the exposome…

Posted on Saturday 28 March 2015

by Tom Insel

… This update of our Strategic Plan is a commitment to take a fresh look at our horizons so that we can refine priorities and energize our path of discovery.

We know that some scientists reject the concept of “directed science,” believing that science rarely follows a plan. True, important discoveries often result from serendipity or side roads rather than a premeditated, carefully articulated strategy. On the other hand…

While the tools of genomics and neuroscience now permit rapid progress, equivalent tools and paradigms to study environmental influences are just being developed. Over this next 5-year period, we can expect this new approach to environmental factors, sometimes called the exposome, to yield more scientific traction in understanding the mechanisms by which environmental factors alter brain and behavior, from prenatal development through the process of aging…

Strategic Plan Strategic Objective 3
Director’s Message Strategic Objective 4
Introduction Highlights
Strategic Objective 1 Appendix
Strategic Objective 2 References
Strategic Research Priorities
After a number of years of reading someone’s writing, you sort of pick up on their rhetorical style. For example, when Tom Insel is discussing something he’s been criticized for [like being a control freak], he always puts the criticism first ["important discoveries often result from serendipity"], then says something like "On the other hand…" and carries on along the path he favored in the first place, ignoring the criticism altogether. In this case, it means continuing to be a control freak. And watch out for his neologisms – things like genomics, protenomics, connectome,  – or buzz phrases – personalized medicine, translational medicine, neural circuits, etc. This new one [the exposome] is particularly creative [not to be confused with the envirome or the the interactome]. At first, I thought that the exposome looked promising [are we finally going to recognize that there are factors outside the genetic endowment that effect the mental state?]. But, alas, these are terms generated after the Genome Project that have to do with speculations about how the outside world might shape biology. I was looking for something more like having nutty parents or life-changing events. Oh well… And don’t let the brevity of my quotes and links up there fool you. They connect to a labyrinthine Strategic Plan [insert and grandiose]. There’s really not going to be much room left for that serendipity he was mentioning. For example [in Objective 1: Strategy 1.1]:
To unravel the mechanisms that lead to mental illnesses and target novel treatments to those mechanisms, more comprehensive descriptions of the molecules, cells, and circuits associated with typical and atypical behavior are necessary. What classes of neurons and glia are involved in a given aspect of mental function? Which brain regions contribute to a single thought or action, and how are these regions interconnected? These questions will be answered by defining the cellular components of circuits, including their molecular properties and anatomical connections. New tools and techniques that span biological scales—from single-cell analysis, to macro-electrode arrays, to systems-level brain imaging — are needed to address these questions.
I think the thing that bothers me the most, besides the impossibility of serendipity in Insel’s NIMH, is that his grand plan is monomaniacal and based on hypotheses cum speculations that have yet to be anchored in the reality of solid science. I’ve spent my days with the simple idea of a Hardware/Software dichotomy for mental illness [Hardware «Melancholia, Manic Depressive Illness, Autism; maybe Schizophrenia, etc» and Software «most everything else»]. So a lot of this stuff Insel dreams of has felt like he’s trying to reprogram a computer with a screw·driver and a soldering iron. I’ve focused more on the programming languages.

Pushing that simple analogy, many critics would go further and say that it’s all software [as in the BPS Report Understanding Psychosis and Schizophrenia] or Schizophrenia: a critical psychiatry perspective] taking the psycho·social·perspective to extremes, saying that mainstream psychiatry is totally at sea in its hardware bio·perspective. But as much as I enjoy reading about the neuroscience, my take on Insel’s NIMH 2015 Strategic Plan is that it’s wildly speculative, making fantasmagoric extrapolations that move way, way beyond the frontiers of anything we know [but then again, I felt something similar in the other direction about the those psycho·social articles].

Back to Insel, I first started thinking about his rhetorical On the other hand… trick back when I read this blog of his a few years ago:
NIMH: Director’s Blog
by Thomas Insel
January 26, 2012

NIMH, like all Institutes at NIH, has an advisory council that meets three times each year. The National Advisory Mental Health Council [NAMHC] is a distinguished group of scientists, advocates, clinicians, and policy experts. Each of our meetings includes a closed session to review individual grants considered for funding and a session open to the public that engages this diverse group in discussions about the larger issues that guide NIMH funding.

At last week’s session, we heard a recurrent tension around one such larger issue. Some members of Council bear witness to the poor quality of care, the unmet medical need, and the diminishing investments by states on behalf of people with mental disorders. They reasonably ask, “How are we ensuring that the science that NIMH has produced is implemented where the need is greatest?” They also question on the pay-off of genetics research. After all, two decades after the gene for Huntington’s disease was identified, we still have no effective treatments, and Huntington’s disease is genetically far simpler than schizophrenia or bipolar disorder. In contrast to so many neurological diseases, we have effective treatments for schizophrenia and bipolar disorder. NIMH should be investing to ensure these are available.

The opposing argument runs something like this. There has been no major innovation in therapeutics for most mental disorders since 1960. Current treatments are not good enough for too many. Rather than investing scarce dollars for incremental improvements or increased dissemination of mediocre interventions, we need invest in the fundamental science of brain and behavior so that we can understand how to develop better treatments…
And in that blog, at the end, he pulled out the polio miracle to bolster his case.
Sixty years ago, the nation faced a similar short-term vs. long-term debate about polio. The needs were growing and the causes were unknown. Some wanted funds invested only in better services, including improved iron lungs. Others argued for investing in a vaccine with a long-term goal of eradication. As David Oshinsky explains in his outstanding retelling of this debate, the government went with the services approach, leaving advocates and families to raise funds for vaccine development. Let us hope we don’t short-change our grandchildren, sixty years from today, by failing to invest in the long-term promise of more effective diagnostics and therapeutics for mental disorders.
I’m convinced that so long as it’s Insel’s show, the only alternatives are to send him on a prolonged [permanent] sabbatical or rename the NIMH the National Institute of Neuroscience. I mean that without tongue in cheek. He’s so far into his on-the-other-hand-land basic neuroscience that there’s little hope that he will ever take a balanced look at Mental Health. Even when they fund a study like RAISE-ETP in First Episode Schizophrenic patients, the psychosocial component is heavily weighted towards being a chemical imbalance and take your meds manual. And as for his ability to predict the future, how about this 2005 effort from his psychiatry as clinical neuroscience days?

And I think I would insist that his successor, if we ever get one, be required to spend at least a half-day a week seeing patients in a local mental health clinic – something Dr. Insel has never done since his residency training.
    Bernard Carroll
    March 28, 2015 | 10:54 PM

    Who writes this stuff for Insel? You rightly called it grandiose. Let’s add obsessoid, too, which fits a control freak. We could also charge him with the mereological fallacy, as here: “What classes of neurons and glia are involved in a given aspect of mental function? Which brain regions contribute to a single thought or action…,” This is reminiscent of the old saw about no twisted thought without a twisted molecule. One cannot take him seriously.

    link added by 1bom

    James O'Brien, M.D.
    March 29, 2015 | 2:11 AM

    This is utterly ahistorical and illogical…basically he acknowledges that science is often the result of happy accidents, YES BUT YES BUT YES BUT we will control how everything is done and conceptualized.

    That YES BUT hiccup is the clear signal to any self-aware individual that your defenses are getting in the way of progress or what you know is the right thing to do.

    On Dr. Carroll’s point, Dr. Satel once noted that most of the brain is mixed use real estate…the oversimplification from the groovy 2015 crowd continues as it does from the groovy 1965 crowd.

    Steve Lucas
    March 29, 2015 | 7:58 AM

    Another blog is having a discussion on the make up of medical educators and the need for those teaching to have professional backgrounds, not just an academic understanding of medicine. The concept that new doctors can teach other new doctors has been called into question.

    A topic on a number of blogs has become EBM and how experience and knowledge are no longer rewarded or even considered in medical decisions. The young tech savvy doctor along with Dr. Google is placed at the same level as the old practitioner with decades of experience.

    Pharma and the EMR vendors want to see this approach adopted since it will sell product and free thinkers are eliminated from the system.

    Insel is very much a shill for this system knowing if he pushes his ideas through he will reap the financial rewards.

    Steve Lucas

    March 29, 2015 | 11:57 AM

    Someone should tell Insel it is time to pack his bags and take his central planning research initiative to Russia. After all, before the implosion of the USSR, the Kremlin was famous for five year plans for the economy. And look how well that worked out! Maybe Putin can find a place for him.

    James O'Brien, M.D.
    March 29, 2015 | 12:52 PM

    His path to personalized medicine is working out about as accurately as Michael Mann’s hockey stick…not that modus tolens will be any logical barrier to “my theory uber alles”

    The move Idiocracy was about the average person getting stupider at an alarming rate…I am really concerned about smart people getting stupider at an alarming rate…a top researcher in the 1950s put in a time machine forward to today would really have a tough time dealing with academic bureaucrats and pitchmen and would see the environment as antiscience.

    March 29, 2015 | 6:07 PM

    Quite a few people on my site are showing up having had various tests by psychiatrists and alternative practitioners supposedly showing the “most effective” psychiatric drug, or blocked pathways, such as MTHFR variations, that explain why this or that drug or supplement isn’t working and why the person continues to feel so crummy.

    Identifying poor or rapid metabolizers via P450 liver enzyme analysis does not indicate the “most effective” drug, it indicates which drugs are more dangerous for a specific reason. Adverse effects of psychiatric drugs can occur for reasons beyond liver enzyme incapacity.

    MTHFR analysis and treatment of what are, after all, NORMAL genetic variations (as are the liver enzyme variations), has become an immense fad. There is no way to test if a treatment has corrected the putative deficiency other than the person feels better. “Treatment,” such as it is, involves trial-and-error of perhaps 2 dozen different supplements and a lot of hand-waving.

    And there is a lot of Deplin being prescribed, which should make Mauricio Fava very happy.

    That is where we are with “personalized” medicine. By the way, alternative practitioners love this. They order lots and lots of unvalidated tests usually paid out-of-pocket by the client.

    Susan Molchan, MD
    March 29, 2015 | 6:55 PM

    Mickey hits on a number of great points as usual, starting with language/use of words. I was reminded of what Orwell said in Politics and the English Language, on how “science” is one of the words frequently used with the writer’s “own private definition,” allowing “his hearer to think he means something quite different” (a strategic plan that may actually help people with mental illness).
    I hadn’t realized Insel didn’t see patients for years, so just prairie voles and monkeys. No wonder he’s out-of-touch.
    It’s easy to do science—set up experiments, publish papers. It’s hard to do science that matters, in those messiest subjects of all—people—in long-term studies, where observations and interventions include all matter of things in their environments, and their communities.

    March 29, 2015 | 7:15 PM

    Well, I can say without hesitation that my exposome is going quite well. How about you?

    James O'Brien, M.D.
    March 29, 2015 | 8:08 PM

    There is a relevant biomarker in depression and SGA treatment and measuring it is free and easy


    Joseph Arpaia
    March 29, 2015 | 11:36 PM

    Exposome?? Is that something that happens on Facebook??

    It is impossible to do rigorously controlled studies on humans. There are too many variables that cannot be controlled and every study simply assumes that many of them do not matter. That is not science.

    When I was at CalTech I did research on the spectroscopy of transition metal compounds. I knew the exact molecular structure of the compound I was studying, measured the mass of the reagents to the microgram, used an ultra pure and de-gassed solvent and measured the wavelength of the emitted light with sub nanometer precision. Those were controlled experiments.

    The Ham-D for measuring depression, or, worse, the PHQ-9? Subjects who may or may not take their medications as prescribed? Paid subjects who exaggerate their symptoms or make them up to qualify for a study? The double-blind RTC is not a gold standard, its a fools-gold standard.

    Then there is the internal state of the person. I use hypnosis in my practice for people with pain. I recall working with someone in a burn unit who was in agony during debridement. I changed the manner in which I was talking to him and he went to sleep. How do you control for suggestion, when suggestion can cause such changes?

    I have seen very depressed patients suddenly get better, amazingly better at times, when their abusive boss left, or when they found a partner, or when they found a job. These things are all happening to the people in the studies.

    My more cynical side is of the opinion that trotting this tripe out as if it is science takes attention from the role that the increasingly oppressive socio-economic environment is playing in mental illness and using pseudo-scientific jargon like “neuroscience” and “genomics” to blame the serfs for their lot. Or it could just be about money.

    James O'Brien, M.D.
    March 30, 2015 | 12:50 AM


    Is there any reason why not to do an MMPI-2 and tox screens to look at this issue? If you have a Ham D confirmed by a valid 2, this is noise reduction. You cut out the high Fs and high L/Ks thereby eliminating the exaggerators and the deniers. Why wouldn’t you want this in every antidepressant study? Bueller?

    Do this and watch the placebo response rates go back down to 1975 levels.

    Sandra Steingard
    March 30, 2015 | 7:23 AM

    Dr. O’Brien,
    I just reviewed a book on the placebo effect by Walter A. Brown. Your guess about how to reduce it does not appear to match up to the findings of recent studies.

    James O'Brien, M.D.
    March 30, 2015 | 11:40 AM

    Thank you for clearing all that up with cogent easily understandable and thorough analysis.

    March 30, 2015 | 10:40 PM

    Thank you for bringing in another viewpoint, Dr. Steingard. I’m sure everyone interested in this topic will thoughtfully consider Dr. Brown’s book.

    March 30, 2015 | 10:43 PM

    The MMPI-2 is useless in uncovering unconscious dissimulation. The PAI is much better at teasing out purposive versus “unconscious” profile distortion. I suspect the placebo group would be found with the PAI better than the MMPI-2.

    James O'Brien, M.D.
    March 31, 2015 | 1:20 AM

    I guess we all have to go buy the book since she didn’t actually make a point based on it.

    This is the first time I’ve ever heard anyone claim the PAI is superior to MMPI-2 which has a much greater research database. Can you tell us a little about your background?

    April 1, 2015 | 10:57 PM

    Dr. Insel might consider grounding his ship there at NIMH by having an advisory board made up of family members who lost their loved ones to psychiatric drugs. Given the variety of ways one can die from such drugs – be it suicide, profound hyperglycemia or numerous other systems failures, and given that such events can happen in any family, the variety of experiences that such a group would bring to the table – and their views on what might help people with mental health conditions “going forward” just might help Dr. Insel envision some new priorities other than those laid out here.

Sorry, the comment form is closed at this time.