the trend is in the right direction.

With the official death toll around 5000 but the real toll probably more like 10,000, this was the next epidemic everyone feared. But “fear” is the operative word here, because the hyperbolic reaction outstripped the reality. I read columns in which opinion leaders blamed the World Health Organization, blamed doctors, blamed Obama (for goodness’ sake). If you believed any of this nonsense, you would think that no one did anything they should have.

But the reality is precisely the opposite.

Before 2006, there was no real global public health system. The World Health Organization (WHO) tracked only a few developing-world diseases. But that all changed, and the thing that changed it was SARS. When SARS broke out in China, the Chinese public health system did not have the tools in place to cope with it. It then took the Chinese government much too long to admit that the country had an outbreak. By that time, SARS had reached Canada, and the WHO said people should stop travelling here. Conferences were cancelled and Toronto streets were empty, which was ridiculous given that very few people were exposed, and most of them were doctors and nurses treating the sick. Canada’s economy suffered a loss of billions of dollars unnecessarily.

In the wake of SARS, a lot of people around the world got together to put in place a functioning world early-warning and intervention system. The result was the International Health Regulations, which came into effect in 2006. All UN members agreed to abide by the regulations, which give the WHO new powers to monitor outbreaks and knock on government doors, asking, “What’s going on?” The regulations also require countries to have a public health system. If a serious situation arises, an emergency committee is formed of experts from around the world. They can declare an international emergency, which has important ramifications. It means that the host country has to get on top of the epidemic, or the UN will walk in. But — and this is key — it does not mean trade and travel stop. On the contrary, the WHO tries to keep supply lines open.

The regulations got their first work-out during the H1N1 epidemic, which was the first declared international emergency. My Mexican colleagues explain that Mexico welcomed the involvement of the WHO, which worked side-by-side with the Mexican government to get the outbreak under control there. The WHO has also worked closely with China during its avian influenza outbreak and with Saudi Arabia during its outbreak of a new SARS-like virus, MERS. Neither was declared an emergency, but the close monitoring by the WHO nudged and supported the Chinese and Saudi Arabian governments to handle the outbreaks properly. The next emergency declared was an outbreak of polio in war-torn Syria… who knows what is going on there.

After putting out these fires, WHO was hit with the conflagration: Ebola. This was the nightmare the regulations had been set up to face: an outbreak growing at a geometric rate in countries with poor public health infrastructure and few resources. The WHO was quickly overwhelmed, and the UN set up a special body to cope with the outbreak.

I get the WHO’s daily progress reports, and amid the skyrocketing death toll there was a lot of good news. Many countries committed money and health-care workers to fighting Ebola right on the ground. Several African countries contained small outbreaks and conducted careful contact tracing to find all those infected. They quickly eliminated the virus. Local education and safe burial practices were instituted and started working to contain new infections. Travel and trade were kept open, and countries like Canada that imposed ridiculous entry conditions had their wrists slapped. (If it had been Canada with an outbreak like SARS, we would have been singing a different tune.)

In fact, as some commentators have noted, this was the first real test of the International Health Regulations, and the WHO passed. Ebola has been turned around. It did not become a pandemic, and most of the world is safe. Sure, there will be some lessons learned, but the fundamental approach is sound.

We have a lot to thank the WHO for. And it behooves us to cooperate with the WHO and abide by the regulations against the day that an emergency is declared here and we need to keep things going while battling to save lives.

Another day older and deeper in cell senescence

I don’t know about you, but I’m getting older. It has even started to show: grey hair, thinner skin, “fine lines,” more muscle pains that take longer to get better.

But while more of us are older than at any other time in human history, we are in our infancy in understanding aging. In the mid-1990s, I attended a talk by Leonard Hayflick, author of How and Why We Age (1994). Work conducted over the 30 years before Hayflick’s book had established some of the mechanisms of aging. But before that, we had little idea why the body aged.

Hayflick is a folksy, easygoing talker, who walked a group of non-specialists through how cells – and we – age. At one point, he picked up a fireplace poker to point at his projected slides. He said cheery things like there’s no reason for us to be around after we reproduce and raise our children. That is, from an evolutionary point of view.

Hayflick explained that the reason we get old is that our cells get old. Here’s why: every time they divide, cells lose a few of the little repeated bits of DNA at the ends of the chromosomes. This is not good, because that DNA might have some genetic code that runs something in our body. So the chromosomes have caps at each end, called telomeres, that don’t do any protein coding and that shorten after each division. As well, telomeres prevent chromosomes from joining or rearranging, which could result in abnormal cells, which could lead to cancer. Eventually, those telomeres are all used up, at which point the cell stops dividing. This was one of Hayflick’s breakthroughs, and the finite number of divisions is called the “Hayflick limit.” At that point, the cell may enter the cell’s equivalent of old age (senescence), in which does not divide and barely functions, or self-destruct (apoptosis). As various cells stop growing or die, we age, losing functions of our body, until one day some vital function stops altogether.

It’s a good thing cells get old and die, because it turns out the only type of cells that don’t age and die are cancer cells. These cells are immortal; their telomeres don’t shorten; they keep on going. That’s why the cells taken from the cervical cancer suffered by Henrietta Lacks, an African-American woman, in 1951 are still alive today and used extensively in scientific research (HeLa cells).

It’s ironic that the search for eternal life is ultimately self-defeating: the only immortality to be found is in cancer, which can end your life. So stop complaining about getting old, because the only biological alternative is worse.


But the relationship between aging and cancer turns out to be more complicated than that. As a scientific editor, I work with a number of authors on papers for submission to journals (among other things I do). One of the authors I work with, Richard Richardson of AECL and McGill University, studies cancer and aging.

Cancer rates go up with age. Here’s a typical graph, from one of Richardson’s papers (data for all types of cancer from Statistics Canada, graph reproduced here under a Creative Commons licence; ASR stands for age-standardized rate):cc-12-2468-g1

You will notice that the cancer incidence rates also begin to fall after about age 80.

Richardson looks at why these rates change with age, rising quickly and then falling off. As he explains, “Aging and cancer are inextricably entwined and involve multifaceted mechanisms.”

One such mechanism is a gene called TP53, which other authors have called the “guardian of the genome.” It is involved in some of these end-of-life processes for cells, ensuring that cells go into either senescence or apoptosis once their telomeres are used up. In an article published in Cell Cycle (doi: 10.4161/cc.25494) in 2013, Richardson looked at TP53’s role in aging and cancer. TP53 is a gene that often mutates as we get older. Mutations can stop it from doing its job in keeping old and abnormal cells from becoming cancerous. As a result, these mutations have a significant role in cancer, and can make a tumour malignant or invasive. As well, the mutations are implicated in cancer affecting a wide range of organs and cells. Richardson looked at large global databases of cancer tumours to tease out the relationship between TP53 mutations in these tumours and patient age. One theory of why cancer rises quickly with aging is “genomic instability” – problems with the entire genetic code that develop as we age. Experiments have shown that TP53 mutations may be a cause of this genomic instability. Based on his study findings, Richardson estimates about one-quarter of the aging-related rise in cancer is probably due to mutations in this gene.

So, aging is what cells do normally, and the only cells that resist aging are cancer cells. But aging also raises the chance of cancer if the TP53 gene is no longer working the way it is supposed to.


That’s not all that is happening as we age. Cells are growing and dying, and our organs are changing as a result. Richardson’s research shows that some of these processes actually start early in adulthood, and may hold clues to cancer and age-related changes.

First, cells in the body are replaced on a cycle, and the “turnover” time to replace cells varies widely, depending on the type of cells. Some cells with a fast turnover (but, mysteriously, not all) are more prone to cancer. Epithelial cells, for example, have a far higher turnover and cancer incidence than any other type of cells. These cells make up our skin and the tissues lining the inside cavities of our bodies, as well as many glands.

We also know that most of the tissues and organs of the body lose mass as we age. We may not realize that they are getting smaller because the mass lost is “functional” mass of the organ tissue, which may be converted to fat (in case you hadn’t noticed) or fibrous tissue.

In a paper published in Experimental Gerontology (doi: 10.1016/j.exger.2014.03.015), Richardson and his colleagues found that the tissues and organs start to lose mass when their owners are 12 to 50 years of age, depending on the organ, with most organs starting to decline in a person’s 30s. As well, in many organs the mass loss accelerates as we age, although in some organs this is not a strong or consistent effect.

They also showed that cell turnover time and this mass loss are related. As we age, the cells enter their old-age state or self-destruct, there are fewer and fewer replacement cells, and the organ or tissue shrinks. This happens earlier in cells that turn over faster because of the Hayflick limit – the number of divisions that can happen before the cells stop dividing. There are other factors that could lead to mass loss, too, so it’s not entirely straightforward.

So far we’ve tied together cell turnover, mass loss, our old friend Leonard Hayflick, and aging. Now cancer comes in.

Prevailing theories of aging and death hold that we lose overall fitness (all our bodily functions, not just why I can’t do the tougher exercises at the gym anymore) and generally decline with advancing age for an evolutionary reason. Evolution has selected humans who are strong and bear and care for children when they are young, but the trade-off is that we age and decline. Basically, these theories say, when humans were evolving we never made it to old age because of accidents and diseases, so the fact that our bodies started breaking down when we were older (through DNA damage as well as “wear and tear”) wasn’t part of the equation. (Both Richardson and I dispute this view: there is evidence that even early Homo sapiens achieved old age.) But Richardson asks, if this theory were true, then why would our organs start to shrink when we’re young adults? It seems like there’s a reason why the aging process starts soon after we start to have children. Richardson’s research seems to contradict the longstanding theory that evolution just turned a blind eye to aging.

The mass loss seen even in young adults is linked to cell turnover, which leads cells to exhaust their divisions and attain the old-age state (senescence). If more cells are becoming senescent, and fewer are growing, this prevents cancer. In fact, Richardson theorizes, this mechanism may have evolved to prevent cancer in young people in their prime reproductive (and just plain productive) years. If so, it has done a good job, as cancer rates in young people are low (see graph).


Richardson thinks the patterns of cancer throughout the human lifecycle may also have to do with stem cells. Stem cells start the process to grow or replace tissues and organs. The stem cells produce progenitor cells, which can then “differentiate” into other types of cells, such as blood cells or bone cells, that are needed by the body. Stem cells can divide also into two stem cells (self-renewal).

Throughout life, the stem cell capacity slowly diminishes. While the body is growing, there are plenty of stem cells to supply the huge demand for cells for development. Growth tails off in the 20s, but then the demand for new cells starts to increase again as existing cells enter the old-age state (senescence) or self-destruct (apoptosis) and need to be replaced. In particular, the need for new cells to replace damaged cells increases throughout life. At a certain point, the demand for cells starts to outstrip supply. This is when the tissues and organs shrink. However, Richardson believes that, in some people, this demand-to-supply ratio becomes very high, either because of extremely high demand for new cells or “exhaustion” of stem cells. In this condition, some of the stem cells may become precancerous, and lead to cancer after a lag of a few years.

Richardson explored this hypothesis in a paper in Mechanisms in Ageing and Development (doi: 10.1016/j.mad.2014.06.001) by looking at age patterns and stem cell supply in relation to bone tumours; the demand-to-supply ratio fits the patterns seen in common ages when bone tumours are found.

And that drop-off in cancer rates in people over 80? Telomere length and cell senescence stabilize in elderly people, which means that the rising demand-to-supply ratio for stem cells peaks and then declines.



What I like about research – all research – is that it points us in a useful direction. For example, researchers have long wondered why women live longer than men, on average, and looked at estrogen, immune factors, oxygen usage and so on. Well, it turns out women’s telomeres are about 9% longer than men’s (according to evidence from peripheral blood cells), which is probably an important factor.

Understanding the relationship between aging and cancer may one day open doors in preventing and treating cancer. It is basic research like this that leads to the big health breakthroughs. But that can take time. I find that understanding how our bodies work can also help us accept the current reality of our human lives.