The Awe of BRCA

Awe: the word has been pasteurized, connotized almost beyond recognition. But I suppose that’s what happens to all really powerful words. There’s a life-span to language; a generation if you’re lucky; a year if social media gets hold of it –likes it… But I think the ship of awe and all of its elegance went down quickly -even before Facebook or Twitter could sink it. It’s a shame because I am sometimes filled with it.

Different things inspire it in me; there’s no formula, no recipe for the appeal. I am sometimes simply stopped in my tracks, occasionally accorded an audience with grandeur. Majesty. Awe: the ineffable sublimated and instilled wordlessly into my head.

Most recently it was occasioned by genetics -unsurpisingly, because I understand so little of it nowadays. Since the genetic code was cracked and genes in all their undress were unfurled from where they ruled unseen in their closet, I have been a stranger in an even stranger land. I sometimes feel as a child must, confronted with an explanation that has not lost any of its initial magic. Any of its mystery…

And it’s not merely the unravelling of the genetic puzzle that intrigues me. I am scarcely moved by the knowledge -no, not the knowledge, the words- that on the short arm of chromosome 3, position 21 (have I got that right?), there exists a gene that makes a chemokine (a what?) that has an important role in the resistance to infection. I suppose I should care more, but I don’t.

The gene that has captured my interest is the BRCA gene. ‘BRCA proteins are required for maintenance of chromosomal stability in mammalian cells and function in the biological response to DNA damage’ -that from the Journal of Cell Science. In other words, they make sure that the DNA is okay, and deal with it if it is not… They repair damage and keep the cell growing normally. They suppress tumours; mutate the genes -cripple them- and the oversight is lost.

That much I knew, but what intrigued me was that the BRCA genes also occur in plants. They evolved about 1.5 billion years ago in whatever single-celled creature that was the common evolutionary ancestor to both animals and plants. The fact that these genes also exist in plants (most studied in a small flowering plant called arabidopsis, because in 1990 it was chosen by the National Science Foundation as the first plant that would have its genome sequenced) suggests they have an important and enduring function throughout the phyla and kingdoms. Plants, too, need to manage what happens to their DNA: they are rooted to a spot and can’t avoid recurring environmental stress factors that might damage it. As an example, some mutations in the arabidopsis BRCA allow certain cells to divide uncontrollably making the plant very sensitive to various forms of radiation. Sound familiar..?

Not all of the BRCA gene is the same in different organisms, of course: different domains, or portions, with different functions are preserved that seem to have an evolutionary importance relevent to each entity. Why re-invent the wheel? Nature fiddles with what it already has -what it knows. That mutations in this same gene should have such important effects on breasts and ovaries in humans is interesting, to say the least. All organs have DNA that is responsible for their growth and development; all DNA needs surveillance and repair; all organs have a cancer potential…  So was there a common ancestor somewhere whose BRCAs first assumed uber guardianship of breasts? Whose unintended mutations engendered these hereditary risks -a family, an individual..? Presumably stuff has to start somewhere.

And although arabidopsis doesn’t have analogous organs to humans, similar BRCA mutations do not seem to be as lethal, so I suspect that studying them may lead to some important insights. Maybe they already have: I can barely understand the way the studies are worded and find myself perusing only the Introduction and then skipping past the Results section to Conclusions where the authors discuss whatever ramifications they feel obtain from the experiment. I still read through a glass, darkly.

But somehow, the knowledge that we are in a sense all part of the same organism is epiphanous. Humbling… As Shakespeare (in Troilus and Cressida) has Ulysses say: “One touch of nature makes the whole world kin.”

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HPV

Cancer of the uterine cervix is a sexually transmitted disease; it is the second most common cancer of women in the world and it is spread sexually. Who would have guessed? The clues were there all along, of course: it was more common in sex workers, and women who had become sexually active at an early age; it was rare in nuns… But it took a while to connect the dots -and for technology to catch up with suspicions: viruses couldn’t even be visualized until the invention of the electron microscope, although their existence was suspected much earlier using filters with holes too small for bacteria to pass through. And then their DNA had to be identified in cervical cancer cells… and classified. It was a long journey all right.

But sexual transmission? The jump from abnormal Pap smear to the bedroom was -and is- a hard sell.  The fact that more than 80% of sexually active humans have been exposed to the virus was hard enough, but add to that the knowledge that the vast majority of teenage infections will clear on their own because of the vigorous immune response at that age, and you have a recipe for confusion. Or complacency.

Cancer of the cervix is rare before the age of 25 -the virus has a long prodromal developmental period- so after telling women how important Pap smears were in preventing, or at least detecting, this infectious cancer, raising the age of the initial Pap smear from the time of first sexual activity to age 21 in North America, did little to foster understanding. And then playing with the frequency and mode of surveillance for the rest of the age groups… Well, it was almost a breach of trust; changing the rules after years of teaching was just not on.

I mention this only to put the contemporary problems of counselling young women into some perspective. Especially now that vaccination against some of the more common and troublesome varieties of Human Papilloma Virus is possible. Vaccination has always had its opponents, and HPV is no different. But for my practice, there seem to be two major questions that arise: the need for continuing screening after vaccination, and the need for vaccination if a woman has already had a pre-cancerous condition treated.

These are confusing, if not vexing questions. There are at least 15 types of HPV that cause cancer but only two major varieties that account for the vast majority of cases in the community: types 16 and 18 (they’re numbered, rather than given cutesy names). These are the strains that are incorporated into the current vaccines. So if a woman has already had dysplasia -the pre-cancerous condition caused by the virus- it will have been caused by only one of those types and she is still vulnerable to the other. And therefore she still needs to be vaccinated. I get asked this every day, I think. Fortunately the schools in my province have incorporated the HPV vaccination into the early grades at school -hopefully before sexual exposure- so the question may well be an anachronism in the foreseeable future.

But the need for continuing screening in a vaccinated population is more difficult to understand in an era brought up on the concept of herd immunity: the idea that the more people who are vaccinated, the less prevalent the virus, and hence the less chance of being exposed to it. What tends to get forgotten, however, is that there is never a completely protected group: we are a heterogeneous society with new, unprotected people entering it from outside; immunity may wane; less common strains or perhaps novel viruses might gain prevalence and not be incorporated into the contemporary vaccine products. No, there are many reasons not to let down the guard of vigilant surveillance.

But a problem still persists: HPV doesn’t behave at all like a sexually transmitted infection in the minds of most people. We have come to expect cause and effect to be temporally accountable: the unprotected sexual encounter last week results in identifiable symptoms this week. Blame is assignable; lessons are learned. But with HPV, cause and effect are often separated by uncharted and imponderable years of time. There are seldom symptoms, seldom acquired wisdom. No one -or everyone- seems culpable: a difficult take-home message indeed. As I have already suggested, the voyage from Pap to Prevention is a stormy one.

But maybe this is just a generational thing: what we find difficult to assimilate today, will be greeted with a knowledgeable shrug tomorrow. We are creatures of more than structural evolution; more than linear accrual. As Shakespeare says: We know what we are, but know not what we may be. Or even better: Lord, what fools these mortals be!

Screening Systems

Science, or at least the scientific method, can disappoint can’t it? We are informed -assured- that something is correct, the right thing to believe, and then with the passage of time and the arrival of new data must suddenly disavow that ‘Truth’ and start all over again. The comforting feeling that we have at last apprehended the underlying essence of something is torn away, leaving us with yet another useless fragment: a wide tie in a narrow-tie world… And the change, not fully understood, is apt to leave us bewildered and suspicious that nobody really understood it in the first place -not even those in charge. We are short-term creatures and our lives are brief; certainty is a luxury we long to indulge. A longer view of things is usually difficult and often opaque so a whole generation will espouse one thing, but the next another.

Medicine is not exempt. We spent a lot of time educating people -and governments- that a yearly health check-up was a good investment of time and resources: it would diagnose conditions at an earlier stage when treatment would likely be more successful and less expensive. It would save lives, save dollars; it was, and is, intuitively appealing. After all, a car needs periodic oil changes and during the process the mechanic might notice a tire that is abnormally worn, or a pipe that is almost rusted through; why would we be any different?

It’s a good question, and one with which I have struggled as well. And yet studies have suggested that although the occasional asymptomatic condition may be detected for which treatment, or at least counselling with follow-up would be indicated -things like hypertension, diabetes, cervical cell abnormalities detected by Pap smears or breast lumps with mammography come to mind- the inevitability of falsely positive tests often lead to far more extensive -and expensive- investigations that go nowhere. The yearly checkup, in other words, is being repudiated, despite its visceral appeal.

I remember when I was an intern and a new process was introduced that allowed multiple tests to be performed on a single sample of blood. One ordered, say, a hemoglobin to investigate a patient suspected of having anemia but as well as getting the hemoglobin, several other parameters were also reported. Statistically, there was a good chance that one of them would be abnormal -not necessarily the one being investigated, but merely a random error produced perhaps by medicine the patient was taking or food she had eaten, maybe even the time of month or hormone status. But it couldn’t be ignored, so further investigations would be undertaken -usually unnecessarily. The hospital continued to use the systemic multiple analysis on the blood tests, but soon realized that it made more sense to report only the entity requested. False positives can be a problem.

People become accustomed to certain screening systems, too; the programs become self-evidently appropriate, and any change to them is resisted as being either mean-spirited, or short-sighted. Prostate Specific Antigen testing, Mammography, and even Pap smear screening have all come under scrutiny of late. False positives, and even false negatives have been implicated as problems associated with undo reliance on them.

Take Pap smears, for example. Recommendations have varied over the years and jurisdictions, but the idea was that since cervical cancer was once so prevalent and deadly, it made sense to try to detect abnormal cells as soon as possible in a woman’s life. Suspicions that it was somehow associated with sex lead to the suggestion that Pap smears be started soon after she was sexually active -often within three years. Then how often? Well the recommendation in my center -assuming the first Pap was normal- was to repeat them once a year for three years and then every two years thereafter if they stayed normal. It seemed an entirely appropriate and reasonable approach at the time, so the public was educated accordingly. It became a widely accepted and normative routine and embedded itself within the public psyche: a woman needed regular Pap smears, and to wait too long between tests courted disaster. Hard to argue against that.

Until, of course, it was realized that certain subtypes of the Human Papilloma Virus (HPV) were responsible for cervical cancers and that young people often seemed to be able to mount an immune response to them without the need for treatment. So it became apparent that Pap smear testing too early in a woman’s life might lead to unnecessary interventions and the possibility of complications, not to mention the ever-attendant anxiety. Therefore the recommendations were amended (in some centers anyway): Pap smear screening might best be commenced at 21 years of age, and not shortly after sexual activity began. Many women did not feel comfortable with this approach, either for their daughters, or themselves, for that matter. More frequent was better, even if it led to further investigations such as microscopic examination and biopsies of the cervix (Colposcopy) that might prove negative. We need handles to grasp, doors that open; we need something we can trust. And they had been assured they could trust a regular regime of Pap smears. After all, it had certainly reduced the incidence of cervical cancer in the population. Once again hard to argue.

And now, yet again, it changes. If HPV is required to cause cervical cells to become abnormal, and the usual time for this to occur can be measured in years after the infection, wouldn’t it make sense to lengthen the interval for screening to take this into account -every five years, say? Maybe co-test with a Pap smear at the same time to make sure that abnormal cells hadn’t been brewing there for a while and then apply an algorithm to account for discrepant results? Or perhaps give the nervous public a choice: Pap smears every three years, or HPV and Pap every five? But because transient HPV infections are statistically more likely to occur in younger women (immune differences or amount of sexual activity, possibly?) don’t offer HPV testing to women under 30 because that might lead to unnecessary investigations… Confusing? Scientifically justified, but emotionally difficult to swallow?

I raise these issues because, well, my patients do. It’s not a little thing to change a habit, especially one inculcated by the profession and then rescinded or at least amended after widespread acceptance –generational acceptance. It requires not a little humility to reveal that we have not yet arrived. But, Wisely and slow, they stumble who run fast: Shakespeare again seemed to understand. But, do we?