Cancer moonshot and slow-learners

Motivated by Vice President Biden's son's death at an early age from cancer, President Obama recently announced a new health initiative which he's calling the cancer 'moonshot'.  This is like a second Nixonian 'war' on cancer but using a seemingly more benign metaphor (though cancer is so awful that treating it as a 'war' seems apt in that sense). Last week the NYTimes printed an op-ed piece that pointed out one of the major issues and illusions belied by the rhetoric of the new attack on cancer, as with the old:  Curing one cancer may extend a person's life, but it also increases his or her chances of a second cancer, since risks of cancer rise with age.

Cancers 'compete' with each other for our lives
The op-ed's main point is that the more earlier onset cancers we cure, the more late onset, less tractable tumors we'll see.  In that sense, cancers 'compete' with each other for our lives.  The first occurrence would get us unless the medical establishment stops it, thus opening the door for some subsequent Rogue Cell to generate a new tumor at some later time in the person's life.  It is entirely right and appropriate in every way to point this out, but the issues are subtle (though not at all secret).

First, the risk of some cancers slows with age.  Under normal environmental conditions, cancers increase in frequency with age because they are generally due to the accumulation of multiple mutations of various sorts, so that the more cell-years of exposure the more mutations that will arise.  At some point, one of our billions of cells acquires a set of mutational changes that lead it to stop obeying the rules of restraint in form and cell-division that are appropriate for the normal function of its particular tissue. A tumor is a combination of exposure to mutagens and mutations that occur simply by DNA replication errors--totally chance events--when cells divide.  As the tumor grows it acquires further mutations that lead it to spread or resist chemotherapy etc.

This is important but the reasons are subtle.  The attack on cells by lifestyle-related mutagens like radiation or chemicals in the environment becomes reduced in intensity as people age and simplify their lives, slowing down a lot of exposures to these risk factors. However, cell division rates, the times when mutations arise, themselves slow down, so the rate of accumulation of new mutations, whether they be by chance or by exposures, slows.  This decrease in the increase of risk with age at least tempers the caution that curing cancers in adults will leave them alive for many years and hence at risk for at least some many more cancers (though surely it will make them vulnerable to some!)

Apollo 11, first rocket to land humans on the moon; Wikipedia

Competing causes: more to the story, but nothing at all new
There's an important issue not mentioned in the article, but that is much more important in an indirect way.  This is an issue the authors of the op-ed didn't think about or for some reason didn't mention or perhaps because they are specialists they just weren't aware of.  But it's not at all secret, and indeed is something we ourselves studied for many years, and we've blogged about here before: anything that reduces early onset diseases increases the number of late onset diseases.  So, curing cancer early on (which is what the op-ed was about) increases risk for every later-onset disease, not just cancer.  In the same way as we've noted before, reducing heart disease or auto accident rates or snake bite deaths will increase dementia, heart disease, diabetes, and cancer--all other later-onset diseases--simply because more people will live to be at risk.  This is the Catch-22 of biomedical intervention.

In this sense all the marketing rhetoric about 'precision' genomic medicine is playing a game with the public, and the game is for money--research money among other things.  There's no cure for mortality or the reality of aging.  Whether due to genetic variants or lifestyle, we are at increasing risk for the panoply of diseases as we age, simply because exposure durations increase.  And every victory of medicine at earlier ages is a defeat for late-age experience.  Even were we to suppose that massive CRISPRization could cure every disease as it arose, and people's functions didn't diminish with age, the world would be so massively overpopulated as to make ghastly science fiction movies seem like Bugs Bunny cartoons.

But the conundrum is that because of the obvious and understandable fact that nobody wants major early onset diseases, it seems wholly reasonable to attack them with all the research and therapeutic vigor at our disposal. The earlier and more severe, the greater the gain in satisfactory life-years that will be made.  But the huge investment that NIH and their universities clients make in genomics and you-name-it related to late-age diseases is almost sure to backfire in these ways.  Cancer is but one example.

People should be aware of these things.  The statistical aspects of competing causes have long been part of demographic and public health theory.  Even early in the computer era many leading demographers were working on the quantitative implications of competing causes of death and disease, and similar points were very clear at the time.  The relevance to cancer, as outlined above, was also obvious.  I know this first-hand, because I was involved in this myself early in my career.  It was an important part of theorizing, superficial as well as thoughtful, about the nature of aging and species-specific lifespan, and much else.  The hard realities of competing causes have been part of the actuarial field since, well, more or less since the actuarial field began.  It is a sober lesson that apparently nobody wants to hear.  So it should not be written about as if it were a surprise, or a new discovery or realization.  Instead, the question--and it is in every way a fair question--should be why we cannot digest this lesson.  Is it because of our normal human frailty wishful thinking about death and disease, or because it is not convenient for the biomedical industries to recognize this sober reality front and center?

It's hard to accept mortality and that life is finite.  Some people want to live as long as possible, no matter the state of their health, and will reach for any life-raft at any age when we're ill.  But a growing number are signing Do Not Resuscitate documents, and the hospice movement, to aid those with terminal conditions who want to die in peace rather than wired to a hospital bed, continues to grow.  None of us wants a society like that in Anthony Trollope's 1881 dystopic novel The Fixed Period, where at age 67 everyone is given a nice comfortable exit--at least that was the policy until it hit too close to home for those who legislated it.  But we don't want uncomforable, slow deaths, either.

The problem of competing causes is a serious but subtle one, but health policy should reflect the realities of life, and of death.  I wouldn't bet on it, however, because there is nothing to suggest that humans as a collective electorate are ready or able to face up to the facts, when golden promises are being made by legislators, bureaucrats, pharmas, and so on.  But, science and scientists should be devoted to truth, even when truth isn't convenient to their interests or for the public to hear.

Real Truth in Labeling for the new statin replacement

The FDA is about to or just has approve a new cholesterol-fighting drug to supplement or replace statins.  But is it taking all the 'side effects' into account?  Should it?  The new substances (several pharmaceutical outfits apparently have them near to market) inhibit a different genetic pathway from what statins do and can be used to treat high cholesterol in those who can't handle statins, or for whom statins aren't lowering their LDL cholesterol, and may also actually be much more effective even for the current millions who take statins.

These drugs inhibit the action of a gene called PCSK9 and interfere with the liver's detection and response to LDL levels in the body; see the NYT story here from last week for more details about the drugs.  The excited news reports, at least, describe what are truly remarkable reductions in LDL levels without untoward side effects. If these facts stand up to larger or longer term trials and experience, it will be a major pharmaceutical success....in more ways than one.

One immediate issue is the 'usage creep' that almost inevitably seems to follow the appearance of a new drug, and in this case one with fewer side effects and higher efficacy with regard to lowering the most dangerous type of circulating cholesterol (the 'bad', or LDL form). Recommended approval is for use in three groups of patients: those whose high LDL cholesterol can't be lowered sufficiently with statins, those at particularly high risk because of previous heart attack or diabetes and high LDL, and those with high levels of LDL who can't tolerate statins.

But if these agents are as effective as reports suggest, and with less or even no serious side effects, then even if they are initially approved or recommended for just these specific groups, usage will surely expand as the definition of who is 'at risk' expands. Perhaps people whose cholesterol is responding to statins but who don't like the side effects, or someone whose close relative has had heart disease but whose current LDL levels are not high will ask for this treatment as a preventive, or doctors will think 'off label' usage is absolutely proper, assuming no serious side effects. Hell, if the makers are extremely lucky, maybe it will turn out it even treats erectile dysfunction or male-pattern baldness! And then, what about extending to, say, younger ages or even simply to everyone, like putting vitamins in milk or iodine in salt?  This is what we mean by usage creep.

One might reasonably say that this is just what should be done.  Precedent might suggest that eventually we'll find that the agents are less effective than current tests suggest or have some serious long-term but as yet undiscovered downsides.  However, things that can't be known until the drug is used by millions of people for numbers of years.  Making decisions about usage is harder than one might think.

One reason for concern about usage creep is already being mentioned in the blaring news stories about the apparently genuinely major advantages of these compounds.  That is, the obvious issue of the financial mega-bonanza to be reaped by the pharmaceutical firms.  These drugs are going to be very expensive.  The money to be made is certain to encourage usage creep.  Could we expect otherwise?

But worse than just profiteering is that, even with Obamacare available so that presumably even the poor could have access to these beneficial drugs, putting the whole population, so to speak, on these pills for their whole lives, could bankrupt the health-care funding system that is already a heavy burden on society.  It's being suggested that these new pharmaceuticals could simply by themselves eat up any reasonable premium level for health care plans.

But there is another issue, and that relates to truth in advertising and the issue of side effects--and here we don't refer to incomplete data that may be leading to premature approval or anything like that.  Instead, it's more of a philosophical issue:  What does a list of side effects mean, in this case, and what would the whole truth actually be? What should the manufacturer or the FDA tell you so you would be truly better informed when you take the new drugs for the rest of your life, as so many are likely to do, across the developed world?

From the Sanofi website; Sanofi is one of the makers of these statin replacements

What the FDA and medical community doesn't list on the label
The FDA requires that known side effects of drugs be clearly stated on packaging or labeling material, and surely physicians will know about them.  Isn't that right?  It should be, but there is a sleeping tiger here, that apparently nobody has thought about or, if they have, that they've buried so deep you never will realize it.  In fact, there will be huge unstated negative side effects of these new drugs.  Indeed, shouldn't a proper labeling for these new medications include something like the following?:

"WARNING: Use of this product will greatly increase your risk of Alzheimer's Disease and other dementias, arthritis and other muscle and joint diseases, some forms of cancer, diminished vision and hearing, other degenerative disorders, and accidental death."

Of course such truth in labeling won't happen, and the reasons are subtle and if taken seriously would lead us, as a society, to think more deeply about the role of medicine in health, and of the meaning of health, in a real world in which life is finite.  There is no one who can provide 'the' answers to the problems that are raised, and indeed each person would, in principle, provide his/her own answers.

But at least, there should be a societal discussion.  The reason has to do with the concept of 'causation' and the demographic realities in a world of competing causes.  If these drugs lower LDL cholesterol anywhere nearly as much as they seem on present evidence to do, and if the association between LDL cholesterol and heart disease is as linear as is hoped, then that by itself will eliminate or greatly forestall the occurrence of fatal heart disease in those who take them.  But then what?

If people live much longer as a result, they will inevitably get the sorts of diseases that could be included in an empirically correct labeling!  If you don't get heart disease, it is simply obvious that you will get something else, and it is likely to be slower and more progressive than the quick end to life that heart attacks can be.  Note that our warning list did not include some causes, like kidney failure, diabetes, and the like that could be stalled or avoided by lowering LDL cholesterol--so we are being quite conservative here.

The problem is that of what are known as competing causes, and we've written about it before.  It is inevitable that you will die of something.  If not heart disease, something else.  One might say, well, OK, but at least I'll have more years of life before that something-else gets me. This is likely to be true to some extent, but there are two cautions.

First, people with heart disease often have other health issues because by and large heart diseases gets people at older age, and they are more likely to have less healthy lifestyles.  That includes more risky conditions than high cholesterol.  So, these other causes may be lurking just around the corner, so the removal of heart disease may mean that the gain in years might not be very much!

Secondly, other disorders that those saved from heart attacks will eventually get, if they don't have them already, are ones with gradual onset: you become more and more affected over time.  Mental deficiencies, joint and mobility problems, vision and hearing, are clear examples.  And the nature of accelerating risk is that if you slow it down you defer the onset of serious-level symptoms but you also stretch out the decay process at the end: you have more years with more and more serious symptoms before your body finally conks out.

What is 'cause'?
Are we just playing word games here?  Is it accurate to suggest that the new drugs will 'cause' dementia?  Surely the chemical doesn't mess with neurons!  Let's assume that's true and that no such direct molecular effect is ever found. Then the effect of the medication is related to the occurrence of these other traits, but not in a directly causal way.

This raises questions about causation.  It is more than simply saying that correlation is not the same as causation, because while the active mechanisms responsible for, say, Alzheimer's or joint disease, are not affected by the LDL-reducing drugs, they open the way for the former to act because the person lives longer.  Correlations such as the brand of car you drive being associated with some forms of disease arise because both may be the result of income levels and associated dietary habits. The dietary habits, not the type of car, are causes of interest.

But in the case of competing causes of disease, reduction of one is a sort of mechanistic effect, not just a spurious cause.  If a mechanism is changed in a way that allows a different mechanism to proceed for longer times, this is part of the overall mechanism of the related traits.  The chronic late-onset diseases most of us in the rich world die of now are directly the result of so successfully controlling infectious diseases, our previous killers. One definition of cause is that if you remove it, the effect changes, in this case the protective effect, relative to cancer, of dying of a heart attack.

And what if widespread use of these new drugs puts serious pressure on the health care system, so that some treatments will have to be deferred or denied to more people than presently?  Is that so unlikely?  And is that then not a cause of deteriorating health?

And what if it worked miracles and the relative fraction of our population (and the world's population) of wearing-out old people substantially increased?  That puts all sorts of pressures and pinches on everyone else, indeed, even on the normal living needs of the increased elderly segment.

Causation is not so simple and straightforward a notion.

So, what is 'health care'?
The new LDL reducers raise many deep, and deeply important questions.  The point here is to be realistic about disease in our society and have an open consideration of how to deal with the kinds of game-changing environmental or behavioral aspects of our society, and their long shadow of implications.

In a very serious sense, even if indirectly, the new LDL-lowering agents might have disastrous effects for countless numbers of people.  It's a discussion we should be having.  The news media should be leading the way, to force that on the scientists and health system.

Indeed, these issues should force us to consider what, exactly, we even mean by 'medical care' and 'health care'.  How do they relate to each other, and to the idea of 'public health'?

We think these are real, complex, disturbing, serious truths that have no one answer, and that affect individuals as well as society.  This is not a matter of complaining about science, policy or even drug company profits.  It is about profound issues in human life, that should be discussed openly and fully, because they affect everyone's future.

The "war" on cancer....retreat, defeat, or on its feet?

The BBC reported the other day that we are facing a 'tidal wave' of future cancer cases, and we had better prepare for it.

The globe is facing a "tidal wave" of cancer, and restrictions on alcohol and sugar need to be considered, say World Health Organization scientists. 

It predicts the number of cancer cases will reach 24 million a year by 2035, but half could be prevented. 

The WHO said there was now a "real need" to focus on cancer prevention by tackling smoking, obesity and drinking.

The point is that treatment isn't going to do the trick, and could even bankrupt world healthcare resources, and what is really needed is prevention.  The article doesn't really talk about whether resources pouring into things like cancer genomics and other sorts of omics should be diverted to prevention, but it's certainly a legitimate view.

And the article also doesn't point out that the rise in cancer rates is also a reflection of the fall in rates of other causes of death, like heart disease for example.  Indeed, it's not clear that that's clear to people at the WHO.

Chris Wild, the director of the WHO's International Agency for Research on Cancer, told the BBC: "The global cancer burden is increasing and quite markedly, due predominately to the ageing of the populations and population growth.

We've written a number of times before about competing causes of death: when one goes down, others must go up.

From the BBC

But this does all raise the question of whether the 'War' on cancer that was declared by President Nixon in 1971 was a waste of time.  After all, nearly 45 years on, there are more cancers and perhaps even a higher cancer rate (risk per person) than back when Tricky Dick was calling the shots.

What about all the high promises by us geneticists?  After all, cancer is a disease of cells not behaving themselves in their tissue context, and growing or not adhering as they should in their tissue type.  That is basically about the cells' use of genes, so cancer should be the very epitome of a genetic disease.

There has been much progress in identifying genes involved in cell-cycle regulation, growth control and inhibition, and genes that when mutated clearly add to cancer risk, sometimes quite dramatically.  There are also tests that, experts say, identify tumor genotypes as to whether they'll respond to particular chemotherapeutic agents.

Let's not forget the HPV vaccine that can end cervical cancer.  Also, the discovery of Helicobacter infection of the gut may lead to prevention of stomach cancers.  Likewise, viral causation of esophageal and some oral cancers or leukemias in animals if not also humans. These are purely research-discovered, reflect increases in genetic knowledge of all kinds, and thus have to count as major War-on successes. 

There still aren't many--if indeed there are any--gene-specific preventive or gene-targeting therapies and some attempts have failed or had only mixed results.  There have apparently been huge advances in some chemotherapeutic, surgical, and radiation treatments, often guided by the tumor cell type, that greatly jump the survival odds for many types of tumor.  In a sense, bone marrow transplants are dependent on knowledge of genetics and we personally know a number of people for whom such transplants have worked.

Cancer is a very complex and diverse set of diseases, some due to outright mutations, some due to failure to correct mutations, some due to viruses and chromosome rearrangements.  Some susceptibility genotypes can be inherited or can occur somatically during life, and it appears to be combinations of these that generate tumors rather than one inherited mutation or one caused during life.  We think it's fair, however, to say that a lot of trumpeting of cancer genome projects and profiling has far exceeded the successes to date.

An indicator of the state of play is the rapid building programs at the nation's major cancer research institutes: if they were doing so well, why aren't they shrinking in size--turning their buildings into apartments or office buildings?

But is this fair?
After quadzillions of dollars spent, all sorts of massive data bases and so on, one can say that the reason cancer rates are going to be overwhelming is the failure of research to win the War.  Cancer is a hugely complex problem, but the increase is not due to a failure of the researchers.  Instead, it's a failure of the patients!

We continue to live in ways that are epidemiologically known to increase cancer risk.  Smoking is the main culprit. Being overweight seems for some reason to be another.  Alcohol is, too, or so the story goes.  These and other lifestyle factors have indirect mechanisms, mostly unknown, by which they increase cancer risk.  Mainly, however, they lead to needless mutations in our cells, even if just because bad lifestyle habits increase the numbers of cell divisions we experience.

The failure is not one of geneticists, but of the inability of society to put to work what science has discovered.  Here we include epidemiology as well as health education, not just--indeed, not mainly--genetics (even if, at the cell level, cancer is largely a genetic disease).  We don't know how to get people to stop risky behavior even when they know it's bad.

One can debate the reasons, and libertarians will differ about this from interventionists.  Unfortunately, one way or another, we all have to bear a share of the costly treatment (and research) that bad behavior occasions.

Worse is that the excess cases due to exposure to bad behaviors blurs the distinction between cases that might have clear-cut genetic causes that really could benefit from focused research.  This applies as well to heart disease, diabetes, and other quasi-pandemics of our time.

So you can wage a War-on, and be technically quite successful even in the face of daunting complexity, but if the enemy forces just keep increasing like a tsunami, you will be overwhelmed and it will seem that you've lost.  Here, the loss is in terms of prevention.  Unfortunately, preventive measures can save or spare more people from cancer than all the genetics and similar research one could throw mega-bucks at.

Playing the waiting game
Things are not as simple as is being claimed.  For example, CNN's reporting on the cancer-tsunami release is headlined "Cancer doesn't have to happen."  It says that "Most cancers in our world pandemic are preventable -- here's how."  But this is quite misleading if our understanding of cancer is true.  Because the truth is that cancers are all preventable -- but only if you die of something else first!

Cancer is caused by the accumulation of DNA changes--mutations, viral incorporation events, expression-regulation, sequence elements rearranged among chromosomes.  These are, as best we understand, probabilistic but the probability is not zero. Mutations happen by molecular chance when cells divide, even if they're not exposed to environmental carcinogens.  This means that the probability you get cancer at age x is the probability that none of your cells has by then accumulated enough 'bad' changes to start to grow out of control.

This means that if you live long enough you will get cancer, indeed basically every type of cancer.  Each has its own age of onset pattern depending on the number of cells at risk, their division rate and so on.  You can speed this up by exposure to radiation or other carcinogenic factors, or slow it down by not being exposed.  This in essence is what the news stories are about.

But eventually, you'll be unlucky, or rather, your luck will eventually run out.  Unless....unless you die of something else first.

One reason for the predicted increase in cancer is that antibiotics have reduced earlier deaths from infection, surgery and medication prevent death from other causes like heart disease, diabetes, stroke and injuries, leaving people alive longer.  So the 'War' on heart disease is a kind of battle being won at the expense of the battle on cancer being lost.

This is what is meant by competing causes (and we've blogged on it in the past).  It's a Devil's kind of trade-off.  We can only avoid this evil bargain if Francis Collins' promises of immortality (on earth--he presumably also believes you'll persist after death as well) comes to pass, which even he probably can't promise NIH massive genomics and other 'omics' research will achieve.   And then, well, you may not get cancer but you will be so demented and immobile for so long, that you won't know it but you might yearn for an end.

That's life, but it's hard to face up to it.  At least, it is one factor that adds nuance to the whole subject of the War on cancer.

On the other hand
We scientists are grabbing up a lot of resources for our relatively small Wars, compared to what might be gained by prevention, even though the latter is not glamorous and won't feed the University professor welfare system.  This is a failure of policy, not science.

And there's another thing.  Our love of technology is responsible for a major part of the coming cancer tide, if current estimates are to be believed (and in this case, projections are likely to be accurate).  That is by the gross, excessive, almost game-like over-use of radiation technology. So much overkill with CT scans and their like will cause near-epidemic scale cancer if the recent projects are accurate.  This is the result of the research-corporate-medical complexes drive for money, credit, attention, or whatever aspect of the science-religion you want to blame it on.

Worse is that some of this excess scanning doesn't just expose people to carcingens, but leads to diagnosis of cancers that would never lead to clinical disease in the first place.  Evidence shows this in relation at least to prostate cancer in men and breast cancer in women.

So stories about a tidal wave of future cancers, probably by now unavoidable because the mutational risks have already been piling up, reflect a mix of factors.  Reducing heart disease has worked to some extent, so people who don't die of a heart attack live longer, free to develop cancer. And, the War on cancer has been a success and a failure at the same time.  We know how to do better: avoid what we know are needless cases so we can focus research attention on those that really are genetic or caused by some mechanism that technical research is so very good at attacking.

But this is a worrying post to write, and we need a smoke and a couple of scotches to calm ourselves down.

The problems with genomic prediction. Need it be stated again?

We often write about the challenges to prediction of phenotypes, especially disease, from DNA data.  If the trait is clearly due to variation at a single gene, then prediction can be useful.  If most instances are due to variation at a single gene, but not always the same gene, DNA data can be useful as well.  Of course if the variation is in regulatory or other DNA, rather than protein coding parts (genes proper), unless the whole genome is sequenced (not just the 'exomes'), things may be much more unclear.

Most common disease or behavioral traits aren't like that, however.  As we have piles of data to show, traits like cancer, stroke, dementia, and heart disease are typically due to very many but individually minor, contributing parts of the genome, plus, oh yes!, maybe some Environmental factors that, if we're geneticists, we don't really want to have to think much about)  But the big E is the key to trouble, in ways reflected by two stories in yesterday's NY Times Sunday Review section.

The cancer example
One story suggests what is presented as a surprise, that cancer (despite the 40-year 'war' against it by NIH) is rising in lifetime risk, not falling, or at least is going to affect more rather than fewer people in the future.  But, despite the fact that the 'war' on cancer was a bad way to waste a lot of money (good proposals would have been funded without the attraction of a poorly disciplined pot of gold), even if cancer treatments are better (sometimes true, at least), more victims will fall to cancer.  This seems counter-intuitive, so why?

The answer is something well-known to those who know, but poorly explained to the public.   We've written about it before here on MT.  It's called 'competing causes'. As long as we all have to die of something, and the older we are the more damage our various cells sustain, if you remove one cause, those who are spared that then stay alive to be vulnerable to the remaining causes.  Heart diseases can strike relatively early, but cancer, which in many if not most instances is due to mutational and other cellular damage, is a risk that keeps on growing as cells continue to be exposed to mutagens and the like.

This is no new discovery or surprise and the public and all geneticists should by now be well aware of it.  Also, earlier treatment that is developed for other diseases will have similar negative consequences (though of course to those who were saved from earlier death).  The overall health care cost burden is likely the result of research that is successful against earlier-age killers.

Other diseases are part of the Environment of cells unaffected by those diseases. Spared of those, you are exposed to continued mutagens throughout your life.  Yet these changes cannot be predicted, and as a result, genotype-based risk estimates (that aspect of 'personalized genomic medicine') are a fantasy: they may or may not be right and are of unknown--and unknowable--accuracy.

Socioeconomic advances
The other Times article yesterday that caught our attention was about the increased risk of various diseases to those who work their way out of the lower socioeconomic strata in our society.  As they rise in education, wealth and so on, and perhaps because of the stress required to dig oneself out of poverty, people suffer risks of various diseases that are higher than they would have experienced or of their peers in their newly achieved SES group.

Again this is the mixed blessing of changing lifestyles.  It is the again-unpredictable effect of Environmental change.  It's unpredictable even if we knew the specifics of a given sample of cases, because they are always retrospectively analyzed, after things have already happened to that sample, but we can't know how things will change in regard to SES-specific risks or in SES-mobility patterns in the future, the future of those who want to know their risks.  You cannot tell these things from the person's genotype, of course, and social science is even farther behind genomics when it comes to having a crystal ball for the future.  Indeed, all the Big Data resources in the world will have this problem, and to that extent will be a huge waste of public health funding.

These are not new major discoveries of new principles.  They just happened to be in the paper and to reflect the issues.  They just sound the warning bells that should be being heard, and heeded, in the labs and offices of NIH and medical schools, and the companies who have been giving what is essentially misleading (and inconsistent) DNA-based health advice, the whole community making rather careless promises of genome or other 'omic' based miracles.  These are facts of life, so to speak, that in themselves should be the subject of investigation. But that's a real, legitimate challenge, unlike the weak challenge of proposing to collect more and more data without being obligated to deliver on promises made to justify that or to address the real problems in an effective way.

A fat chance with trans fats...but chance of what?

Well, if they actually do it, the FDA is reported to be all but banning the use of trans fats in food. The idea is that this will be a huge health benefit to society because partially hydrogenated foods are unsafe. According to the piece in the New York Times, "Dr. Margaret A. Hamburg, the agency’s commissioner, said the rules could prevent 20,000 heart attacks and 7,000 deaths from heart disease each year."

Source: Wiki Commons

But is this good....or bad....news?
This seems like unambiguously good news.  After all, who wants to die of heart disease?  And that will save our brobingnagianly expensive health care system lots of money, no?  But it could actually be bad news, and here's the inconvenient reason:  surprise, surprise, you'll have to die of something!

Heart attacks are fearful events.  They often kill quickly, even without warning.  That might be a kind way to go.  But if you aren't susceptible to heart attacks because your arteries remain clear, then what?  The other things that are going wrong all over your body, and they are even if they're silently doing so, will continue.  The good side is that you may live longer.  The bad side is that you may die more slowly and in a vastly more costly way.  Cancer, bone, joint and other physical decay, loss of mobility, the consequences of obesity, and neural degeneration will require expensive diagnostic testing and treatment.  Those diseases will develop more slowly, and linger for a long time.  Many will require years of institutional care.

This is the ineluctable problem of competing causes, one very clearly understood by public health systems, if not advertised by the medical research and health-care establishment.  Costs may balloon out of control if too many live too long in too degenerated a condition. And there are already other bad behaviors which, if we stop eating trans fats, may rise in proportion and do us the same amount of damage, even if in a different way.  Even, say, if we live longer and hence drive more at increased  ages.

The implications
It's not just that we'll probably live longer on average if we don't suffer from 'transfatism'  but we may have to be retired longer.  At least for a while, if this ban takes, the retirement age will remain roughly what it's heading for (say, 70?).  Even if people are still functional at that age, they'll have expected to be free by then, free to enjoy their final life-stage.  But that stage will last longer.  That means pensions will have to be paid out longer--regardless of the increased health care cost.

And who will pay for those health-care costs?  Oh, no problem, the Affordable Care Act will!  That's an illusion.  The young will pay for it, because current dollars pay for current expenses, not the dollars the elders put in years ago (which payed for their elders' care).  And the young are already likely to be heavily burdened by caring for the normal daily life costs of the huge fraction of our society that will be made of retirees.

It's a real bind.  It produces a fundamental tension between individual and population concerns.  Individuals mainly want to live as long as they can, but from a population perspective the turnover should not be so slow as to outpace resources.  One might think things were different if we had a religion that promised heavenly life thereafter.  If we really believed that and we acted according to God's instructions, we should not fear mortality, and should on the contrary be willing to get out of the way so our descendants could have as much chance to life the moral life as possible--not being so squeezed by poverty or deprivation as to act with hate, greed, violence, and so on.  Sadly, religion doesn't seem to act that way--at least, societies in  which a lot of people profess to believe in the afterlife rewards of a good life lived here, typically don't act any differently from anybody else.  Those who may be religious but continue to have large numbers of children violate both views: they don't live morally if that means considering one's fellows, and they risk putting their own offspring in the kinds of squeeze that leads to selfish behavior.

The connections between trans fats and these broader considerations is not as distant as one might think, especially because trans fats are only one of many aspects of our society that have similarly complex consequences.

Nobody would argue that we should advocate  heavy smoking, drinking, and trans-fat diets in order to get rid of people earlier in their lives, before they degenerate and develop much more costly diseases.  We don't want to wink-out sooner if we Twink-out, but if we Twink-off then we'll spend more time winking off in the ol' rocking chair. 

If there are solutions to this problem, rather than some future mass catastrophe, it is that to which the public health establishment should be giving attention.  There are no easy answers that we know of.  But that is not a reason to be an ostrich and pretend the issues aren't clearly there, waiting for each of us (who shun trans fats!).

The best cancer protection: live less!

Cancer is a tragic disease given the lives it takes and the way it takes them.  For many victims, the cost of treatment even if they survive, is very unpleasant.  A current BBC story documents the heavy burden cancer takes on the European population.  Of course, the story is a plea for more research on causes and treatment.  But there are subtleties here that seem nearly always to be missed, or ignored, or intentionally avoided.

The real news story!
The general tenor of such stories, of which there is a daily flood, is that if only we could do the research to get rid of this (or that) pesky disease, we would walk straight into Nirvana, perpetual bliss in the tavern of our choice.   But that's not the grim reality. The grim reality is the Grim Reaper.

Grim Reaper

A lot of medical researchers seems to forget that there is a pine box (or ceramic jar) that's just our size waiting for each one of us at the end of the road.  We're all temporary.  Life is a molecular way for blobs of reactions to produce fuel (that is, food) for other blobs.  In our case, we're likely to be on the menu at the Bacteria Café.

So this should help mold our thinking about stories like the one cited above.  And the hopeful thing, that really does have strong scientific support, is that we really do know how to avoid the vast majority of cancers.  It is so simple, that even a scientist--or even, believe it or not, a politican, could understand it.  The trouble is, the press and research community, for some inexplicable reason, don't want you to know about it.  So, strictly as a pro bono public service, we're going to use our modest blog site to tell all.

Death is the most effective cancer avoidance program
If you want to avoid the trauma of cancer, the simple preventive therapy is:  die young!

Cancer is a genetic disease at the cellular level.  A cell--a single solitary cell--that acquires an unfortunate  (for the person whose cell it is) set of genetic variants, becomes the progenitor of the tumor that eventually is diagnosed.  It is this 'transformed' cell that begins uncontrolled division, proliferating and as its cellular descendants acquire further mutational changes, can shed from the primary tumor and metastasize to other locations, where it can damage those local tissues, and so on.

Cancer predisposition can be inherited, by involving a variety of genetic variation, most of which consists of numerous mutations (changes) in DNA sequence, and probably hundreds or even thousands of sites in our genomes could, if altered by mutation in an undesirable way, contribute to this risk.   So not being born is a perfect preventive for this....except that rarely is a newborn affected by cancer.  Instead, most cancers arise when, later in life, new body-cell ('somatic') mutations arise, until some single cell acquires a carcinogenic combination of changes.

Mutations occur all during life, as cells sit there exposed to cosmic rays, chemicals, viruses, and other potential mutagens.  When a cell divides, its changes will be transmitted to the daughter cells, unless they are detected and corrected first.  This sometimes does happen, but you have lots of cells that divide lots of times during a lifetime. Most of the evidence suggests that eventually, if you live long enough, some one or more of your cells will acquire such changes that aren't corrected.

In this sense, cancer is inevitable.  In some, perhaps especially in older people, the cells aren't dividing very rapidly anyway, and transformed cells may take very long to be manifest as a tumor that threatens their lives--if they're still alive.  In other words, even then, if you live long enough, you will be destroyed by cancer.

Competing causes, and the paradox of public health policy
The same inevitability applies to many other diseases (also mentioned in the above-cited report), if not to all diseases.  It has long been clear in principle that an organism faces a variety of ways in which its biology will deteriorate with time.  Many if not most diseases have patterns of onset, predisposition, and severity that reflect our biological development, and for which harmful life-experience can accumulate to increase risk.

Risk of a given disorder generally has a characteristic age of onset pattern.  Risk for many diseases rises with increasing rapidity with age.  Cancer is one, but so are adult diabetes, heart and kidney diseases, and cognitive deterioration.  Others have onset at puberty, etc. Many can be related to known cellular processes.  Some slow down with age if those processes do.

But in the end, we face what is called competing causes.  Mathematically, if a given cause is eliminated, or its age-risk pattern tampered with by lifestyle or public health or medical changes, the relative risk of the remaining diseases increases. So, if you stay in physical shape and hence reduce your risk of heart disease or stroke, you inevitably increase your risk of something else.  You may live longer by not having an early stroke, but what you experience instead will not necessarily be preferable except by occurring at an older age.

What would a most-sane public health (and research) policy do in the light of this?  What we have now is a set of interest groups pleading for funds to eliminate some specific disease--understandable enough--but little if any policy about priorities.  Should we reduce effort against later-onset traits, and really push hard for inborn problems, childhood diseases, lifelong quality threats?  If so, should we reduce investment in cancer or Alzheimer's Disease research?

There are no obvious answers to these questions.  There's hardly anyone even asking the questions.

Getting the picture

In discussing the cost of geneticizing complex common diseases, a colleague quipped a few years ago that it would be cheaper to hire a personal trainer for every diabetic than to continue the kind of research that has been going on in relation to this disease. It was a joke, but it wasn't funny because, seriously it is the right idea.

And believe it or not, our nation's less than noble citizens, the health care industry, might be catching on. A story in the NY Times says that UnitedHealth Group is teaming up with the YWCA to implement a lifestyle program--diet and exercize--to reduce the cost of treating people with Type 2 diabetes (which used to be called adult type diabetes, but now kids are getting it too).

All we can say is finally someone is getting with the program! If this were done nationally, the cost of healthcare from an insurance point of view would go down. Tons of wasted high-tech research such as big GWAS and other kinds of studies would not be done and the costs of that research could be redirected towards behavioral intervention, or even studies of how to implement behavioral intervention (so long as the latter were not just more school of public health professor welfare, but instead actually implemented programs).

Doing this would have benefit for everyone (except, perhaps, the genetics industry): countless people would lead healthier, longer lives. Health insurance would drop for everyone (in a properly regulated industry, because premiums amortize group costs to every participant's bill, and the total cost for the groups of insured would drop). And what would remain would be the cases of diabetes that really are genetic. Then, legitimate genetic research would be able to focus on genetic problems.

Cases that really are genetic might involve less genetic heterogeneity, or genes whose mutations showed up regularly in cases, or mutations with very strong effects. These would suggest targetable pathways for therapy, and for various genetic or other pharmaceutical engineering to tackle the problems. That would be the right way to spend health research funds, good for everyone.

Except..... Except that if thousands upon thousands of diabetics lived longer, more active lives, they would also be more likely to get some other degenerative diseases, like cancers, simply because they didn't succumb to diabetes first. And those diseases would need health care with its associated costs. Ah, well, one can't have everything!

Competing causes everywhere

We've written about recent studies in which one has to do risk-benefit analysis in order to statistically determine the least (or most) beneficial treatment outcome, as in the currently hot debate about mammography. Risk-benefit concepts are a manifestation of causal complexity, in which many factors are at play.

The problem arises when a cause doesn't act alone to produce an outcome of interest, or when a factor is causally associated with more than one outcome, in which other such causes are also involved. Thus, lowering exposure to the cause may reduce the likelihood of outcome A, but increase the likelihood of outcome B.Genetic pleiotropy, in which a gene has more than one biological effect, is widespread if not nearly universal. Indeed, it is difficult even to determine all of a gene's 'functions' since even the definition of what a gene is is expanding rapidly as we learn more and realize how much more we have to learn about genomes.Biological traits are universally the result of many genetic factors interacting (signals and their receptors, genes and the transcription factors that activate or repress them, the mechanism that translates them into active protein, etc.).

Evolution works on the net result and while one manifestation of a gene's action may be favorable to survival or reproductive success, some other action of the gene may be unfavorable. Evolution takes some viable middle ground.This is one major reason why genetic causation is often so difficult to work out. It is likely why many drugs work well for their intended purpose, but have negative side effects in some people. It's why some drugs turn out not to work as well as expected on their intended target, while having a surprising Viagra effect that one might say makes hope 'rise' in other aspects of life.

In biomedical research, investigators study one disease, like diabetes, aiming to prevent or cure it. But inevitably, if they succeed, the rates of some other diseases will increase. If you've effectively dodged the diabetes bullet you’ll live longer, or be more active, or eat more, or drive more aggressively at night (because your vision’s not impaired), and so on. Each of those things increases risks of other negative outcomes.A commentary on page 1731 of the Nov 21 issue of the Lancet is by a Dr Nutt, a British doctor sacked from his position on the governments Advisory Council on the Misuse of Drugs, illustrates some of these issues. Dr Nutt stated what is rather obviously true, that "alcohol was more dangerous than many illegal drugs, including cannabis, ecstasy, and LSD." This apparently outrageous if true statement -- a threat, if implemented in regulatory policy, to every pub owner in the Kingdom! -- was simply too much.

But it's timely for us, because the fact of societal and other consequences of alcohol abuse is, along with a number of diseases for which alcohol abuse seems a clear risk factor, goes against the findings that risk of other diseases, like heart disease, seems to be reduced by alcohol consumption. And this does not include the moral side of alcohol use, which to many can even be a religious issue of abusing the body--the temple of the soul, or damage that the cost and results of drinking does to innocent family members.

Once again, we have competing causes to deal with. Were there a single standard, alcohol might be regulated like tobacco or even currently illegal drugs, given the societal harm it causes. Yet at the same time it might be prescribed as a preventive medicine. Neither science nor society has a good way of deciding how to respond to this mix of factors. This is an unavoidable dilemma, a philosophical or even existential conundrum.

Even if biomedical research were to reach its oft-hinted goal of near-immortality (yes, leading geneticists have seriously and publicly promised even centuries of healthy life as the payoff from our NIH dollars), the consequences might not be so rosy. The earth would be deeper in humans than Darwin’s estimated elephant-jammed world (in the Origin of Species). Food supplies would inevitably be threatened. There would be fights over other resources, adding violence to the causes of death and misery. New York apartments would become even smaller than the closets they are now. Psychological existence might be much worse.

Unless, of course, we colonize outer space? Though probably not, because if science is right about the universe, the same laws of complexity will operate on Mars as they do here at home. So when science has social or policy implications, it's always a balancing act.