The circuitry of a honeybee’s brain.
The circuitry of a honeybee’s brain.
Earlier this fall, the (most excellent editor Eliza Strickland at IEEE Spectrum) invited me to write an article about the BRAIN Initiative. Initially I had many reservations: I knew about the project mostly through news articles written when its original, nebulously-defined-but-mostly-about-neuron-recording incarnation was announced in April, and what I’d read had irritated me. The proposal seemed much too narrow (what about data storage? interpretation? and everything that’s not a neuron?) and the grand-challenge-of-our-time rhetoric swollen with hype.
I also had, and still have, reservations about the importance attached to neuroscientific explanations, particularly of complex human behaviors. What’s so condescendingly referred to as “folk psychology” might better be called “knowledge produced through other social processes than the institution of science,” and includes all those endeavors encompassed by literature, history, art, the social sciences and collectively distilled experience. To illustrate this, I like to use the example of love: What if we had a billion-dollar love project, intended to better understand and promote love? Neuroscience would have just one of many seats at the table, and it probably wouldn’t be at the table’s head.
That said, after poring through various NSF and NIH documents associated with BRAIN, and speaking to roughly a dozen neuroscientists, I feel much better about the project. I’m impressed by its scope, fascinated by the questions seeks to answer and those it might generate. It is, in a word, exciting. I also feel that the people involved are more thoughtful and modest than I’d expected. And of all the scientists, I was profoundly impressed by Cori Bargmann, the Rockefeller University neuroscientist who oversaw the NIH’s interim BRAIN report. Below is the interview we conducted by email.
Q: Something I wanted to ask first, in case the other questions turn the discussion dry, is: What scientific questions are the most exciting to you? What it is that fascinates you, that keeps you thinking late at night … and do you hope the BRAIN Initiative will answer these questions?
Bargmann: The human brain is a miracle. It gives rise to infinitely many thoughts, emotions, memories, actions. How can one biological organ, a collection of cells, do all that? No matter how long you’ve been a neuroscientist, it is still an amazing that this complexity emerges from such mundane biological components. That’s what motivates me. Yes, I think the answer will come from understanding brain circuits and dynamics, and electrical and chemical signaling, and theory. (I have a mental picture of how this works in the tiny worm, but it’s not proved yet; in larger brains, even the mental picture is elusive.)
Q: The Initiative has evolved a great deal since its conception (and, as an aside, it’s been tremendously heartening to see criticisms articulated and incorporated into the interim NIH report; that sort of thoughtful, constructive, perspective-harnessing process is really science at its best, and makes this bystander proud.)
Bargmann: Thank you! We were very fortunate because many people were willing to give us advice. On very short notice, flying around the country. It’s also been heartening that several other independent groups have arrived at overlapping ideas (NSF, the Allen Brain Institute, the Kavli think tank, others). It gives us more confidence that we’re on the right track.
Q: Do you expect it to continue to evolve over the next year, and in what ways — will we continue to see substantive additions, such as the attention newly paid to glia, or are the next stages more about deciding how to apportion emphasis among the research priorities?
Bargmann: This is an interim report. We hope this is the right direction, but we want feedback. We may realize that we’ve missed something important, and add an area. We will definitely try to sharpen and focus the ideas.
This will be both informal and formal. Formally, we will meet with “partners” and “stakeholders” (Washington-speak). For example, in theory we are just an advisory group to NIH, but there are many groups involved in the BRAIN Initiative. All of these groups should talk about what everyone will be doing, and who else should be involved. This will happen soon — the people who are already in the loop are NSF, DARPA, Allen, Kavli, HHMI. In the longer tern, I’m excited to say that several tech companies are expressing interest in being part of the BRAIN Initiative! Microsoft, Google, Intel would have a lot to provide. And then there is broader input from neuroscientists (eg SFN), clinical and translational scientists (eg AAN), and patient advocacy groups.
Q: Timeline-wise, assuming the shutdown ends tomorrow, what do you expect this year from the agencies and foundations? Do you think we’ll see priorities set and grants reviewed by year’s end?
Bargmann: Oh, this is so upsetting. We worked hard on the interim report, with much advice, all pro bono, from leaders across the field. The interim report went in, it was accepted with enthusiasm, and now it’s in the hands of the government. NIH was poised to formulate and issue requests for proposals. Scientists across the country were getting ready to submit grants and review them (which needs to get set up by NIH). And if that all went well, we could have been starting the science in months! And then the government shut down, and now the start of the BRAIN project in 2014 is definitely at risk. No external force could do as much damage to research in the US as this is doing — can you imagine how we’d react if a foreign government sabotaged our scientific enterprise for this kind of time?
Q: Among the priorities, are there some that strike you as being preconditionally necessary — e.g., we can’t start collecting large-scale data without the platform for sharing it? Is there any concern that early priorities may preclude others — e.g., if the push is to develop technologies for recording electrical activity in brain cells, it’ll divert attention from the potential importance of chemical activity?
Bargmann: Science is always creative chaos — you can’t wait for things to be perfect to get started! Parallel work has the best history of success. The nature of the data determines the best design for data platforms, for example. Some areas will have great new ideas and a spurt of growth, other may take a while to reach the next level. This is how bottom-up science works best — set out the problems, and then find the people who have the best solutions.
Q: In the report, you point out the difficulty of measuring internal cognitive processes and mental states in animals, and the importance of doing so in a careful way. This difficulty has certainly received much attention over the last few years, particularly in regards to the limitations of mouse models for complex psychological states. Are those concerns something that the Initiative can address directly — e.g., by making more-informative use of animal models possible, or even reducing our reliance upon them — or are the concerns simply something to keep in mind?
Bargmann: Not sure I have a great answer to this. We’re getting pretty good at interpreting certain complex processes in the mouse brain, such as representation of space in the hippocampus. We can even tell based on brain activity when a mouse is “thinking” about going right versus going left in a maze, which is pretty cool. However, at this point we can’t say with confidence that we can recognize a complex psychological state like depression, let alone schizophrenia in a mouse. What we can say is that we recognize patterns of brain activity and behavior that are similar to those we might observe in a depressed person, and that respond to some of the same medications. I just want to point out that these states can also be challenging to identify in humans! We need to be appropriately humble at every level.
Q: A concern I’ve heard raised by researchers who are supportive of the BRAIN Initiative is the gap between what we now understand and the project’s ambitions. The C. elegans example is the usual one — “We can record every neuron in a C. elegans brain, and still can’t explain _____.”
Bargmann: Well, we can’t do that in a worm yet, or at least no one has yet done so. We have fragments, one neuron at a time. We need a more global picture of their relationships. That’s exactly why we need a multi-pronged approach: structural maps, activity maps, the ability to record and manipulate in the context of behavior, and theory
Q: The C. elegans reservation isn’t offered as a reason not to pursue the Initiative, but a restraint on what to expect from it in the near future (and perhaps not without more money than is presently being discussed.) What are your thoughts on this? How does one walk the line between overpromising in order to secure funding, or being so restrained in expectation as to discourage it?
Bargmann: I think that in ten years of the Brain Initiative, we could have a fundamentally different picture of how information flows through the brain in space and time, and what that means. I do not think we should promise that cures will come tumbling out of this initiative in the short term. I think we should promise that we will shed light on many core properties of the normal, active brain. And that with that illumination, we can turn to translational researchers, physicians, engineers, biotech, and big pharma, and begin a new era of translation into the brain disorders that cast a shadow on all of our lives — because even if you aren’t affected, your grandmother or nephew or best friend may be suffering from Alzheimer’s, or autism, or post-traumatic stress disorder.
Q: Do you get a sense of whether the NIH, NSF and DARPA funds will be new, or coming from existing budgets? To what extent, if any, are they guaranteed beyond 2014?
Bargmann: Not really — but I think everyone knows that a grand challenge takes more than one year! Ten years seems more like it.
Q: It’s certainly very early, but it seems some themes are emerging: a general unity of purpose/sense of what’s necessary between the NIH and NSF, with the NIH leaning towards the “wet” side of things — working with organisms, collecting the data, making the connections to disease, behavior and cognition — and the NSF leaning towards the “dry”: developing the recording technologies, data-analysis techniques, data-sharing platforms, and so on. Does that seem like a fair assessment to you? Do you have a sense of what DARPA and the private foundations will emphasize?
Bargmann: I like this formulation but it’s not my place to tell anyone what to do, especially not outside the NIH! My sense is that DARPA has a major commitment to injured veterans, and therefore has a big push on brain-machine interfaces and brain-computer interfaces, for example. Private foundations have their own interests, some overlapping closely with the Brain Initiative’s goals. HHMI/Janelia is making genetic reagents for the fruit fly, and developing sophisticated new microscopes. Allen is mapping long-range physical connections throughout the brain with their new tracing methods.
Q: In the interview with Eliza you referred to the multi-agency, public-private collaborative nature of this as “an interesting experiment.” Is there a precedent for this type of collaboration? So far it seems the various players have listened to the conversations each has led, but remained autonomous in setting their own priorities; do you get a sense of how everyone will continue to interact, especially when it comes time to decide what gets funded?
Bargmann: There’s plenty for everyone to do. Right now there is also a lot of good will; the tone of the conversations between different partners has been positive and collaborative. We know that resources are limited — we will get much further if we share ideas, technologies, and data.
Q: I’ve had a question bouncing around my head for a while, and wasn’t sure whether to pose it because I don’t think it bears directly on what I’ll write for IEEE … but what the heck:
Why should brain science deserve such a prominent seat at the table when it comes to understanding “the interior terrain of thinking, feeling, perceiving, learning, deciding, and acting to achieve our goals”?
For understanding behavioral disorders like extreme depression, to prevent and treat dementia and Parkinson’s, to help victims of stroke or brain-damaging circumstance, I can *absolutely* understand the paramount importance of neuroscientific research. But for understanding our inner lives, it seems to me like the sort of physical scales at which neuroscience works, the questions that can be asked within its methodological frameworks, and ultimately the answers generates, are not necessarily more illuminating than what emerges from the humanities.
Put another way, to live with grief, or guide the education of my godchildren, I do appreciate the insights neuroscience (and cognitive science and psychology) provides me — but also those from literature, poetry, history, religion, philosophy and all those endeavors by which humans seek to understand ourselves. This isn’t a zero-sum, either-or choice, obviously — either science or humanities! — but when regarding the BRAIN Initiative, which right now seems like our society’s flagship expedition into the interior terrain, it feels disproportionately tilted toward one side.
Thanks for bearing with that ramble, and I hope it doesn’t sound combative — I think the BRAIN Initiative is an excellent and exciting thing, and would like to see it receive quite a bit more funding. And, like I said, the answer to the “Why brain science?” question isn’t immediately IEEE article-relevant; but if you’ve a chance to reply, I’d very much appreciate it for my own edification.
Bargmann: This is an excellent point. It is not either-or; science and human culture are both essential ventures. Recently I read the Bhagavat Gita, and there is nothing from brain science that helped me think about my relationship with the world as deeply as it did. On the other hand, writing the Gita did not require high-end microscopes, electrodes, and data analysis, and therefore it’s not the topic of a technological initiative. Science and technology make progress in different ways than the humanities and philosophy make progress, at least in our era.
You are right that much of our understanding of the mind is still more in the humanities than in the sciences. I also find it stupid when people take naive biological approaches to profound human questions. When people tell me my personal decisions are genetically determined by my ancestors on the African Savannah, I reach for my revolver. I suspect that the brain sciences will eventually lead to a deeper understanding of more profound issues. For example, the relationships between cognition and emotion don’t seem to me to be well-defined in either the sciences or the humanities yet. Biology may have something to say about that.
You are also right that in our time, the sciences are given priority over the humanities in our public discourse. But the humanities are also flowering compared to historical standards. Many more people are literate than at any time in the past. More voices and viewpoints are heard. Universal education is becoming a reality.
With respect to disorders of the brain, I think you and I agree that many, most, probably all have some biological cause and biological manifestation in the brain. That doesn’t mean it’s the only cause. I would say that the biological part may be the easiest to solve right now, and maybe that’s the reason to focus on it in our time. Memory is a rich, emotional, cognitive experience. But narrative memory is linked to the hippocampus in the most irreducible way. No hippocampus means none of that rich experience of personhood that comes from memory.
Q: Also, one other question, this one more article-relevant: Why weren’t more ethologists invited to the discussions? I’d think that with so much riding on animal models, and an acknowledged need for innovation in their use, it’d make sense to have some animal people there.
Bargmann: We had implicit ethology and what you might call techno-ethology. Implicit, through people like Eve Marder and David Anderson, who think about it extensively. Techno, Kristin Branson from HHMI spoke; she worked with Mike Dickinson, the ethologist who was featured in yesterday’s NY Times Science magazine. (High-throughput ethomics in large groups of Drosophila. Branson K, Robie AA, Bender J, Perona P, Dickinson MH. Nat Methods. 2009 Jun;6(6):451-7.). Plus Bill Newsome, my co-chair, considers himself a hard-core behaviorist. He’s the source of the “Nothing in the brain makes sense except in the light of behavior” line, a references to Dobzhansky of course, that appears in the report.
Even 80 neuroscientists is not very many when you consider that we were trying to go from math and physics to human brain imaging — we couldn’t invite very many of anything! We tried to find people who would take a broad view, and I have to say, the message of the importance of behavior came from many directions. That message is probably the biggest difference between the Brain Initiative in its current form and the original Kavli idea of the “Brain Activity Map” (BAM).
These analyses confirmed that personality similarities between humans and great apes are best explained by genetic and phylogenetic affinity and not by anthropomorphic artefacts.
It is a commonly held assumption in the West that attributes of personhood, with all that this entails in terms of language, intentionality, reasoning, and moral awareness, belong exclusively to human beings. Animals are understood to be wholly natural kinds of being, and their behaviour is usually explained as automatic and instinctual. However, among the Yukaghirs a different assumption prevails. In their world, persons can take on a variety of forms, of which human beings are only one.
I started working as a blogger back in 2007, when online science journalism was still relatively new and bloggers were expected to be high-throughput link aggregators, adding perhaps a paragraph of pithy value. I’d crank out 10 or 12 posts per day; later on, I only had to write six, but was expected to have my own particular take on things. It wasn’t enough to link. I needed to have an opinion.
It’s not easy to produce insightful opinions on demand, day after day, especially with very little time to inform them. I sometimes fell into the trap — and still do too frequently, truth be told — of assuming my own knowledge to be more complete than it was. I’d pass judgement on people or research or other journalists without bothering to pick up a phone and call someone who might think differently than me, or know more. Neither did I especially want to; I knew I was right, had a point to make, and didn’t feel a need to challenge that.
Eventually I started working for an editor who didn’t want me to write casual takedowns, especially of other science coverage. I chafed a bit at first: the content beast demanded to be fed, and takedowns were fun! And poking holes in someone getting something wrong (cough British tabloid science coverage cough) was always good for quick content. But over time, I came to appreciate my editor’s requirements. It was good, old-fashioned wisdom regarding the limitations of one’s own knowledge and self-assurance, wrapped up in professional principle: Be careful about going negative unless you roll up your sleeves, put on your journalist’s hat, and talk to people with different perspectives than your own, even if you think you know plenty.
Good advice in any circumstance, but especially so when what you write can do damage. And I’ve been thinking of those days recently after seeing a takedown by Matthew Herper in Forbes of Moises Velasquez-Manoff, a science journalist and author of An Epidemic of Absence, a book about autoimmune diseases and a proposed explanation for what causes them. (You can read Velasquez-Manoff’s rejoinder here.)
Full disclosure: Velasquez-Manoff is a friend of mine as well as a colleague. We went to journalism school together, and we frequently talked about the book during its writing, which took more than two years. So I’m absolutely not a disinterested party, and am biased, and probably wouldn’t be writing this if there wasn’t a personal connection. But I’ve also got a good sense of the reporting and research that went into his book, have read large parts of it, and have also done some reporting of my own for several microbiome-and-disease articles.
So when Herper writes, regarding Velasquez-Manoff’s three New York Times op-eds about relationships between the human microbiome, immune system regulation and autoimmune diseases, that “scientists or experts might find Velasquez-Manoff’s conjectures, well, to be polite, to be conjectures,” I know that quite a few don’t. This isn’t hard to find out, really: aside from the scientists and experts Velasquez-Manoff cites, a Google Scholar search for “autoimmune microbiome etiology” returns a bounty of results from this space, both of single studies and large-scale literature reviews. (See this, this, this, this, this, this, this, this and this (1). And that’s just scraping the first few pages of results.)
The main sources of Herper’s post, though, are a critical New York Times review of Epidemic of Absence by infectious disease specialist Abigail Zuger and a critique by science writer Emily Willingham of Velasquez-Manoff’s August 2012 NYT op-ed on possible links between maternal immune dysregulation and autism (2).
To take these in order: Zuger’s credentials are impressive, yet she doesn’t seem to have understood quite what the book is about. According to Zuger, Velasquez-Manoff writes about the “hygiene hypothesis,” which holds that “the modern immune system … is stymied by the sudden absence of its customary microbial targets. With nothing constructive to do, it is crazily spinning its wheels, resulting in soaring rates” of autoimmune disease. This is, more or less, a 20-year-old version of the hygiene hypothesis, and not the one being discussed.
What Velasquez-Manoff is talking about, and what quite a few researchers are working on — also see this and this — is subtly but fundamentally different. It’s also described nicely by science writer Matt Ridley in a far more positive Wall Street Journal review of Epidemic: “Parasites have evolved to damp our immune responses so that they can stay in our bodies. Our immune system evolved to expect parasites to damp it. So in a world with no parasites, it behaves like a person leaning into the wind when it drops: The system falls over.”
(That the reviewer who actually understood the science, or could at least describe it accurately, also liked the book quite a bit more, is an interesting fact. Of course, it’s just one data point — but it ought to be noted that Epidemic was also favorably reviewed twice in Nature (by a Yale University doctor and by one from the NIH) and in Annals of Allergy, Asthma & Immunology.)
As for Willingham’s critique, it raised some fair points, in particular that Velasquez-Manoff wrote incautiously, without the caveats and qualifications befitting a hypothesis — especially when it’s about a topic as important and sensitive as autism, and even if it’s an op-ed rather than a more formal journalistic form. Willingham also called the article “frequently unsourced and unreferenced.” That was true when the article came out, though Velasquez-Manoff subsequently posted a long list of sources on his website.
Whether those sources are satisfactory is a judgement call. To me, at an admittedly quick reading, they are: While any one study or observation is limited and imperfect, the weight of evidence, drawing from epidemiology and biological observation and animal model perturbation, makes it at least plausible that microbiome-mediated maternal inflammation may fuel autoimmune responses leading to autistic spectrum disorders in a subset of children with those symptoms. Correlation isn’t causation, but when multiple lines of evidence support a causal link, there’s reason to pay close attention.
Others, including Willingham, might disagree with this assessment of Velasquez-Manoff’s sourcing. Fair enough. Personally I’d have more confidence in certain of Willingham’s criticisms if there was some evidence she talked to a few of the scientists referenced, who might have provided a different perspective than her own. [Update: Willingham says she did speak without about 10 autism researchers, including Paul Patterson, about the maternal microbiome/autoimmunity/autism idea.] It feels to me that, having decided at the outset that Velasquez-Manoff’s article was poor and even dangerous — linking maternal immune disregulation to autism, says Willingham, echoes the “refrigerator mother" theory of the 1950s that blamed autism on emotionally distant moms — she then approached the references with an eye to finding flaws. Does that mean she’s wrong, or that there aren’t flaws? Of course not. But as a journalist, it’s the sort of critique I’d use as one of multiple sources, and not as a primary source without corroboration.
(For what it’s worth, in writing this post I emailed several researchers, among them Kevin Becker, an NIH geneticist who appears in Velasquez-Manoff’s autism article and who originally proposed, back in 2007, a possible link between autism, inflammation and exposures to microbes and parasites. Responded Becker, “In my view the pattern of aspects of autoimmune disorders is compelling for a portion of autism cases…. It is certainly not kooky science.” His full reply is reproduced below (3). On the broader question of whether microbiome-mediated immune dysregulation leading to autoimmune diseases is conjecture, Becker said, “In my view there is an enormous amount of epidemiological and immunological evidence,” a view echoed by other researchers who responded to my emails (4).)
At least Willingham, however, took some time to engage with Velasquez-Manoff’s actual work and the research he cited. That wasn’t the case with a number of science writers and journalists who, after Willingham’s original article came out, promptly circulated it without giving any indication of having taken more than a cursory look for themselves at the actual science (5). Herper’s article is just the latest example of this.
As for Velasquez-Manoff’s other two NYT articles, on microbiome links to celiac disease and to allergies, Herper has general criticisms — “overblown language about cures” in the allergies article, and a failure to “give readers a sense of the other side of an argument” in both. I think there’s some validity to the latter point, albeit limited: in the second paragraph of the celiac disease article, the microbiome link to is clearly identified as one of multiple “intriguing possibilities,” and a paragraph beginning “The caveats here are numerous” goes on to enumerate them. In the allergy article, the third paragraph reads, “What prompts some immune systems to err like this, while others never do? Some of the vulnerability is surely genetic” — and a primarily genetic explanation is addressed later in the article.
That said, I think Velasquez-Manoff could and should have talked more about the alternatives. A couple history-lesson paragraphs up top — “here’s some of the explanations that came before, they don’t seem to work very well, or are not mutually exclusive to this work, etc. etc.” — would have done wonders. He might also have done a better job addressing gaps and uncertainties that exist in the research, which on the clinical side is still in its very, very early stages. But there’s a big, unjustified leap from issues like these to dismissing Velasquez-Manoff’s reporting-based, general-audience translations of solid science as “conjecture,” his book (which Herper admittedly did not read) as “kooky” and Velasquez-Manoff as “a zealot” for an idea. It’s the sort of language usually reserved for homeopathy and water crystal healing. And to pass along that rush judgement uncritically is just as bad.
This tendency has bothered me more than anything else in the whole affair involving Velasquez-Manoff and his NYT articles. Science writers and journalists are qualified — even obligated — to investigate claims made about science. The writers criticizing the articles have not done that. [Update: Willingham did.] The amount of actual reporting done in this debate by anyone other than Velasquez-Manoff [and Willingham] amounts, as best as I can tell, to zero.
Instead, the dynamics have felt like a high school cafeteria’s, with cool kids sitting together and circulating hearsay about someone outside their circle, repeating it so often it becomes assumed fact. And here’s where my friendship with Velasquez-Manoff definitely comes into play: I happen to know how, rather than going to science-writer conferences and building his personal brand and tweeting at the right people and cultivating relationships within the community, he put his head down and worked on his book, for two long, hard years. He’s not one of the gang.
If he were, I truly believe the situation would have played out differently. I think quite a few of his critics would actually find the science quite interesting, even compelling. At the very least, someone would have had the basic courtesy, or even just the curiosity, to pick up a phone before dismissing it and him.
(1) A neat synopsis of research in this space can be found in the beginning of this Trends in Ecology and Evolution article by John Pepper, an NIH cancer researcher interested in microbiome links to cancer. Writes Pepper: “The shared mechanism linking these disparate diseases” — inflammatory bowel disease, gastric ulcers, obesity, diabetes, esophogeal and colorectal cancers, central nervous system disorders, autism, major depressive disorder — “is apparently the immune system and its interactions with the gut microbiome during development.” Pepper also replied to my questions about the microbiome and autoimmune disease; see below.
(2) Herper did also quote, after posting the article on Facebook, the response of Jonathan Eisen, UC-Davis microbiome researcher who said of Velasquez-Manoff’s new piece, “Uggh. Him again.” It’s the sort of reaction that should inspire follow-up reporting — but this isn’t, in itself, good source material in a dismissal of someone’s work as “kooky” and “conjecture.” Eisen’s research emphasis is phylogenetics. He’s a sequencer and tree-calculator extraordinaire, a specialist in evolutionary and ecological dynamics. Of 67 publications on which he’s been a co-author since the beginning of 2007, I see just two — one on H. pylori infections and rhesus monkey microbiomes and another on the human microbiome and bowel transplants — that are germane to the research under discussion.
Interestingly enough, in Eisen’s blog post on the autism article, he criticized Velasquez-Manoff for failing to distinguish between correlation and causation … but also said, “Overall, I do like this current article.”
(3) I asked Becker two questions:
Q: Is the theory that many autoimmune diseases are produced by microbiome-mediated immune dysregulation a solid one, or merely ‘conjecture’?”
Becker: I think it is due to immune dysregulation in pregnancy and early infancy. There are multiple paths to dysregulation.
In my view there is an enormous amount of epidemiological, and immunological evidence to support the so-called “hygiene hypothesis”. As you probably know that name is unfortunate since it is misinterpreted as having to do with personal hygiene. It is almost certainly more related to population burden of types of microbial bugs. This alters immune T cell development and promotes a hypersensitive state, in early infancy.
In genetically susceptible people this can lead to autoimmune and allergic disorders. Early exposure to microbial and other organisms primes the immune system which protects against autoimmunity and allergic disease. This is pretty rock solid in experimental studies. Mice raised in germ free environments get an increased number of autoimmune diseases. You can protect them by exposing them to microbes in early life.
The whole hookworm thing, although probably very real, just grosses people out. I really don’t see why the probiotic industry is not all over early infancy to build immunity.
Q: Do you think there’s good evidence for a maternal inflammation-mediated mechanism in some significant subset of cases?”
Becker: This is weaker [than the links between microbiome-mediated immune dysregulation and established autoimmune diseases —BK] but in my view the pattern of aspects of autoimmune disorders is compelling for a portion of autism cases.
i) Large epidemiological studies of increased numbers of family members with an autoimmune disease in a family with an index case of an autoimmune disease. That is, if you take 1000 families with a family member with Type 1 diabetes, there will be an increase in other family members, not with Type 1 diabetes, but with any type of autoimmune disease/ inflammatory disorder… T1D, thyroiditis, multiple sclerosis, etc. It reflects the shared genetics of autoimmunity that leads to immune dysregulation. That is what you find in autism. Large independent epidemiological studies from multiple countries that show an increase in autoimmune diseases in families with an autistic kid. Does that mean it causes autism?
ii) Altered and increased immune response. All autoimmune disease patients, have many kinds of autoantibodies, altered T cell patterns, altered cytokines, etc.. That pattern is seen in autistic kids. Is it causative? Don’t know.
iii) Asthma has been associated with use of acetaminophen (paracetamol) in pregnancy or in early infancy in many large epidemiological studies worldwide. (I believe because it is due to the immune suppressive effects again leading to altered immune response). A recent large study just came out of Norway associating paracetamol with phenotypes of autism. More studies in different parts of the world are needed. They are beginning.
iv) Activation of microglia (immune cells) in the brain of autistic kids.
There are other intriguing aspects of similar features between autism and autoimmune/inflammatory disorders that suggest that there is a link. It is certainly not kooky science.”
(4) Also responding to the question of, “Is the theory that many autoimmune diseases are produced by microbiome-mediated immune dysregulation a solid one, or merely ‘conjecture’?” was Stephen Paget, a rheumatologist at New York City’s Hospital for Special Surgery, who has written about the microbiome and inflammation in arthritis. Paget didn’t mince words; he simply wrote, “Very sound and correct.”
A lengthier response came from Alessio Fasano, head of Massachusetts General Hospital’s Center for Celiac Research & Treatment. Wrote Fasano, “There is an ongoing heated debate (far from being settled) about the causes of the epidemics of immune-mediated diseases. The fact that recent changes of microbiome composition can be responsible, at least in part, of [sic] these epidemics, is recently gaining momentum within the scientific community. However, it should be pointed out that we only recently acquired the proper tools to move our studies on the microbiome from merely descriptive (simply learning about the composition of the microbiome) to mechanistic (linking specific changes of the microbiome composition to disease states (now we have evidence for several autoimmune diseases, including IBD, celiac disease, Type 1 diabetes, just to name a few).
As concern the “epidemics” of celiac disease, I think that dysbiosis (change in microbiome composition) is one of the possible reasons, but it is hard to exclude other environmental causes, including quantity and quality of gluten, feeding patterns (breast feeding vs. bottle feeding), time of introduction of gluten in the diet, maturation of the gut functions, including its intestinal barrier and immune functions (just to name a few).”
Finally, John Pepper, the aforementioned NIH cancer specialist interested in links between cancer and the microbiome, also replied. To the question of whether the idea that many autoimmune diseases are produced by microbiome-mediated immune dysregulation is solid, he said:
“There is substantial evidence that the immune system develops normally only if it interacts with microbes, or more specifically, with bacteria, that have been typical of the human environment during our evolutionary history. Unfortunately, writings about the hygiene hypothesis often muddle together two ideas that are different in important ways. One idea is that the bacteria that play a key role in immune development are pathogens (disease-causing bacteria). The other idea is that the bacteria that play a key role in immune development are species that have had a mutually beneficial relationship with humans for as long as humans have existed, that are normally present ( especially in the gut), and that promote health rather than causing disease.”
I also asked, “If you read Velasquez-Manoff’s NYT articles, particularly on allergies and celiac disease, do you feel they unfairly ignored alternative explanations?”
Replied Pepper, “I think it’s fair for anyone to push their own pet hypothesis as hard as they like, and to ignore others, unless they claim to be presenting a balanced review. Velasquez-Manoff certainly does push just one hypothesis, although to be fair, there aren’t many plausible alternatives for explaining the allergy epidemic, which does seem to be real.
To add one more strand to this complex story, I’ll throw in the fact that over-active immune systems, and the chronic inflammation they can create, are also strongly implicated in causing various kinds of cancer, as well as cardiovascular disease, etc.
Where the Forbes article asserts that “scientists or experts might find Velasquez-Manoff’s conjectures, well, to be polite, to be conjectures,” I prefer to hope that scientists might find the hypothesis to be worth urgently testing so that we can either discard it or use it as an avenue to address these pressing health problems.”
(5) Especially egregious were two Knight Science Journalism Tracker posts by Deborah Blum in which she described the science as “shaky” and said Velasquez-Manoff had apparently “built his theory by largely avoiding autism research." When Velasquez-Manoff left a comment in the post with links to research, including a response from Caltech neurobiologist Paul Patterson — who studies autism and immunity, and wrote that “the crucial importance of this article is that it gets the message of immune involvement in autism out there in the public eye” — Blum didn’t reply.
It is sometimes assumed that ‘simple’ and ‘miniature’ nervous systems such as those of insects implement cognitive faculties by radically different mechanisms compared with vertebrates, rather relying on innate routines and elemental forms of associative learning. However, constructing a great division between simple and advanced nervous systems will lead us astray, because the basic logical structure of the processes underlying spontaneity, decision-making, planning and communication is similar in many respects in big and small brains.
Wilcox and Jackson (1998, 2002) have found extensive experimental and observational evidence of complex cognition in jumping spiders of the genus Portia, which often prey on web-building spiders. To solve the challenges of preying on larger venomous spiders, Portia must reach moderately complex and appropriate decisions about spatial relationships, taking long detours around obstacles to reach a favorable location even when this requires losing visual contact with the goal. They engage in a complex form of communicative exchanges with their prey that include elements of deception. They approach the web quietly and set some of its threads into vibrations similar to the vibrations used in the courtship of the web-builder. The Portia adjusts its own vibratory signals in response to those of the web-builder in many subtle ways, tending to emit a wide variety of vibratory signals but to repeat those that attract the web-builder to the edge of the web. Wilcox and Jackson (2002) conclude that their investigations “bring us closer than we initially expected to something like the cognitive implications of verbal language” (Wilcox and Jackson 2002, p. 31).
In summary, a particular set of elements at a particular spatio-temporal scale yielding a maximum of integrated conceptual information (max Φ MIP) constitutes a complex, a ‘locus’ of consciousness. The set of its concepts – maximally irreducible cause-effect repertoires (max φ MIP>0) specified by various subsets of elements within the complex – constitute a
maximally integrated conceptual information structure or quale (Fig. 4) – a shape or constellation of points in qualia (concept) space.
However, it should not be overlooked that radical forms of parsimony as applied to behavioral science were (and may still be, at least in part) a historical burden.
— Dimensions of Cognition in an Insect, the Honeybee — BCNR289522.qxd - 9 Menzel & Giurfa 2005.pdf
Currently, not only has Strong AI failed in its endeavor to build a system that is as intelligent as you or I, but it cannot even build a system as intelligent as the ubiquitous cockroach. Instead of locating the failure in the lack of a proper theory of concepts, representation, or semantics, this paper locates the failure in the underestimation of how complex even relatively simple biological organisms, such as the cockroach, really are. The implications of biological complexity on research in Strong AI are briefly explored.
Social interactions such as courting behaviour and aggregation are also profoundly affected, suggesting that the lack of social contacts during early development precludes the learning of cues essential for the assessment of mate quality and social recognition.
In spite of the three Rs, the number of animals used in experiments has steadily increased, in part because of the flourishing of biomedical research and in particular because of advances in transgenic modification of animals. Ten years ago, around 2.7 million animal procedures were done annually in Britain; today, that number has grown about 50%.
These findings highlight the potential long-term negative consequences of acute social disruption in cognitively advanced species that live in close-knit kin-based societies, and alter our perspective on the health and functioning of populations that have been subjected to anthropogenic disturbance.
The solution to the mystery of species extinctions in the Western Desert may lie at least in part, in linking Dreamtime logic to these ecological consequences. The belief that it is not hunting that causes prey decline, but the lack of it, seems paradoxical, and to some, evidence of a religiously mandated mythology that has little to do with ecological reality . Here, we propose one ecological hypothesis that is consistent with (if not part of) Dreamtime logic: that the creation of finer-grained habitat mosaics through the application of fire (patch mosaic burning) in the course of hunting acts as a type of ecosystem engineering that provides net positive effects to some species, including humans themselves. Over time, these ecosystem engineering effects change the availability of habitat niches, supporting a range of species that would not otherwise persist in this desert region: such evolutionary consequences would turn ecosystem engineering into a form of niche construction .