What do rising mortality rates tell us?

When I was a student at a school of public health in the late '70s, the focus was on chronic disease. This was when the health and disease establishment was full of the hubris of thinking they'd conquered infectious disease in the industrialized world, and that it was now heart disease, cancer and stroke that they had to figure out how to control.  Even genetics at the time was confined to a few 'Mendelian' (single gene) diseases, mainly rare and pediatric, and few even of these genes had been identified.

My field was Population Studies -- basically the demography of who gets sick and why, often with an emphasis on "SES" or socioeconomic status.  That is, the effect of education, income and occupation on health and disease.  My Master's thesis was on socioeconomic differentials in infant mortality, and my dissertation was a piece of a large study of the causes of death in the whole population of Laredo, Texas over 150 years, with a focus on cancers.  Death rates in the US, and the industrialized world in general were decreasing, even if ethnic and economic differentials in mortality persisted.

So, I was especially interested in the latest episode of the BBC Radio 4 program The Inquiry, "What's killing white American women?" Used to increasing life expectancy in all segments of the population for decades, when researchers noted that mortality rates were actually rising among lower educated, middle-aged American women, they paid close attention.

A study published in PNAS in the fall of 2015 by two economists was the first to note that mortality in this segment of the population, among men and women, was rising enough to affect morality rates among middle-aged white Americans in general.  Mortality among African American non-Hispanics and Hispanics continued to fall.  If death rates had remained at 1998 rates or continued to decline among white Americans who hadn't more than a high school education in this age group, half a million deaths would have been avoided, which is more, says the study, than died in the AIDS epidemic through the middle of 2015.

What's going on?  The authors write, "Concurrent declines in self-reported health, mental health, and ability to work, increased reports of pain, and deteriorating measures of liver function all point to increasing midlife distress."  But how does this lead to death?  The most significant causes of mortality are "drug and alcohol poisonings, suicide, and chronic liver diseases and cirrhosis."  Causes associated with pain and distress.

Source: The New York Times

The Inquiry radio program examines in more detail why this group of Americans, and women in particularly, are suffering disproportionately.  Women, they say, have been turning to riskier behaviors, drinking, drug addiction and smoking, at a higher rate than men.  And, half of the increase in mortality is due to drugs, including prescription drugs, opioids in particular.  Here they zero in on the history of opiod use during the last 10 years, a history that shows in stark relief that the effect of economic pressures on health and disease aren't due only to the income or occupation of the target or study population.

Opioids, prescribed as painkillers for the relief of moderate to severe pain, have been in clinical use since the early 1900's.  Until the late 1990's they were used only very briefly after major surgery or for patients with terminal illnesses, because the risk of addiction or overdose was considered too great for others.  In the 1990's, however, Purdue Pharma, the maker of the pain killer Oxycontin, began to lobby heavily for expanded use.  They convinced the powers-that-be that chronic pain was a widespread and serious enough problem that opioids should and could be safely used by far more patients than traditionally accepted.  (See this story for a description of how advertising and clever salesmanship pushed Oxycontin onto center stage.)

Purdue lobbying lead to pain being classified as a 'vital sign', which is why any time you go into your doctor's office now you're asked whether you're suffering any pain.  Hospital funding became partially dependent on screening for and reducing pain scores in their patients.

Ten to twelve million Americans now take opioids chronically for pain.  Between 1999 and 2014, 250,000 Americans died of opioid overdose.  According to The Inquiry, that's more than the number killed in motor vehicle accident or by guns.  And it goes a long way toward explaining rising mortality rates among working-class middle-aged Americans.  And note that the rising mortality rate has nothing to do with genes.  It's basically the unforeseen consequences of greed.

Opioids are money-makers themselves, of course (see this Forbes story about the family behind Purdue Pharma, headlined "The OxyContin Clan: The $14 Billion Newcomer to Forbes 2015 List of Richest U.S. Families;" the drug has earned Purdue $35 billion since 1995) but pharmaceutical companies also make money selling drugs to treat the side effects of opioids; nausea, vomiting, drowsiness, constipation, and more.  Purdue just lost its fight against allowing generic versions of Oxycontin on the market, which means both that cheaper versions of the drug will be available, and that other pharmaceutical companies will have a vested interest in expanding its use.  Indeed, Purdue just won approval for use of the drug in 11-17 year olds.

In a rather perverse way, race plays a role in this epidemic, too, in this case a (statistically) protective one even though it has its roots in racial stereotyping.  Many physicians are less willing to prescribe opioids for African American or Hispanic patients because they fear the patient will become addicted, or that he or she will sell the drugs on the street.

"Social epidemiology" is a fairly new branch of the field, and it's based on the idea that there are social determinants of health beyond the usual individual-level measures of income, education and occupation.  Beyond socioeconomic status, to determinants measurable on the population-level instead; location, availability of healthy foods, medical care, child care, jobs, pollution levels, levels of neighborhood violence, and much more.

Obviously the opioid story reminds us that profit motive is another factor that needs to be added to the causal mix.  Big Tobacco already taught us that profit can readily trump public health, and it's true of Big Pharma and opioids as well.  Having insinuated themselves into hospitals, clinics and doctors' offices, Big Pharma may have relieved a lot of pain, but at great cost to public health.

Understanding pathways leads to drug discovery. Really?

One of the most often heard rationales for studying the genetics of disease is that increased understanding of gene pathways, or the products of gene pathways, will lead to new drug discoveries.  The idea is that even if mapping studies, like GWAS (see many of our earlier posts) don't discover 'the'  or 'blockbuster' genes 'for' a trait, they reveal genetic pathways in the biology of the trait that drugs can target.

However, while there have been some successes or hopeful trials, overall there is only limited evidence yet that this is as yet happening -- in fact, after a burst of initial enthusiasm for the new doors opened by the sequencing of the human genome, pharmaceutical companies have been cutting back on research and development, and few new drugs are currently in the pipeline -- drug discovery is risky, and payoffs are few.  This constriction of the new drug pipeline is why Francis Collins, director of the National Institutes of Health, has pushed "translational medicine" and NIH's involvement in drug development.

Well, as the special report on allergies in the Nov 24 issue of Nature notes, immunologists and allergists have long thought they understood what causes asthma, but the disease has increased dramatically in the last 3 decades or so, and new treatments are few and far between.  So much for the benefits of understanding pathway components. 

Since the discovery of immunoglobulin E (IgE) almost half a century ago, there has been a massive expansion in knowledge about how IgE antibodies work. Research has unravelled IgE's role in a myriad of cellular and molecular targets driving inflammatory responses and underlying complex allergic disorders. This knowledge might have been expected to lead to novel preventative and therapeutic pathways — unfortunately, this has not been the case.

The dramatic rise in allergy and asthma worldwide has increased the clinical need for treatment, but research focusing heavily on IgE as the main malefactor in allergies has not been translated into widespread patient benefit.

One problem, according to a piece by Stephen Holgate on why this is so, has been the pharmaceutical industry's reliance on animal models to both better understand the disease as well as to test new treatments.  But, humans are not mice.  In addition, allergic disease is complex, and involves not only biological pathways, but their interactions with environmental triggers as well as, presumably, an underlying genetic susceptibility.

Traditional therapy of allergic disease has in large part relied on the abatement of symptoms with H₁-antihistamines (rhinoconjunctivitis, food allergy, urticaria), adrenaline (anaphylaxis) or β2–adrenoceptor agonists (asthma), and the suppression of inflammation with corticosteroids. Besides improving the pharmacology of known drugs, the only novel asthma therapies to emerge are leukotriene inhibitors (for example, montelukast) and the non-anaphylactogenic anti-IgE, omalizumab, both of which are directed at targets identified well over 40 years ago.

There have been disappointments with a wide range of biologics targeting activating receptors on T cells, cytokines, chemokines, adhesion molecules and inflammatory mediators. Having shown convincing efficacy in in-vitro cell systems and animal models, and possibly some level of efficacy in acute allergen challenge in mild asthma, all of these have fallen short of expectations when trialled in human asthma. In moderate–severe asthma, where the unmet therapeutic need is greatest, trials of novel biologics have revealed only small subgroups in which efficacy has been shown or is suggestive.

And, it has long been assumed that asthma is primarily an allergic response, but this is no longer thought to be so.  The idea now is that perhaps impaired innate immunity comes first, and leads to allergy.  So, much is known about allergies and asthma, but nowhere near enough.

The asthma question is one that highlights many of the current problems in epidemiology, genetics, and the understanding of causation.  Asthma prevalence has been climbing in the US and other industrialized countries since the 1980s.  Given its precipitous rise, it would seem that the problem is quintessentially one for environmental epidemiology, but even when looked at from that perspective, no convincing environmental cause has yet been identified, and in fact studies have produced a frustrating litany of contradictions -- it's cleanliness or dirt, breast feeding or bottle, this gene or that.  Yes, epidemiologists have turned to genetics to try to understand the disease, but clearly there's no genetic explanation for such a recent epidemic. 

Like most other common chronic conditions, asthma is a complex disease, with multiple causes and multiple pathways.  As Holgate concludes:

In the future, it is essential that asthma is not treated as a single disorder, but rather defined by causative pathways. We need new diagnostic biomarkers to identify patients most likely to respond to highly selective biologics, such as anti-IL-5 biologic (mepolizumab) and anti-IL-13 (lebrikizumab). These therapies are only active in particular subtypes of asthma, when the molecules they target lie on a causative disease pathway. 

Studies of large numbers of people with a common chronic disease like asthma, or heart disease or hypertension, are necessarily pooling cases with different causes, pathways, genetic backgrounds, and outcomes.  This limits the potential for successful findings.

Biological traits are the result of interactions among many different factors, genetic and otherwise.  Such interactions, and the way that evolution works, leads to redundancy, alternative pathways, overlapping pathways, and the like.  This was a major theme of our book The Mermaid's Tale.  Complexity is an easy word to say, and perhaps it's easy to use it to excuse failure to find blockbuster findings.  But the last couple of decades have systematically shown causal complexity to be real.

Besides complexity itself, a major problem is not simply that humans aren't mice.  It's also that we are all unique in our environmental exposures, genomics, and how our bodies respond.  Identifying single genes that may be involved in complex diseases, or even biophysiological pathways, may be a rationale for sticking with the genetic approach to understanding disease, but it's a far cry from prevention, treatment or cure.

Rather than promising simplistic causation and consequent intervention miracles, we feel that students and young investigators, and the funding mechanisms, should be geared towards coming to grips with complexity, rather than just spinning out ever more details.  Major practical, and we also believe conceptual challenges lie ahead.  Asthma is a good case in point.

RAiN gutter, or RNAi down the tubes?

Here's a story that may not seem so but is actually about the kind of extensive cooperation that characterizes life, and is a major theme in our book.

"Drug giants turn their backs on RNAi," reports Nature this week.  The headline writer must have had a hard time resisting the urge to end that sentence with an exclamation point, because RNA interference has been seen for the last decade or so as the latest greatest drug technique on the horizon, and if that's no longer true, that's news.

Not long ago, a technique called RNA interference (RNAi) seemed to be on the fast track to commercial success. Its discovery in 1998 revealed a new way to halt the production of specific proteins using specially designed RNA molecules, and it quickly became a favourite tool of basic research. In 2006, the scientists who made the discovery were awarded the Nobel prize for medicine, and the New Jersey-based pharmaceutical giant Merck paid more than US$1 billion to snatch up Sirna Therapeutics in San Francisco, California — one of the first biotechnology companies aiming to harness RNAi to create new drugs.

As one company, Alnylam Pharmaceuticals, one of the best endowed RNAi start-ups in the world, describes it:

RNAi is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. RNAi offers the opportunity to harness a natural mechanism to develop specific and potent medicines, and has the potential to become the foundation for a whole new class of therapeutic products.

The discovery of RNAi has been heralded as a major scientific breakthrough that happens only once every decade or so, and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today. 

Well, according to the story in Nature, Alnylam has just laid off 50 workers, more than a fifth of its work force, because the Big Pharma company, Novartis, declined to extend its partnership with them.  Of course Alnylam says they still believe wholeheartedly in the promise of RNAi, but they would have to say that, wouldn't they?  Is protecting your stock prices and nervous investors an excuse for shading honesty, one of our recent themes?

RNAi is a naturally occurring process that interferes with gene expression when the antisense strand of an RNA molecule binds to the sense strand, thus inhibiting its translation into a protein.  The discovery of RNAi was a major discovery worthy of a Nobel prize because it revealed how cells naturally titer their level of gene expression.  They can start using a gene, but then quickly shut it down if brief or highly controlled timing is important, in forming organs in an embryo, for example, or cell differentiation or response to environmental changes.  It shows that nature is like the mushroom in Alice in Wonderland: nibble from one side to get taller, and the other to get shorter.

RNAi was quickly and widely heralded as a major breakthrough, and its potential in treatment of diseases like Huntington's or Parkinson's and so forth was obvious and exciting to researchers, pharma, and patients alike.

But, as with other forms of gene therapy, the realities of delivering the RNAi molecule to its target within cells is proving to be daunting.

The development of RNAi-based drugs has stalled as companies confront the challenge of delivering RNA molecules, which are notoriously fragile, to target cells in the human body, and then coaxing those cells to take up the RNA. "Getting these molecules exactly where we want them to go is a little more difficult than originally thought," says Michael French, chief executive of Marina Biotech, an RNAi company based in Bothell, Washington.

Of the dozen RNAi-based therapeutics in early clinical testing, most apply the RNA molecules directly to the target tissues, or aim to shut down the production of a protein in the liver, which takes up the RNA as it filters the blood. Several candidates also package the RNA within a lipid nanoparticle, a delivery vehicle that both protects the RNA and allows it to be shuttled across cell membranes. 

Alnylam claims to have a number of possible drugs in the proverbial (just-in-time-for-Christmas?) pipeline, and still enough money, even without Novartis, to do some testing, and other companies are still holding on as well.  So apparently we aren't hearing the actual death knell yet, but it's starting to look a lot like the sobering of the dance of enthusiasm for personalized genomic medicine by Big Pharma a decade or so ago because of the realities of complex disease.

There are several things here worthy of comment besides the discouraging news that a hopeful-sounding therapy might not work.  Differentiated organisms rely on internal integrity of their many cooperating parts -- organs, tissues within each organ, and complex interactions among components within each cell.  Stuff from the outside that is not brought in under controlled circumstances is not likely to be usefully incorporated into cellular machinery.  That's why immune systems of various kinds, often quite intricate, exist.  That's why cells highly control what crosses their membranes from the outside in, and get rid of what's no longer needed by kicking it out.

All this involves detection and cooperative action of large numbers of components that must be in the right place, on guard or ready for duty, at the right time.  It is no wonder that trying to sneak in something external, that is supposed to coopt the cell for its own purposes, is difficult!  Especially if this requires shanghaing many different parts of the cell to get this done.  Whether the problem can be solved is only for the future to tell, but the hyperbole by companies about how RNAi would quickly lead to a revolution in medicine was typically highly over-worked.

Years ago, David Stock, a very fine post-doc in our lab (now a prominent faculty member in beautiful Boulder, Colorado) spotted something strange in some work we were doing with embryonic mouse teeth.  We were interested in how teeth are patterned, and were working with a gene we had discovered called Dlx3.  David said he had sequenced some RNA -- purportedly messengerRNA coding for the Dlx3 gene -- but instead he had discovered the reverse sequence.  This was, at the time, 'impossible' and we dismissed it as a laboratory artifact.  RNAi had not yet been discovered, and since it was so unexpected we just never followed up on this finding (maybe we should have!).  That's how surprising RNAi seemed to be when it was shown to be real, widespread, ancient, and important in the biology of normal organisms.

But the idea, including the potential for practical application, was not new.  Even in our lab, we had tinkered with experimental uses of anti-sense RNA.  Various people had thought of using introduced anti-sense RNA in cells to experimentally alter gene expression.  The idea that this could have  application was also expressed by many, and we think some pharma explored this.  If genes are expressed via mRNA, which is translated into protein, then if you could inhibit that translation you could experimentally (or therapeutically) slow or stop the expression of the targeted gene.  AntisenseRNA would bind to the corresponding messengerRNA in the cell, so it couldn't be translated into protein.

Unfortunately, the method proved very difficult to use.....that is, it basically didn't work.  Even in cell or organ culture (such as, in our lab, growing embryonic mouse tooth germs in culture), the cells simply did not like incoming RNA, and RNA is quite unstable to begin with.  We and many others tried this approach, but gave up on it.

Thus it was that investigators thought of doing what nature had been doing, systematically and precisely and unbeknownst to science, for many many millions of years.  And unlike BigPharma, nature has made it work! 

The bottom line here (for science, citizens, and investors) is to keep the enthusiasm under control when making promises or pronouncements.  Stay closer to the truth.  And work harder before drawing conclusions.

Sooner or later technology and engineering often do succeed, and it's dangerous to bet against them.   But not everything works, and it's hard to know in advance what will.  Hopefully something as specifically targeted as RNAi will find useful biomedical or other application eventually, but without the hype.