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Why “Optogenetic” Methods for Manipulating Brains Don’t Light Me Up**

The views expressed are those of the author and are not necessarily those of Scientific American.


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It’s the kind of scitech innovation that, when I was a bright-eyed young science writer, made me think, “Cool!” But now stories like “OCD and Optogenetics: Lighting the brain up to shut a behavior down” bring out the curmudgeon in me.

Does the trendy field of optogenetics deserve all its glowing coverage?

The column, by my Scientific American co-blogger Scicurious, actually does a terrific job describing a recent advance in the fast-moving field of optogenetics. Optogenetics involves tweaking the genes of neurons so that they become sensitive to light. Researchers can then trigger or suppress firing by the neurons by stimulating them with light-emitting devices inserted into the brain.

Optogenetics is a technically sweet technology spawned a decade ago from the convergence of genetics, optics, neuroscience and materials science. (For an overview, see the Scientific American article by Karl Deisseroth of Stanford, a leader of optogenetics.) Optogenetics could–in principle–allow much more precise manipulation of the brain than conventional implanted electrodes, let alone drugs, transcranial electromagnetic stimulation or electroconvulsive therapy (a.k.a. shock treatment).

Researchers are exploring the potential of optogenetics for understanding and treating* a wide range of brain-based disorders, including obsessive-compulsive disorder (the focus of Scicurious‘s column), depression, schizophrenia, Parkinson’s and post-traumatic stress disorder. Just last month, a group at MIT reported that it had implanted false memories in optogenetically altered mice, work that one outside researcher called “really mind-blowing.” [*Most coverage of optogenetics focuses on its potential for basic research, not treatment. See Clarification below.]

Indeed, optogenetics has inspired lots of glowing coverage. Science writer Ed Yong calls it “revolutionary,” and David Dobbs describes a recent experiment as “damned intriguing” and “potentially very significant.” In his recent defense of “scientism,” which I hammered last week, psychologist Steven Pinker alludes to optogenetics when he extols “genetically engineered neurons that can be controlled with pinpoints of light.”

“Word on the street is that a Nobel Prize isn’t far off,” physicist Leonard Mlodinow gushes, adding that optogenetics “is destined to change the way we treat mental illness, and eventually, even, the way we understand ourselves as human beings.”

So what’s my problem with optogenetics? Actually, I have several problems. First is the gross oversell. For optogenetics to become an effective method for treating mental illnesses, you need specific knowledge about the illnesses’ neural underpinnings. You must know which neurons or neural circuits are overactive or underactive or otherwise abnormal.

But we lack such knowledge about depression, schizophrenia, bipolar disorder or any other major mental illness. As the director of the National Institute of Mental Health recently acknowledged, decades of research have not turned up any clear-cut physiological—that is, neural, genetic or chemical–correlates of the major mental illnesses. How can a brain-manipulation technique alleviate mental illness if we don’t know what to manipulate?

Of course, optogenetics enthusiasts hope that optogenetics itself can yield such knowledge, by improving upon conventional electrode-based systems for probing the brain. Implanted electrode systems can relieve symptoms of Parkinson’s, obsessive-compulsive disorder, depression and other ailments in some patients. Deep brain stimulation has been sparingly used for clinical applications because it is unreliable and often leads to infections and other serious complications.

Optogenetic methods would probably be at least as problematic as electrode-based methods. Optogenetics not only requires drilling holes in peoples’ skulls and sticking devices inside their brains; it also involves altering the DNA of brain cells with viruses or other means, which makes optogenetics far more unpredictable and invasive than electrode-based systems. Moreover, whereas conventional electrodes can both manipulate and monitor neurons, optogenetics requires separate devices for stimulating and measuring neural activity.

That brings me to a meta-problem I have with optogenetics: I can’t get excited about an extremely high-tech, blue-sky, biomedical “breakthrough”—involving complex and hence costly gene therapy and brain surgery–when tens of millions of people in this country still can’t afford decent health care.

As I never tire of reminding readers, the U.S. spends far more per capita than any other nation in the world. Yet our life expectancy is about the same as that of Cuba, which spends less than one seventeenth what we do on health care per capita. Technology, far from being the solution to our health-care woes, is part of the problem. Expensive, high-tech tests and treatments have driven up costs of medicine while often impairing peoples’ health.

If optogenetic treatments ever turn out to be viable, my guess is that they will be reserved for the wealthy—or perhaps for American soldiers, both injured and healthy. As I pointed out recently, the Pentagon is a major funder of brain research in the U.S. The Defense Advanced Research Projects Agency is funding optogenetics research at Stanford, Brown and elsewhere.

I hope that you keep all these caveats in mind the next time you read a story like “A Laser Light Show in the Brain,” in which psychologist and New Yorker blogger Gary Marcus calls optogenetics a “godsend” that allows investigators to “direct symphonies of light-induced neural activity inside the brain.” Give me a break. Or as the old New Yorker used to say: “Block that metaphor!”

Postscript: Some commenters on this column have argued that optogenetics researchers have never claimed that the technique might be used to treat mental disorders in humans. Here are examples of researchers discussing therapeutic applications.

*In a 2010 article in the Journal of Neuroscience, “ANTIDEPRESSANT EFFECT OF OPTOGENETIC STIMULATION OF THE MEDIAL PREFRONTAL CORTEX,” a group of 13 researchers, including Karl Deisseroth of Stanford, states that “as electrophysiological data discerning specific patterns of normal cortical activity become available, it will become feasible to induce a particular pattern of activity (e.g., via optogenetic activation, direct brain stimulation, or pharmacological manipulation) to eliminate certain behavioral disturbances manifested during the course of clinical depression (e.g., anhedonia, social withdrawal, etc.).”

In a 2011 TED talk, optogenetics pioneer Ed Boyden of MIT talks about the promise of “optical neural control therapy” and “optical prosthetics” for a wide range of brain disorders, notably epilepsy and blindness. He refers to his experiments on mice as “pre-clinical testing.”

In this 2013 press release from the University of Oxford, optogenetics pioneer Gero Miesenböck states that optogenetics “could be a means to identify nerve cell groups that cause specific diseases as targets for medicines. In the more distant future, there could be the possibility of using optogenetic manipulations directly in humans, in order to restore neural signals that have been corrupted or lost because of injury or disease.”

In a 2011 review paper in Medical Hypotheses, Avi Peled, a psychiatrist at Technion, proposes: “In light of new optogenetic technology time is ripe to seriously consider optional targets of intervention in the brain of schizophrenia patients…optogenetic interventions in schizophrenia should begin in the prefrontal cortex and the Globus-Pallidus Subthalamic nuclei systems.”

A 2011 article in The New York Times quotes Stanford researcher Krishna V. Shenoy, who is doing DARPA-funded research on optogenetics, saying that optogenetics may be able to help veterans with brain injuries: “Current systems can move a prosthetic arm to a cup, but without an artificial sense of touch it’s very difficult to pick it up without either dropping or crushing it… By feeding information from sensors on the prosthetic fingertips directly back into the brain using optogenetics, one could in principle provide a high-fidelity artificial sense of touch.”

*Clarification: Twitter Tussles with Ed Yong and others have persuaded me that I overstated the degree to which coverage of optogenetics has focused on its potential as a treatment rather than research tool. The theme of the stories by Ed and Scicurious–and of the 2010 Scientific American article by Deisseroth–is that optogenetics can lead to insights into brain disorders. These insights may then lead to better treatments, but not necessarily optogenetic ones (although as my Postscript shows, Deisseroth and others have raised that possibility). But the insights-into-mental-illness angle has also been over-hyped, for the following reasons: First, optogenetics is so invasive that it is unlikely to be tested for research purposes on even the most disabled, desperate human patients any time soon, if ever. Second, research on mice, monkeys and other animals provides limited insights–at best–into complex human illnesses such as depression, bipolar disorder and schizophrenia (or our knowledge of these disorders wouldn’t still be so appallingly primitive). Finally, optogenetics alters the cells and circuits it seeks to study so much that experimental results might not apply to unaltered tissue. For a thoughtful discussion of the limits of optogenetics compared to other neuro-research tools, see this new post by neuroscientist Mark G. Baxter.

**Addendum: See also my followup post on optogenetucs, in which I respond to other criticisms: http://blogs.scientificamerican.com/cross-check/2013/09/01/why-optogenetics-doesnt-light-me-up-the-sequel/.

Image: Optogenetics Resource Center, www.stanford.edu/group/dlab/optogenetics.

John Horgan About the Author: Every week, hockey-playing science writer John Horgan takes a puckish, provocative look at breaking science. A teacher at Stevens Institute of Technology, Horgan is the author of four books, including The End of Science (Addison Wesley, 1996) and The End of War (McSweeney's, 2012). Follow on Twitter @Horganism.

The views expressed are those of the author and are not necessarily those of Scientific American.





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  1. 1. M Tucker 12:17 pm 08/20/2013

    “As I never tire of reminding readers, the U.S. spends far more per capita than any other nation in the world. Yet our life expectancy is about the same as that of Cuba, which spends less than one seventeenth what we do on health care per capita. Technology, far from being the solution to our health-care woes, is part of the problem.”

    I’m glad you never tire of it because it is something that people need to know. What a system we have: making a profit from pain, suffering, and early death while driving people into bankruptcy.

    Link to this
  2. 2. looie496 2:19 pm 08/20/2013

    The idea of using optogenetics for treatment of patients is bizarre. It’s a research technique, and a tremendously powerful one. It shouldn’t be disparaged because of what it can’t do — that’s like disparaging cars because they can’t fly to the moon.

    Regards, Bill Skaggs

    Link to this
  3. 3. zstansfi 2:55 am 08/21/2013

    How is this column anything other than a ridiculous straw man? Who has actually proposed using optogenetics to treat mental illness? Would you mind providing a citation, John? Oh wait, we’ll leave that for the scientists.

    The ground-breaking nature of optogenetics has nothing whatsoever to do with whether or not we can insert light-controlled genes into human brains and everything to do with what has already been accomplished in animal model species. The knowledge acquired through the use of this technique has been used to shed some light on the systems-level operation of mammalian brain networks and to better elucidate neural mechanisms hypothesized to be involved in mental illness.

    But that’s it. And anyone who tells you we’re going to “cure mental illness using optogenetics” is high as a kite. That’s probably why none of the people cited by John Horgan actually made any such non-sensical statements.

    Link to this
  4. 4. Chryses 6:07 am 08/21/2013

    Other than the irrelevant, repetitive complaint about the US Health Care System, those are reasonable criticisms.

    Link to this
  5. 5. abolitionist 1:20 pm 08/26/2013

    John,

    “Twitter Tussles with Ed Yong and others have persuaded me that I overstated the degree to which coverage of optogenetics has focused on its potential as a treatment rather than research tool.”

    … and your criticism of the research technique by linking it to the inadequacies of the US Health Care system is a non sequitur.

    Link to this
  6. 6. BrainMoleculeMarketing 4:21 pm 08/27/2013

    I had my genes analyzed for $100. Price is coming down.

    Link to this
  7. 7. 9brandon 5:02 pm 08/28/2013

    I can understand why biomedical researchers might be touchy about criticism of optogenetics, especially in this basic research-unfriendly funding moment, and sci-tech writers might be touchy. But what John calls the “hype cycle” — by which I suspect he means, “excited coverage of basic and early-stage research as though it’s of potential public health importance in the near future” — is a real problem.

    John says it discredits science journalism. Maybe it does, though sometimes I wonder if people don’t necessarily turn to science and especially technology journalism less for relevant depictions of public health-related issues, and more for doses of optimism. Even worse, though, the hype cycle warps public understanding of both science and health.

    Optogenetics is a neat research technique. If a scientist wants to get excited about it, that’s great. Louis Pasteur once got excited about basic research, too. We need that. But a journalist has a different job, and for a journalist to cover optogenetics as something that could have direct or indirect health applications in the near future (1) — and, in the process, to *not* write about other public health-relevant research — misportrays the state of the science, and does a disservice to other issues or research that might have been covered. (2)

    Those types of stories also bely a larger problem: The appetite of our public culture for (often tech-centric) narratives of progress and imminent improvement. An entire industry exists to tell fables of this sort, which we repeat to ourselves endlessly even as America spends far more on both biomedical research and health care than any other developed country in the world, yet has far, far worse health.

    To this point, one might counter that spending on early-stage biomedical research is independent of health care costs (3), much less outcomes, and that we ought to pursue many avenues of research, of which tools like optogenetics are just one. I certainly agree to the latter, and personally think far too little is spent on nutrition, lifestyle and child care-based research applications — on all those things that are orders of magnitude less sexy, and orders of magnitude more immediately useful, than optogenetics.

    Gee-whiz sci-tech coverage of early-stage research distracts us from what we already know. Inasmuch as there’s limited funding available for research, it also detracts from other, equally valuable research (4). And … here the journalist in me would like to write a kicker, and I haven’t got one, except to say that issues like this are precisely why I’ve stopped writing about health except on very rare occasions, when policy and science align or I’m able to spend a lot of time reporting and contextualizing.

    (1) I.e., as John pointed out, could have consequences in the treatment of neurological disorders for which the underlying neurology is poorly understood, and may differ profoundly between humans and the animals used as models of their diseases.

    This might seem a pessimistic assessment, but a science journalist’s perspective is one in which, on a daily basis, researchers or their institutional communications officers advertise medical breakthroughs. After a few years of this in my case, or a few decades in John’s, how else do you respond except to say, “Get back to me when you’re done with Phase III trials?”

    (2) It also affects the funding of science: Researchers whose work is widely covered in the popular press have an easier time getting funded. And, arguably, rewards journals for favoring new-tools-and-methods-centered research over translation and application. Yes, all these things are needed. But right now the balance is out of whack.

    (3) Yes, hospitals & the health industry jack up prices in sometimes near-criminal ways. But sometimes drugs and procedures are just damn expensive. I don’t know how much optogenetics-based treatments might cost, but a journalist has an ethical obligation to ask exactly that question.

    (4) It’s worth taking a moment to remember that the NIH budget is something like five times bigger than the National Science Foundation’s, which pretty much covers everything that’s not narrowly biomedical — but often has very real public health implications, too.

    Link to this
  8. 8. RTomsett 10:05 pm 08/31/2013

    I done a blog post all about what I think is wrong with this article, which to be honest is most of it: http://tomsett.me.uk/anti-optogenetics/
    There’s much to be said about optogenetics hype, and I think that last blog you linked to did a good job. I don’t think you’ve made the case well here at all.

    Link to this

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