Archive for the 'Neuroscience' category

Big Pharma is pulling out of CNS indications, NIMH to the rescue?

Jan 06 2012 Published by under Neuroscience, NIH, Public Health, Uncategorized

A recent blogpost from NIMH Director (and Acting NCATS Director) Tom Insel details the grim future for private sector development of drugs for the brain and behavior disorders.

But change is coming from another direction as well, especially for psychiatric medications. Over the past year, several companies, including Astra Zeneca, Glaxo-Smith-Kline, Sanofi Aventis, and recently Novartis, have announced either a reduction or a re-direction of their programs in psychiatric medication R&D. Some of these companies (such as Novartis) are shifting from clinical trials to focus more on the early phases of medication development where they feel they can identify better targets for treating mental disorders. Others are shifting from psychiatry to oncology and immunology, which are viewed by some as lower risk.

There are multiple explanations for these changes. For instance, many of the blockbuster psychiatric medications are now available in inexpensive generic form. In addition, there are few validated new molecular targets (like the dopamine receptor) for mental disorders. Moreover, new compounds have been more likely to fail in psychiatry compared to other areas of medicine. Studying the brain and the mind has proven to be much more difficult than the liver and the heart. Most experts feel the science of mental disorders lags behind other areas of medicine. The absence of biomarkers, the lack of valid diagnostic categories, and our limited understanding of the biology of these illnesses make targeted medication development especially difficult for mental disorders.

As I may have mentioned already, this sort of change in the development "system*" gives me a better reason to agree with the creation of NCATS and the earlier noises about the NIH taking a more active role in therapy development. There are lots of indications that don't receive enough attention because there is no route to sufficient profit. Drug abuse is one of those indications. Part of the reason we aren't more advanced in pharmacotherapy for substance abuse is on us, the basic science folks. Sure. But a big part is also on private industry which never saw where the paycheck was going to come from. So there was never much enthusiasm for pursuing anti-substance abuse programs. No program, no drugs. Remember, estimates run some 10-20,000 compounds evaluated in a drug development pipeline to arrive at each approved medication.

I don't believe the NIH can improve this by being smarter, that is a foolish conceit of many. But not having to seek blockbuster returns does change the calculus for what indications are worthy of serious drug development effort.

And that would be a GoodThing.
*such as it is

10 responses so far

SfN11: Optogenetics for the masses

Nov 10 2011 Published by under Neuroscience, Physiology, Society for Neuroscience

The Backyard Brains folks are at it again.

Presentation 22.17SU/YY91 will be on display Saturday 1:00 p.m. – Sunday 5:00 p.m. with their presentation time scheduled for Sunday. It is entitled:

The blue light special: a portable, low-cost optogenetics kit for the classroom

The abstract reads:

Optogenetics is an innovative technology for studying brain circuits, but to date the lay public has had little exposure to its potential and limited access to low-cost tools to do experiments. What if you have an interest in cutting-edge neuroscience but you aren’t near a university? What if you prefer to do science in your garage, in a truck-bed, or on a plane on a boat? What if you are a high school biology teacher who wants to keep your students abreast of the most current neurotechnology but the latest millage did not pass? We can help you! We have designed a low-cost, easy-to-build, and portable electrophysiology rig for simple optogenetics demonstrations. The rig consists of a extracellular amplifier (our SpikerBox), a 3D-printed 3-axis micromanipulator, an off-the-shelf monocular 30X microscope, a high intensity blue LED (light-emitting diode), and an LED control circuit that can be precisely controlled with a tailor-made iPhone application or simple tone generator. We have successfully used our first clunky prototype to record blue light-evoked electromyograms from channelrhodopsin-2 expressing Drosophila larvae. We plan to spend the summer refining our prototype (making it more stable, improving control of light emission) and genetic tools. We plan to begin demonstrations in high school classrooms by Fall 2011. We also have other low-cost neurotechnology inventions to show you, so come by our poster to participate in real-time peer review!

Right? RIGHT? You know you think this is cool. Go see their presentation folks, they always amuse, entertain and educate.

Update for additional reading on Backyard Brains and Marzullo and Gage
The $100 Spike
The $100 SpikerBox v1.0
Backyard Brains

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On discovering new medicines

ResearchBlogging.orgA link from writedit pointed me to a review of drugs that were approved in the US with an eye to how they were identified. Swinney and Anthony (2011) identified 259 agents that were approved by the US FDA between 1999 and 2008. They then identified 75 which were "first in class", i.e., not just me-too drugs or new formulations of existing drugs or whatnot. There were 20 imaging agents, not further discussed, and 164 "follower" drugs.

The review also focused mostly on small molecule drugs instead of "biologics" because of an assumption that the latter are all exclusively "target based" discoveries. The main interest was in determining if the remaining small molecule drugs were discovered the smart way or the dumb way. That's my formulation of what the authors term "target based screening" (which may include "molecular mechanism of action") discovery and "phenotypic screening" type of discovery. As they put it:

The strengths of the target-based approach include the ability to apply molecular and chemical knowledge to investigate specific molecular hypotheses, and the ability to apply both small-molecule screening strategies (which can often be achieved using high-throughput formats) and biologic-based approaches, such as identifying monoclonal antibodies. A disadvantage of the target-based approach is that the solution to the specific molecular hypotheses may not be relevant to the disease pathogenesis or provide a sufficient therapeutic index.

A strength of the phenotypic approach is that the assays do not require prior understanding of the molecular mechanism of action (MMOA), and activity in such assays might be translated into therapeutic impact in a given disease state more effectively than in target-based assays, which are often more artificial. A disadvantage of phenotypic screening approaches is the challenge of optimizing the molecular properties of candidate drugs without the design parameters provided by prior knowledge of the MMOA.

You will note that this is related to some comments I made previously about mouse models of depression.

The authors found that 28 of the first-in-class new molecular entities (NMEs) were discovered via phenotypic screening, 17 via target based approaches and 5 via making synthetic mimics of existing natural compounds. To give you a flavor of what phenotypic screening means:

For example, the oxazolidinone antibiotics (such as linezolid) were initially discovered as inhibitors of Gram-positive bacteria but were subsequently shown to be protein synthesis inhibitors that target an early step in the binding of N-formylmethionyl-tRNA to the ribosome

and for target based approaches:

A computer-assisted drug design strategy that was based on the crystal structure of the influenza viral neuraminidase led to the identification of zanamivir

The authors even ventured to distinguish discovery approaches by disease area:

Evaluation of the discovery strategy by disease area showed that a phenotypic approach was the most successful for central nervous system disorders and infectious diseases, whereas target-based approaches were most successful in cancer, infectious diseases and metabolic diseases

Unsurprising of course, given that our state of understanding of nervous system disorders is, to most viewers, considerably less complete in comparison with some other health conditions. You would expect that if there are multiple targets or targets are essentially unknown, all you are left with are the predictive phenotypic models.

Of the follower drugs 51% were identified by target based discovery and 18% by phenotypic screening. This is perhaps slightly surprising given that in the cases of the me-too drugs, you would think target-based would be more heavily dominant. Perhaps we can think of a drug which initially looked to have property X that dominated but then in the phenotypic screening, it looked more like a property Y type of drug.

The authors take on this is that it is slightly surprising how poorly target-based discovery performed within a context of what they describe as a period in which there was a lot of effort and faith placed behind the target-based approaches. I suspect this is going to be in the eye of the beholder but I certainly agree. I can't really go into the details but there are areas where my professional career is...affected, let us the smart/dumb axis of drug discovery. It should be obvious to my longer term readers that I align most closely with animal models of various things related to health and neurobiology and so therefore you may safely conclude that I have a bias for phenotypic screening. And even in the case of the target-based discovery:

at least three hypotheses that must be correct to result in a new drug. The first hypothesis, which also applies to other discovery approaches, is that activity in the preclinical screens that are used to select a drug candidate will translate effectively into clinically meaningful activity in patients. The other two hypotheses are that the target that is selected is important in human disease and that the MMOA of drug candidates at the target in question is one that is capable of achieving the desired biological response.

Right. You still need good phenotypic models and ultimately you are going to have to pass human clinical trials. The authors further worry that this higher burden, especially knowing the MMoA is going to lead to some misses.

in the case of phenotypic-based screening approaches, assuming that a screening assay that translates effectively to human disease is available or can be identified, a potential key advantage of this approach over target-based approaches is that there is no preconceived idea of the MMOA and target hypothesis.

Ultimately I think this review argues quite effectively for an "all hands on deck" approach to drug discovery but it can't help but come off as a strong caution to the folks that think that "smarter" (aka, "rational drug design") is the only solution. Yes, this points the finger at Francis Collins' big thrust for a new translational IC at the NIH but also at the BigPharma companies that seem to be shedding their traditional models-based, phenotypic discover research units as fast as they can. No matter which side you come down on, this is a great read with lots to think about for those of us who are interested in the discovery of new medicines.
Swinney, D., & Anthony, J. (2011). How were new medicines discovered? Nature Reviews Drug Discovery, 10 (7), 507-519 DOI: 10.1038/nrd3480

4 responses so far

"Strong evidence"? "The neurogenesis-depression hypothesis confirmed"? Schweeet!!!

Jul 13 2011 Published by under Conduct of Science, Neuroscience

I admit I got a little excited when I saw a Twitt RT'd earlier today from Noah Gray.

Soon to be in press: Strong evidence supporting the neurogenesis-depression hypothesis, from @jsnsndr:

I'm sort of vaguely aware and following a literature that is trying to establish a causal link between depression and alterations in hippocampal neurogenesis, proliferation and general plasticity based on creating new, functioning cells.

This is generally a non-human literature, typically in mouse models and....highly correlative.

With respect to this latter, the state of the art for a long time has been to treat markers of neurogenesis (there are many stages and concepts here which I'll glomp under one heading. Follow the link in the tweet to the Functional Neurogenesis blog for all your background reading) as dependent variables to be reported. Not manipulated. This is, perhaps obviously, the case for any post-mortem human brain analysis but also for many animal models to date. In essence, you do some thing to the animal and then look at the markers afterward. Then you report whether neurogenesis is up, down or unchanged. So far so good. But this approach doesn't quite get at the question of causality which is important if we think that altering the effects on neurogenesis (say by a drug or behavioral therapy*) would have a beneficial effect on the affective disorder itself. It could, after all, be a result of depression with no causal role.

There is also a question of whether a given animal model is a valid representation of a human affective disorder. Here we can think about issues of predictability- does it matter, for example, what the mouse model looks like if the ability to predict what anti-depression, anti-anxiety or anti-mania drugs will work (ultimately) in the clinic is high? Of course not...if your goal is drug development.

If you goal is understanding the neurobiological underpinnings of the human disease, well, you want to be careful.

My take on the current state of the nonhuman models of depression is that we are not yet at the point where we have high confidence in calling any model "depression". They are models, they have various points of high correspondence to human illness but they also have limitations. They are, in cases, highly predictive of drugs which will ultimately prove useful in the clinical setting.

So I confess that when I see a scientist (Noah Gray is, after all, a scientist by training even if he currently inhabits an Editor job) tweet "strong evidence", well, I'm looking for some coolio stuff.

Following the link to the post on Functional Neurogenesis, I found the post title to include the word "confirmed"! yay, let's read!!!!

So I’m excited to say that we will soon be publishing what (I think) is the best evidence that impaired adult neurogenesis actually causes depressive symptoms (in mice).

"in mice". Fuck.

Okay, so let's scratch the "strong evidence" and the "neurogenesis-depression hypothesis confirmed stuff" for now.

Pretty cool paper, by the sounds of it. Again, from my distinctly nonspecialist position, this is the next step. Manipulations of the neurogenesis processes as independent variables to provide stronger evidence that there is a causal relationship. Between these processes and a behavioral or physiological phenotype. I can't really say where this all fits into the "first demonstration" or "best demonstration" or "critical demonstration" picture so as to give you a valance for exactly how cool it is. But I do recognize that these approaches are the next place the field needs to go to better establish that the neurogenesis-depression hypothesis could be "confirmed".

Me, until the state of animal models are better and more convincingly established, I want to see data in human subjects before I am willing to concede either "confirmation" or "strong evidence".

ps. Do take a read over the Functional Neurogenesis blog. It is really quite good and this area of neuroscience is fun. Many of you may still labor under the old belief that the adult brain doesn't grow new neurons and can't repair itself. It's no liver, but the brain does have some capacity to generate new neurons.

36 responses so far

On being Underrepresented in Neuroscience

Mar 14 2011 Published by under Neuroscience, Underrepresented Groups

The Society for Neuroscience is accepting applications, due May 20, for the Neuroscience Scholars Program. The fellowships are to pay for attending the Annual Meeting of the SfN, membership dues and some unspecified stipend for local activities.

The part that contributes to one of our off-again, on-again conversations around these parts is the specification of Eligibility for the program.

Individuals from racial and ethnic groups that have been shown by the National Science Foundation to be underrepresented in health-related sciences on a national basis.

Okay, standard "minority" stuff here. Light the torches, my affirmative action antagonists, light the torches.

Oh, wait....

Individuals who come from a family with an annual income below established low-income thresholds. These thresholds are based on family size; published by the U.S. Bureau of the Census; adjusted annually for changes in the Consumer Price Index; and adjusted by the Secretary for use in all health professions programs.


Individuals who come from a social, cultural, or educational environment such as that found in certain rural or inner-city environments that have demonstrably and recently directly inhibited the individual from obtaining the knowledge, skills, and abilities necessary to develop and participate in a research career. This is most applicable to undergraduate candidates.

So let us review. A special opportunity for those that are underrepresented in the Neurosciences to get a small helping hand up.

[ UPDATE: The cartoon is from Barry Deutsch ]

Eligibility is based on underrepresentation, not skin tone.

In particular, the socio-economic and impoverished schooling/environment criteria are totally and completely applicable to men and women alike who self-identify as "white".

So anyone who complains on and on that lower-class, socioeconomically disadvantaged whites are ignored or disenfranchised by affirmative action efforts are, yet again, falsified.

Given this, their motivations for continually and loudly opposing affirmative action efforts on the alleged basis of this principle are a little suspect, are they not?

Illustration grabbed from The Hermitage

76 responses so far

"How we wish that you had been differently employed"

This one is for some folks I've been engaging with on the Twitts about Uncle Siggy...

Link to Youtube

Don't forget DrZen's comment:

Freud was a comparative neuroanatomist who made significant discoveries:

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You know you want your very own Robo-Roach

Nov 11 2010 Published by under Neuroscience, Society for Neuroscience

I'm always eager to see what the Backyard Brains braintrust has been up to this past year by visiting their presentation at the Society for Neuroscience annual meeting. Looks like you'll also want to join Drs. Gage and Marzullo at posterboard 206.7/LLL42 Sunday Nov 14 at 10am to find out how you can get your own remote navigation system for your common household pest, the cockroach.

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Neuroscience! The latest fad with the unusually attractive outdoor set

Oct 27 2010 Published by under Neuroscience

Go Read.

Oh, and tell Odyssey he is far, far off base.

One response so far

Repost: The Women of MDMA Research

There is a #womeninscience meme bouncing around the Twitts today. Click the link and you'll see some of the conversation, even if you are not a habitual Twitter user. Please consider joining in with an observation about, well, anything related to the life of women in science. On the Twitts, on your blog, Facebook or in the comments here or elsewhere.

I have an older post that I wrote some time ago to introduce some of the women who have contributed to the science that I talk about on the blog. This post originally appeared 24 Jul 2008.

A comment left by a reader some time ago took exception to one of my posts highlighting another blogger.

wow, that is some excellent PR for a grad student to get for free. perhaps you could spotlight a female grad student as well...?

The ensuing discussion planted the idea for this post. Continue Reading »

One response so far

Online commentary on papers allows scooped authors to argue their priority?

A fascinating vignette into the glorious future of online commenting on papers was passed along to me by a reader.

Laurén and colleagues published a paper in Nature in February 2009 describing a phenomenon related to understanding the process of Alzheimer's disease and a possible role for prion. From the Abstract we can glean the essentials.

Here we identify the cellular prion protein (PrPC) as an amyloid-β-oligomer receptor by expression cloning. Amyloid-β oligomers bind with nanomolar affinity to PrPC, but the interaction does not require the infectious PrPSc conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-β oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-β-oligomer binding to PrPC and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-β. Thus, PrPC is a mediator of amyloid-β-oligomer-induced synaptic dysfunction, and PrPC-specific pharmaceuticals may have therapeutic potential for Alzheimer’s disease.

This is grand stuff. Treatment for AD continues to be a holding/rearguard action to slow progression and maintain cognitive function as long as possible. Our treatments are not so great, even at that limited role. So any new therapeutic targets, particularly ones that interfere with the pathological processes (as opposed to treating the symptoms of such unrelenting processes), are a BigDeal (or BFD as the US Vice President would have it).

However, a "brief communication arising" which has just been published in Nature says "uh-uh, not so fast". Kessel et al (2010) conclude the following from their results:

Laurén et al. suggested that binding between oligomeric amyloid-β ... and the cellular prion protein (PrPC)8 is necessary for synaptic perturbations. Here we show that PrPC is not required for amyloid-β-induced synaptic depression, reduction in spine density, or blockade of LTP; our results indicate that amyloid-β-mediated synaptic defects do not require PrPc.

Laurén et al provided a response, in Nature, to possibly explain the different outcomes.

Great, right? Big new idea/finding, some people jump on it and either confirm or question the results. These get published, and a dialog results. Happy, happy, amirite?

Well, somebody isn't too thrilled and has offered a comment on the Kessels et al paper. A. Aguzzi congratulated the group on their study and then points out that they scooped him. Not by getting their first in offering a counterpoint to Laurén et al

on May 19th, 2009, I have reported my lab's finding indicating that the Prnp genotype (Prnp+/+ vs +/-, /, and overexpressors) exerts no influence on LTP degradation in APPPS1 transgenic mice at the CDD conference in Rome.

but by being the first to be able to publish a counterpoint in Nature.

Marie-Therese Heemels, Nature editor, attended the talk and asked me (during the lunch break) to send her my findings to be considered for publication as ?brief matters arising? in Nature. (3) Following Dr. Heemels? request, we rapidly submitted our paper (Calella et al.). The paper was rejected on August 21, 2009 despite largely positive referees? comments (which I shall be happy to post separately if the blog editor allows for sufficient space). (4) because of the favorable, encouraging comments we opted to perform additional experimentation and to resubmit a further version of our paper, which was again rejected on May 5th, 2010 despite additional commendatory comments by the referees.

Our manuscript was then submitted to EMBO Molecular Medicine, where it received a rather enthusiastic reception and was finally published on July 21st, 2010

Yowsa! Now, I will admit right up front that I am unable to reasonably judge the quality of the papers of Kessels et al and of A. Aguzzi (Calella et al, 2010; EMBO Mol Med) so as to be able to determine why the one was worthy of Nature publication (as correspondence arising) and the other was not. Nor am I able to determine if one is a "better" criticism, counterpoint or elucidation of Laurén et al. But one thing does seem obvious to me. If the publication of Kessels et al in Nature was driven mostly by the mere fact it questioned or pared back the claims of Laurén et al then it would seem that Aguzzi's work was similarly meritorious on this criterion.

I will be fascinated to see if Nature responds to this in any way, including deleting the comment. Clearly they are going to have to take the view that Aguzzi's description of the reviews as largely positive and commendatory is a bit inaccurate. Right? Because beyond the scientific view of the reviewers, the only possible role for nonscientific professional editors is to judge hotness, relevance, impact and all that. And clearly since they published Kessels et al (which Nature received 22 Feb 2010 and accepted 01 Apr 2010), they think critique of Laurén et al is sufficient justification. If Aguzzi's contention that Nature rejected his second submission 05 May 2010 is valid, obviously the journal had both of these criticisms of Laurén et al in hand at the same time and chose to publish one but not the other.

I'd be interested to hear their thinking on that one.

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