Recycling the Old

For everything there is a season, and a time for every matter under heaven

Really? It made sense when I was young, I suppose -when all of Time was ahead. When I needed to think there was some order to things. That past and future meant old and new. But as the years slip past, I find myself wondering about disparate things. Opposites. Like what, really, is the difference between new and old? Is it merely a temporal distinction? A nudge along a spectrum? Or a more fundamental change -a conceptual shift? I suspect it can be any of these, of course, but it still begs the question: does any change, any difference qualify? What if there is no change in form at all, but rather a change in function? In Purpose? Would that be new, or merely a rose with another name?

The concept of recycling has been with us from the dawn of time. When materials were scarce or unavailable things were used again, either in their original roles, or repurposed for something else their makers had not anticipated -a new situation, a new need. And so the old rises from its ashes like a Phoenix, but this time in a different play as another, unfamiliar actor.

The tradition of respecting the wisdom of elders and retelling their stories is also an honoured tradition. But as stories do, they alter over time and are often interpreted in new and unexpected ways. The knowledge is not lost, it’s just explained in different words. Understood in a new context. Reconstituted. Society has learned that there is often a benefit that accrues to re-examining the old and looking at it from an altered perspective. So has Science: http://www.bbc.com/news/health-33635575 Bisphosphonates have been around for a while as treatments for osteoporosis, a condition in which there is decreased bone mass. They help to prevent bone loss and so strengthen the bones themselves. It is most frequently used in the post menopausal woman when she no longer produces bone-protective hormones from her ovaries.

Bone is a common site for breast cancer cells to travel to (metastasize) however, and they can lie dormant there for years after the primary tumour has been removed from the breast. And yet, interestingly, those women who were already being treated with the bisphosphonates in the menopause and later developed breast cancer, showed a 28% reduction in cancers developing in their bones. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60908-4/fulltext And because the patents on bisphosphonates have expired in many jurisdictions, the cost of these bisphosphonates is minimal when compared to other ‘new’ treatments on the market.

But there’s more. A medication originally designed for diabetes –glitazone- has been found to decrease the likelihood of developing Parkinson’s disease. http://www.bbc.com/news/health-33608725 Of course this is just a comet in an otherwise cloud-filled night because glitazone is not without its own serious side effects –bladder and heart problems, to name just two- but it is a promise whispered emphatically, albeit quietly, to anyone working in the field. A starting point for future research…

So I suppose we should keep poking about in the ashes. Stirring embers to see if there is a Phoenix hiding somewhere in the cinders, fast asleep and dreaming of another job. We affix labels to things –categorize, then name them for all time. It’s a way of keeping track. Knowing what to expect. The problem, of course, is that things change. Evolve. Mutate. And as Jiddu Krishnamurti, a philosopher, once said of the disadvantage of naming god, it constrains the concept. Limits it. Doesn’t allow for growth and development. I think it is sort of like naming and classifying something when it is only a seed and we are still unaware of its potential. Maybe old is something like that. Where there is life there is always a seed and its age is beside the point. Meaningless.

I’m beginning to see age as a definitional issue, and not in the currently favoured framework of chronological versus biological –or even psychological- age so condescendingly mouthed by those too young to have experienced the ill-disguised discrimination it entails. There is useful wisdom that accretes with years and experience of course. But age is an oven that cooks whatever has been put inside –changes it into something else. Sometimes something entirely new.

I opened with a quote from Ecclesiastes, so let me close with one from the Talmud: ‘For the unlearned, old age is winter; for the learned, it is the season of the harvest.

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The Body’s Clock

Scientists –well, all of us- have been suspicious about the health risks of shift work for a long time now. Perhaps there is a reason buried somewhere in our genes that suggests night is for sleeping and daytime for working. Originally, no doubt, it was because it was difficult to see things in the dark and lighting, even when it became available, wasn’t very good.

But there is another reason: the Circadian Rhythm (from the Latin circa –around, and dies –day) which is often defined as physical, mental and behavioral changes that follow a roughly 24-hour cycle, responding primarily to light and darkness in an organism’s environment. The body clock, in other words. And there’s the clue: light and darkness. These are not just elements in our environment that we have come to expect, they actually have a biological meaning for us although this is, to a certain extent, entrainable. Malleable. As Wikipedia (sorry!) puts it: The rhythm can be reset by exposure to external stimuli (such as light and heat), a process called entrainment. The external stimulus used to entrain a rhythm is called the Zeitgeber, or “time giver”. But it can take a while to adjust –think of jetlag, or sleep disturbance after starting a new shift at a different time.

The body can adapt to many things, no doubt; the problems seem to arise when the pattern keeps changing. As folk wisdom attests, we are inherently creatures of habit –acquired behaviour patterns that are repeated so frequently they can become almost involuntary. As no less an observer of folkways than Samuel Johnson once said: “The chains of habit are too weak to be felt until they are too strong to be broken.” So one might ask why we –and many other animals- seem prone to develop these routines, these almost unconscious ceremonies. Is it simply a need for predictability? Or is it something deeper, something tied to our evolutionary past..?

In our evolutionary development we obviously experienced disruption of light/dark cycles –they occur as we travel through the seasons- but these are gradual and steadily progressive; shift work –especially rotational shift work- is not. And only recently has it become more obvious that there may be a price to pay. There have been several studies that have looked at this in various ways, but ‘Although epidemiological studies in shift workers and flight attendants have associated chronic circadian rhythm disturbance (CRD) with increased breast cancer risk, causal evidence for this association is lacking’ as the abstract of a paper published in Current Biology noted. I saw this in a July 2015 article in BBC News reporting on a study co-authored by Dr. Kirsten Van Dycke which suggested that the chronic need to re-entrain the circadian rhythm because of changing light/dark cycles can increase the risk for both obesity and breast cancer! http://www.bbc.com/news/health-33569161 Now, admittedly, the study was done on mice who were prone to develop breast cancers anyway, but when the light/dark cycles were switched over a long period of time (‘Mice prone to developing breast cancer had their body clock delayed by 12 hours every week for a year’) they developed them sooner.

Humans are obviously not mice, but it is difficult to control for possible contributing factors in the average human study: ‘Several scenarios have been proposed to contribute to the shift work-cancer connection: (1) internal desynchronization, (2) light at night (resulting in melatonin suppression), (3) sleep disruption, (4) lifestyle disturbances, and (5) decreased vitamin D levels due to lack of sunlight. The confounders inherent in human field studies are less problematic in animal studies, which are therefore a good approach to assess the causal relation between circadian disturbance and cancer.’ http://www.cell.com/current-biology/abstract/S0960-9822(15)00677-6

And the conclusion from this study? ‘Animals exposed to the weekly LD [light/dark] inversions showed a decrease in tumor suppression. In addition, these animals showed an increase in body weight. Importantly, this study provides the first experimental proof that CRD [Circadian Rhythm Disturbance] increases breast cancer development. Finally, our data suggest internal desynchronization and sleep disturbance as mechanisms linking shift work with cancer development and obesity’.

This is worrisome, to say the least. One could certainly argue that a woman with an increased risk for breast cancer –say a heditarily aquired BRCA1/2 mutation- would be best to avoid jobs involving chronic irregular body clock disturbance such as flight attendants, commercial pilots, and so on. But I’m not sure the risk is confined to that population. What about others –especially if they have additional life-style risks such as smoking, diabetes, alcohol issues?

And what about men? If –as the study suggests- a chronic body clock disruption may cause a decrease in tumour suppression, would that not suggest a similarly increased risk? The disruption also seems to have an additional risk for increased weight gain –obesity. Is the risk for type 2 diabetes therefore also increased? Clearly this is an area requiring much more research -further elucidation of the mechanisms involved and mitigation strategies at the very least. Sleep is so important –regular sleeping patterns…

I can’t help but remember the words of Shakespeare’s Macbeth talking to his wife after he has killed Duncan, the king:

Methought I heard a voice cry, “Sleep no more!

Macbeth does murder sleep”—the innocent sleep,

Sleep that knits up the raveled sleave of care,

The death of each day’s life, sore labor’s bath,

Balm of hurt minds, great nature’s second course,

Chief nourisher in life’s feast.

Art, once again, anticipating Science…

Breast and Ovarian Cancer Screening

I am sometimes troubled by the concept of risk. I mean how can we possibly decide whether or not a risk is acceptable? No matter the statistics, if the issue under consideration doesn’t happen, then the risk assumed was acceptable. So far, so good. But of course the converse is also true: no matter how low the risk, if it does occur, well…

Ours is a culture of prediction. Statistics. Guessing. I rationalize buying a lottery ticket by convincing myself that if I don’t buy it, I won’t win -no matter how low the odds, no matter how unreasonable it would be to assume that I would be the one in –what?- ten million who wins the jackpot. Or anything, for that matter…  And no matter that without a year of such profligate spending, I could treat myself to a sumptuous dinner at a good restaurant.

Of course, we all live in hope, and if the lottery ticket funds some worthwhile government project, then it is an almost enjoyable form of indirect taxation. Assimilable because it is freely chosen. Optional.

It is a different proposition entirely if the risk is one to which we do not wish to subscribe but have no choice: genetic defects in a developing pregnancy, cancers, diseases, to name but a few. It is likely to our advantage to interrogate these, if possible. Of course, the question then becomes who should undergo the screening. Only those at the highest risk –those with a family member with the condition, say- or everybody? Just in case.

Screening always seems to be bathed in a soft, warm glow. If you can test, then why not? Just pop in to your local lab and get that PSA; find out if your prostate is betraying you. Demand yearly mammograms as soon as you feel concerned. As soon as a friend or even a friend-once-removed has a cancer scare. And at any age, because you never know…

If only screening was that good; if only all negative tests were reliable –and, for that matter, didn’t have to be repeated at intervals to keep pace with the ravages of Time wreaking its not so subtle havoc on our aging bodies.

Screening for specific inherited genetic mutations for breast and ovarian cancers are the relatively new species of Wunderkind: BRCA1 and BRCA2. These are tumour suppressor genes broadly speaking; we all have them, and they are located on chromosomes 17 (BRCA1) and 13 (BRCA2). But if they contain defects -mutations- they may no longer function efficiently and so be unable to winnow out mistakes such as tumours from proliferating. The mutations are inherited in an autosomal dominant manner and women with these particular mutated genes have a lifetime breast cancer risk of 50-85%. .

So why not screen all women for these genes? Indeed, a recent study published in the Proceedings of the National Academy of Sciences (USA) suggested just that: http://www.pnas.org/content/111/39/14205.abstract

On first reading, it sounds like a reasonable approach. But I’m not so sure. First of all let’s put the whole issue into context. Less than 10% of breast cancers (and <15% of ovarian cancers) seem to be associated with BRCA1 or BRCA2 mutations. And, although even less common, there are hereditary breast cancers associated with other genes, so there might be a false sense of security from testing only the BRCAs.

And then there’s the uncomfortable fact that there have been over a thousand different mutations in BRCA1 and 2 discovered so far. You’d have to know which one to look for. Of course, some populations have more prevalent mutations –so called Founder effects– which might simplify the search. Two per cent of Ashkenazi Jews, for example, carry specific mutations of BRCA1 or BRCA2. And there are other populations carrying unusual founder mutations that might facilitate searches in them as well: people from the Netherlands, Quebec, Iceland, to name a few. Or in still other groups -some families, for example- if the particular mutation resulting in their tumours has been identified, then the process is obviously easier.

The most successful screening is in people with identifiable risks, however. With breast cancer, such things as family history -especially a young age of developing the breast or ovarian cancers (the younger, the more chance there is a risk that can be  inherited), or a family history of so-called triple negative breast cancers –progesterone, estrogen and HER2 receptor negative. Males with breast cancer (yes it happens) are another, albeit infrequent clue to increased risk.

But screening everybody? Let’s get back to risk assimilability. Just what risk is acceptable? Less than 50%? Less than 25%? No risk at all..? Sometimes the answer is easy: a 50-85% lifetime risk of breast cancer if specific BRCA1 or 2 mutations are present is likely not tolerable. But what about the odds if only 2% of the population had that risk, as is the case for BRCA1 and 2 mutations in the Ashkenazim? Or if the chances of those mutations are even lower: 1/800-1/1000 as it is in the general population?

And what if you are not a member of a high risk population, or if there are no cases of breast or ovarian cancer in the family? Should you still be screened? And if so, with what? Remember there are many different mutations possible on the BRCAs -not all of which may result in an increased cancer risk. And there are other genes than BRCA that may play a similar role sometimes. So if you are just concerned that you might be at some risk, or worse, merely curious… Well, its best to remember that we are all exposed to dangers each day that we don’t even think about -and there’s no avoiding them: everything from tripping and falling down the stairs, to slipping on some ice; from having a heart attack, to getting hit by a car crossing the street to shop. We have to put things in perspective: life is a risk, and we are fragile creatures. Remember Shakespeare’s Hotspur in Henry IV:

‘Tis dangerous to take a
cold, to sleep, to drink; but I tell you, my lord fool, out of
this nettle, danger, we pluck this flower, safety.

So, if there is reason to believe there is a risk on the horizon, then it’s best to mitigate it. But don’t go looking for it in places it doesn’t exist.