This Post Has 66 Comments

1. What about the reviewers? Shouldn’t they be taught to use PubMed too?

2. Of course, Prof Zuker is one of those dudes with a long history of Nature and other Glamorismo pubs…

3. Odyssey-

   We have no idea whether the editors ran roughshod over highly critical reviews, made sure to select a certain type of reviewer guaranteed to swoon over the opto….or if they bent to the overwhelming will of reviewers against their better judgment.

   We DO know the editors made the ultimate call, however. So yeah, it is on them.

4. Dr. Aust- Sure. So what?

5. DM,
   True enough.

6. Well, when one sees the Big Honchos schmoozing the Nature (& other glam mag) eds at the Gordon Confs and other places – and the eds the BSDs too, I have to say – you inevitably wonder if they get a more sympathetic hearing. Maybe get past the on-house screen easier, for instance. But agreed, that shouldn’t affect the peer reviewers.

7. There was also always a feeling (right back to my early days in the biz in the 80s) that the glam mags had particular fields they judged special and published stuff in preferentially. Retinal cellular physiology was (for instance) one that Nature had a big interest in in the 80s, and sensory receptor physiology was big in the 90s/noughties. I guess, as you’re sort of implying, certain new/snazzy/”Now”techniques get points too. So maybe if you ‘intersect’ enough points-tally things…

8. As a “PS” I once interviewed for a job as an editor at a glam mag in the late 90s. One of the interview questions was: “You see something at a conference that is going to be BIG. How do you persuade the authors to publish it with us?” And a follow up Q was “The AUs say ‘Editor Q at this other glam mag already promised us XYZ, which is better’. So NOW how do you persuade them to come to us?”

9. Glam mag success is a lot about doing whatever is particularly fashionable at a point in time. Evidently optogenetics is this season’s hot topic. Next season it will be something else. It’s like Slartibartfast and fjords in the Hitchhiker’s Guide.

10. I’m glad to see that optogenetics is still en vogue, so maybe I won’t be too late to the party when our DREADDs stuff goes out…

11. For us non-neuro geeks, what’s the big deal with optogenetics?

12. Also, gets you a job at Caltech:
    http://www.caltech.edu/news/why-do-we-feel-thirst-interview-yuki-oka-45421

13. “For us non-neuro geeks, what’s the big deal with optogenetics?”

    The idea that you are activating specific neurons with your optogenetic intervention, and that through that, you can show a causal role for that neuron in the behavior. Why is better than electrical stimulation? because electrical stimulation is less specific (or that’s the idea).

    I remember having this same reaction when knockouts were hyped as something more miraculous than lesion studies. In theory, genetic deletions could be more specific, but, they, were, in practice, often more general. And initially at least, the folks doing the behavior didn’t understand how to do appropriate behavioral controls, ones that were considered psych 101 knowledge in the field.

14. Dude, you just really don’t understand how game-changing vertically ascending science is done, do you????

15. In for updates on the retraction…..

16. Philapodia:

    Optogenetics gives you millisecond control of *individually-labelled* cells. I.e. you can label a specific sub-population of cells in a given patch of cortex, and then activate/suppress them, and only them, with millisecond precision.

    You can “label” cells according to their cell type (“select PV inhibitory neurons and nothing else”), or even better, for activity (“select all cells of type Y that were active during experimental condition X”).

    Cool examples:

    – The Tonegawa lab “inception” papers: falsely associating a certain environment with memory of electric shock, i.e. creating a “false memory” in the rat (Ramirez et al. Science 2013, Liu et al. Phil Trans Roy Soc B 2014).

    – The Scanziani lab has done really cool stuff with it in teasing apart the functional architecture of V1 microcircuits.

    – The Cardin et al. Nature 2009 paper in dissecting the gamma rhythm. “Hey, let’s start pinging different cell types at frequencies of up to 100+Hz and see what happens! Also, let’s ping each cell type, just once, at a specific phase of gamma oscillation!” Uh, yeah, sure, whatever sis. Wait, they actually did it?

    Not sure how you can do that with DREADD or anything else, but I’m ready to be schooled for my ignorance.

17. Nature is a private company, they can publish whatever the fuck they want and sell the ad space next to it. The chumps are the people who admire a paper because it’s published there. Believing that NPG’s primary goal is rigorous scientific standards instead of whatever is splashy and marketable is like believing Facebook is here to try to bring people closer together and make the world a better place.

    That said, the undeserved credit given to (or claimed by?) this work for their “discovery” is disrespectful, unscientific, credit-stealing, vainglorious hack bullshit. Where is that coming from? Probably the university press office?

18. @ZB and toto: Sounds like some Frankenstein /mad scientist shitte… Pictures of cute little mice in these optogenetic rigs I’ve seen on google puts me in mind of “A Clockwork Orange”.

19. “Not sure how you can do that with DREADD or anything else, but I’m ready to be schooled for my ignorance.”

    Well, if “inception” experiments float your boat, you could look for the Garner et al science paper that predates the one you mention. Of course, the dreads do cause 20% of animals in the study to simply have seizures, but eh, good enough for Science anyways…

20. DREADD and optogenetics have very different strengths, weaknesses and therefore applications.

    The thing I like best about DREADD is that of the two it is the only one that has a prayer of a chance (no matter how faint) of ever being translationally useful.

21. Dude, you just really don’t understand how game-changing vertically ascending science is done, do you????

    No, no I do not.

22. @toto: DREADDs have different advantages, so it depends on the question you’re interested in. You obviously lose the millisecond-level temporal precision, but that’s not always important. You have all the same circuit/cell-type specificity, so the Tonegawa Inception paper could have been done with DREADDs (I haven’t read the other two you mention). Unlike in opto, the animals don’t have to be tethered to anything and depending on your viral strategy, may not even need an implant at all–an i.p. injection of CNO is it. This makes behavior testing easier, reduces stress/inflammation on the animals, and reduces the chance of error (and therefore animal use) due to off-target implants.

23. I think the fact that there are two intermingled populations, with opposing control on thirst, is in fact pretty cool, and couldn’t have been figured out with microstimulation.

    And, people had tried DREADDs in the SFO, but they didn’t work–as it turns out, because one of the populations (or both?) doesn’t express the G-protein-controlled potassium channel that you need for DREADDs to actually suppress firing (GIRK IIRC).

    I might be wrong about some details in that paragraph, but I heard a really lovely talk from Oka and that’s what I remember from it. He seems like a nice guy too.

24. Also, though I’m as happy as anyone to snark on excessively overhyped optogenetics papers, from the standpoint of understanding neural circuits, there can be a lot of off-pathway intermediate effects happening during the slow time course of CNO/DREADD action, whereas the tight temporal control of showing light = animal drinking within 2 s is quite powerful.

25. “whereas the tight temporal control of showing light = animal drinking within 2 s is quite powerful.”

    Once you’ve figured out how to use it to get the kids to do their damn homework by pushing a button, then I’ll be impressed.

26. Holy shit, the second press release has the subhead, “Findings could lead to new therapies for dehydration and excessive thirst.”

    I can see tomorrow’s headline now… “TREATMENTS FOR DEHYDRATION CONTINUE TO ELUDE SCIENCE. IS OPTOGENETICS OUR ONLY HOPE?”

27. And here stupid me always thought “drinking” is the therapy for dehydration, how could I (or put on an iv if non-responsive or otherwise impaired). Apparently its optogenetics.

28. my main problem with it is the blithe assumption that whatever cre line you happen to be using corresponds to a meaningful functional category of neuron. sometimes this is trivially true (VGAT = inhibitory), but often it is just some random transcription factor. the relationship between gene expression patterns and neuronal types suggests that for any given promoter or cre line, you have many true functional subtypes included, even with highly local stimulation. it’s like saying dudes named Thad who live on Beacon Hill are all stock brokers. You might be kind of right, but you are mostly wrong and the reasoning is terrible.

    so the idea that driving all of these neurons at the same time resembles any reasonable internal brain state is almost certainly wrong (not that they checked). driving highly artificial neural activity induces highly artificial behavior. eureka. oh sorry… I mean: driving highly artificial neural activity with millisecond precision.

    i agree these experiments provide evidence that there different populations of neurons in the SFO that do different things. and that’s cool, but not very far fetched. i’m not willing to accept, based on these results, that they have identified expression markers that identify 2 classes of neuron that under reasonable physiological conditions are dedicated to “drink” and “don’t drink.” and even if I did accept that, that is no worth of the kind of attention they seem to want from this.

    this is why the tonegawa memory manipulation papers are so much more compelling…they used past activity patterns as a template for future stimulation, rather than just cranking thousands of cells up to 11 all at once based on sharing a freakin promoter.

29. “Pictures of cute little mice in these optogenetic rigs I’ve seen on google puts me in mind of “A Clockwork Orange”.”

    Protip: Whatever you do, do NOT search for “scleral coil”….

30. I think the fact that there are two intermingled populations, with opposing control on thirst, is in fact pretty cool, and couldn’t have been figured out with microstimulation.

    That is NOT the question here. The question is whether this represents a significant advance worthy of the alleged standard for acceptance in Nature. Or, as I see it, if this is a tiny little incremental advance of real understanding of thirst/drinking regulation all tarted up in a fancy new technique.

    Or, to put it in your favored parlance, how is this a “complete story”? Is that encapsulated in all the controls which basically just tell us the fancy new technique actually worked as represented?

31. I’m going to step lightly over the question of optogenetics as hype versus not, because there’s more heat than light being shed on that right now – what I’ll say is that in my experience opsins have been much easier to get to work consistently than DREADDs have been, though we’re still plugging away on getting those to work in our hands – I’m sure we’ll get there eventually.

    @rxnm, on the subject of Cre lines mapping onto cogent classes of neurons, you may be interested in the Matters Arising + Response in this issue of Neuron – there’s a nice conversation between the Malenka and Stuber labs there on this point. http://www.cell.com/neuron/abstract/S0896-6273(14)01145-3 and http://www.cell.com/neuron/abstract/S0896-6273(14)01143-X

32. Now we’re cooking with gas!

33. @rxnm Yo. There’s increasing and cool evidence for the respecification of neurons depending on stress and other environmental factors. You can’t necessarily say that reporters, particularly those based on expression of specific neurotransmitters/peptides, are completely specific all the time.

34. thanks, GS. I see 2 kinds of problem: 1) like they are pointing out here, your cre lines might not be what you assume they are (supplemental figure 14 showing the chr2 expression overlapping with marker X to prove they are the “right” neurons are often pathetic in these papers–no one cares as long as the mouse hops when it’s supposed to). 2) cre expression off promoter X is not necessarily a meaningful functional class of neuron in your circuit even if it is a perfect fiducial mark of cell lineage or transmitter class or whatever.

    the other thing missing from the vast majority of these “I opto’d X so now we know the circuit for hopping” is any attempt to show the activity you caused with chr2 resembles endogenous activity in the circuit. because it won’t…you can talk about temporal precision all you want, a fast sledgehammer is not precise.

    I don’t think sledgehammers are bad. mutations are great. lesions are great. decorticating guinea pigs is great. opto is great. it’s just extremely artificial and invasive and nothing like endogenous activity. that’s fine, we’re scientists, we fuck with things to see what happens. what infuriates me is this “precise manipulation of neural circuits at the level of…” oversell.

    and this paper “discovered” the circuit for drinking behavior the same way my cousin bill “discovered” burning man in 2002.

35. Eh, I didn’t say I thought it was Nature-complete-story-blinkety-blink, just that there is an important biological reason that your pet DREADDs didn’t work here, and opposing control by intermingled cell types is interesting. I agree on all the oversell shit.

    Also, @anon, this paper alone didn’t get Oka a job–he had an earlier, excellent paper with Zuker on the neurons that taste salt. This paper was just his “preliminary data” in his job talk, which I saw.

36. From an article about this paper in The Scientist…

    Since “you can’t really directly connect the activation of a specific region to drinking behavior or motivation,” Oka explained, he and his colleagues used optogenetics to study only the neurons they were interested in.

37. Odyssey – IMO the most surprising thing is that the paper twice implies that the subfornical organ is part of the hypothalamus. It’s not. Presumably at least one of the authors/reviewers/editors knows where the hypothalamus is located…

    DJMH – The Nature paper only uses ChR2, there is no loss of function experiment. So the question of whether inhibitory DREADDs (e.g. hM4D) work in the SFO is interesting but beside the point. Excitatory DREADDs should work because angiotensin works by the same mechanism (also: a little birdie told me they work in the SFO)

    As for acknowledging the prior literature, here is the first author in an interview with The Scientist:

    Since “you can’t really directly connect the activation of a specific region to drinking behavior or motivation,” Oka explained, he and his colleagues used optogenetics to study only the neurons they were interested in.

38. DM, you are usually so vocal about how glamour humping is the “real problem”. I got the impression that in your ideal world, glamour journals would cease to exist, or at least there wouldn’t be such an “eliteness differential”. But here you really seem to want Nature to maintain its elite status by only publishing truly high impact papers — you are here saying “that paper didn’t *deserve* to be Glamour”. I’m confused. How can you hate glamour humping and also want glamour mags to remain in existence / remain elite?

39. think a little harder about my purpose here, anon. It’ll come to you.

40. ““you can’t really directly connect the activation of a specific region to drinking behavior or motivation”

    You can if you browse through the 296 papers on Pubmed that talk about the SFO and drinking behavior.

    Again, who gives a shit that it’s in Nature. It’s the baseless claims of discovery that are eye popping.

    Here’s a nice experiment that not only connects a “specific region” but a specific, physiologically-relevant signaling pathway to drinking behavior. http://www.ncbi.nlm.nih.gov/pubmed/24965793

    Didn’t see the press release? Maybe the University of Iowa’s press office and the PR wing of Am J Physiol Regul Integr Comp Physiol aren’t quite as rabid as Columbia’s or NPG’s. Or maybe the author just has a sense of fucking perspective.

41. With all the apparent problems with this paper, would it behoove the neuro-geek community to raise some of these concerns on PubMed Commons for the article? That way everyone (including the editors if they ever look at PubMed) can know that this paper is just a rehash of previously discovered work.

42. Let’s say, hypothetically, one were going to do this article for journal club. And let’s say, hypothetically, one wanted to say “So fucking what?” about the novelty oversell, but sound a wee bit more professional. What is the story-behind-the-lab? Why is this actually published in Nature?

43. Charles Zuker is a BSD GlamourDouche with platinum plating and blinking lights.

44. From The New Yorker, May 2006

    “We like to experience the edge, to push our sensory systems to the limit,” Zuker told me later, in his car. “Whether it’s tasting things or driving very fast cars, we like to enjoy things we should not enjoy.” He took a winding road down the coast, past a cluster of surfers in wetsuits paddling into the Pacific, and a pair of hang gliders getting ready to throw themselves from the cliffs of La Jolla. When the road peeled away from the shore, he shifted into third gear and accelerated to a hundred and fifteen, hurtling past a red truck that nearly turned into our lane. He glanced at me, backed deep into my seat with my hands clutching the armrests, and laughed. “You’re a pussy!” he shouted. Then he jammed the stick shift forward and threw the car into the next turn.

45. Ironically, the full article is paywalled, but can be found here

    http://www.daytonent.com/articles/0706.asp

46. Couple things:

    Any of my truly respected colleagues wanting to hold up the Ramirez “inception” paper, or indeed much of Tonegawa’s optogenetic work on “defining the engram”, as a shining light of neuroscience (pun lulz) may want to reconsider. One issue is what we know (and don’t know) about how long after withdrawal of doxycycline it takes for tTa driven transcription to be affected, and further, over what timeframe the effect is completely eliminated. In prior work, these transcriptional “on/off” mice have been reliably used to target much…broader…timeframes than the relatively limited span of the Ramirez paper. While it should be relatively rapid in theory, in practice there can be long-term activational and deactivational hangovers for unknown reasons that require very careful controls to tease out. If you speak to boots-on-the-ground people working in this area, it is suddenly an open question of what exactly is being targeted in these experiments, other than something that makes the animal “freeze”. Just, you know, a consideration.

    I applaud Jessica Tollkuhn’s investigative journalism and thank her for bringing that New Yorker article to our attention. What a chode.

47. Jessica- hypothetically, that is *exactly* the kind of flavor text a journal club needs. Thanks! 🙂

48. @rxnm: “the other thing missing from the vast majority of these “I opto’d X so now we know the circuit for hopping” is any attempt to show the activity you caused with chr2 resembles endogenous activity in the circuit. because it won’t…you can talk about temporal precision all you want, a fast sledgehammer is not precise.”

    Exactly. Opto is still in its gee-whiz look-at-that phase. When it’s finally actually used in combination with careful neural analysis – measuring neural activity, stimulating properly, correlating stimulation and blockade effects with downstream neural activity and readouts of behavior and cognition – then opto will have become useful to actually figuring something out. Until then, we have to sit around watching all the opto early adopters work out the bugs in the technique (a la the Malenka/Stuber papers cited above) while they continue to publish glammy meaningless stuff and suck up grant money to pay for it all.

    With opto, scientists who care about how the brain works (as opposed to getting papers in Nature) should aim to be like Charlie Brown. There’s an old cartoon that goes something like this: Charlie Brown tells Linus all the reasons why he doesn’t want to be the first man on the moon (too much publicity), the second man on the moon (kind of boring to be second), the third man on the moon (probably a lot of paperwork), etc. At the end, Linus tells his sister that Charlie Brown is the only person he knows who wants to be the 43rd man on the moon.

    By the time 42 opto scientists have come before you, the technique will work swimmingly, you will know all of its strengths and weaknesses, and you can use it to convincingly solve a problem about how the brain works. In the meantime, the grant money left over for the rest of us will buy us some popcorn so we can watch the first 42 have it out.

49. Zuker has 11 post-docs, 8 graduate students, 2 techs, 1 tech assistant, 1 lab manager and 1 lab administrator.

    That blows my mind. I mean, what the fuck is a ‘tech assistant’? Seriously?

    Anyway, back to the important stuff. From the NYT article:

    He owns a house on the cliffs above Del Mar, drives a Porsche Twin Turbo to work, and is married to his college sweetheart, a Spanish instructor at the university who resembles the actress Charo

    Not convinced my wife would be happy with that comparison.

50. One of the many fascinating / curious things about the Zuker lab (aside from CZ, the character) are the fact that the lab hasn’t published outside of C/N/S since 1999!!! There have been comments about glam pursuits elsewhere on the blog – but CZ’s been playing this game longer and, arguably better than any of our collective glamour-humping dreams.

    The second, follow-up curiosity is that CZ pulls this off in taste/ingestive behavior – sub-fields that are most certainly NOT ‘the current hip thing’. One might imagine his earlier cell-bio peeps reading all this work in taste/thirst and saying “thank god someone with proper expertise finally figured out taste/thirst” – without editors bothering to consult taste/thirst people on taste/thirst papers. This is the only story that makes sense, because a subset of CZ’s recent papers follow the theme of: “we knew this, but now we know it with lasers!”…

51. ” a subset of CZ’s recent papers follow the theme of: “we knew this, but now we know it with lasers!”…”

    That currently describes a very large subset of ALL opto papers, not just Zuker’s.

    By the way, I disagree that ingestive behavior is not “the current hip thing.” There are plenty of glammy papers on ingestive behavior because (cynical explanation) finding a cure for obesity (which comes from, you know, too much ingestive behavior) would be incredibly lucrative.

52. Look, Zuker is a crazy guy, but let’s have some perspective. His lab has been responsible for identifying and cloning a lot of the fundamental taste receptors: sour, bitter, salty, sugar, etc. Those are giant accomplishments. The fact that the guy is maniacal, or that he sometimes publishes a paper that isn’t such a big achievement (but still ends up in Nature), doesn’t change that….he is if anything much less prone to publishing the Opto-gee-whiz papers than many of his peers.

53. Again, oh defensive one, the issue at hand is the fact that Nature published it. This paper is a fine incremental advance. It is not some giant leap that we are led to believe is required for acceptance in Nature.

54. Yeah, fine fine. I was addressing some of the later comments acting as though all of Zuker’s stuff was like this. It isn’t.

55. And, more:

    http://magazine.columbia.edu/features/fall-2012/brain-trust?page=0,5

    “On a July afternoon, Charles Zuker sat slouched in a cushiony leather chair in his office at Columbia’s medical campus. He looked stylish and relaxed, his tall and slender frame draped in a loose-fitting cotton shirt and designer blue jeans, sandals on his feet and a pair of reading glasses atop his head.

    “You want to know why I’d leave Southern California, right?” he asks with a wide grin. “I’ll tell you why: because I believe in magic. And when you take the craziest, most wildly ambitious and brilliant minds in neuroscience and stick them all together in one building and let them go nuts, that’s what is going to happen.”

    Zuker is MBBI’s most prominent recruit aside from Shadlen, and like his new colleague, he is gregarious, funny, and inclined to discussing big philosophical issues related to the brain. But whereas Shadlen has a touch of the earnest and eager schoolboy, Zuker is all cool, calm, and suntanned charisma. He drives a Porsche Twin Turbo, and if you saw him pulling onto campus, you might guess he was somebody famous you should recognize. Shortly before coming to Columbia from UC –San Diego three years ago, he built himself a waterfront home that appeared on the cover of Dream Homes San Diego magazine.”

56. I do not trust scientists who only publish in glamour journals. I think that’s the change I’ve seen in the labs and the journals that publish in them. I think in the olden days, big important labs would have a big result every few years (or less) and would publish that in the glamour journals (which were, relatively, less glamorous, and fewer). Now, some labs want push everything there — they oversell stories or don’t publish or delay. In some fields, I remember papers circulating for 5+ years (with the same data) before they finally made it into journal.

57. I don’t have a problem with scientists who want to act like rock stars. The ones that are also assholes though? Problem.

58. I have a problem with assholes. At best, they make science less fun. At worst…

    OTOH, aging doods in midlifecrisismobiles are hilarious.

    So mixed bag overall.

59. the consolidation of glam labs is due to the feed forward exclusive nature of the system. when you get glam papers, you get to review glam papers, and you can be damned sure that many of the reviews are not so anonymous and there is plenty of back scratching. this is why people can publish good, but incremental work. Further, neuroscience has long had a huge fetish with technology and methods without really answering questions. Always a vague assertion that, well once we know the specific cell, we can understand pathology better….but oddly, none of those groups ever try to do that. because it is way fucking harder than shining a light or looking at a calcium transient.

60. Zuker is one of the most grotesquely offensive and personally vile and smarmy individuals in the field of neuroscience. He is widely reviled, except by other smarmy creepy fuckes like Axel and Jessel. This is why all these sleazy nerds are all excited to stroke each other’s rods in Manhattanville: because no decent people want anything to do with them.

61. Really people? Really?

    It’s not like this guy is a huge *public* ass like Watson, is it?

62. They’re just jealous that this fellow can apparently pull off not wearing socks and drives a Porsche Twin Turbo. We need these types of scientists around to convince the public we don’t all look and act like St. Kern.

63. I don’t have a problem with scientists who want to act like rock stars. The ones that are also assholes though? Problem.

    You say that as if the two are mutually exclusive.

64. You say that as if they are never non-overlapping.

65. Nature at it again, this time with circadian rhythms.

    http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.3937.html

66. I just reviews on a paper that did much more than this, and one of the reviewers claimed that ‘artificial stimulation is not enough for nature’ should I include a link to this paper to suggest that it is indeed?