tag:blogger.com,1999:blog-37304116774271585942024-02-08T10:29:48.676-08:00Psychopharmaceutically speakingTomhttp://www.blogger.com/profile/01214880769550787697noreply@blogger.comBlogger11125tag:blogger.com,1999:blog-3730411677427158594.post-1870321005438618472011-09-26T06:48:00.000-07:002011-09-26T06:48:13.529-07:00How to move forward - published results don't replicate<div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">Powering better drug discovery research(ers):<o:p></o:p></span></div><span style="font-family: Calibri;">Most people working in and around the pharmaceutical industry agree that it must become more efficient, more effective, and less costly.<span style="mso-spacerun: yes;"> </span>How to do this is still being debated. One prominent view is to reduce internal research within larger companies, relying on academia and start-up companies to provide grist for the development mill.<span style="mso-spacerun: yes;"> </span>Another view is that stand-alone pharmaceutical companies must retain strong internal research groups (see John LaMattina).<span style="mso-spacerun: yes;"> </span>Both sides agree that a primary goal is to lower the cost of products going to the market.<o:p></o:p></span><br />
<span style="font-family: Calibri;">There is little doubt that novel drug discovery must be grounded in unfettered academic-type research.<span style="mso-spacerun: yes;"> </span>The question is how best to apply those findings to drug discovery.<span style="mso-spacerun: yes;"> </span>I’ve written previously that a primary hurdle lies in the evaluation of which early stage findings to follow up on.<span style="mso-spacerun: yes;"> </span>Academic research has no incentive to provide replication of findings or presumes that other researchers will provide for replication.<span style="mso-spacerun: yes;"> </span>Those of us in pharmaceutical research know that replication of published biological results is not common.<span style="mso-spacerun: yes;"> </span>This leads pharmaceutical researchers to using gut instincts, read subjective preferences, to decide which new ideas to follow up.<span style="mso-spacerun: yes;"> </span>It also leads to hard feelings among academics about pharmaceutical companies. This real concern has recently been given quantitation (James Choi, The .Plan: A Quasi-Blog)); fully 2/3 of published findings could not be replicated!<span style="mso-spacerun: yes;"> </span><o:p></o:p></span><br />
<span style="font-family: Calibri;">The situation makes it impossible for pharmaceutical companies to efficiently, cost-effectively, start drug discovery programs.<span style="mso-spacerun: yes;"> </span>With the goal of containing the final cost of new drugs, dependent on the amount of money the company selling the product spent to develop it, pharmaceutical development companies simply cannot follow up on one-shot publication discoveries.<span style="mso-spacerun: yes;"> </span>The hurdle posed by the irreproducibility of findings is compounded by the fact that non-replications, i.e. negative results, are extremely difficult to publish.<span style="mso-spacerun: yes;"> </span>Information that a result cannot be replicated is primarily carried word-of-mouth and is not directly verifiable.<span style="mso-spacerun: yes;"> </span>The presumption by academics that replication will occur elsewhere is, in reality, nowhere.<o:p></o:p></span><br />
<span style="font-family: Calibri;">This reality means that the view that pharmaceutical companies should cut internal research and rely on discoveries from academia and start-ups can only come from people who have never attempted to discover a novel drug.<span style="mso-spacerun: yes;"> </span>It is a dead-end approach.<span style="mso-spacerun: yes;"> </span>It is true that development and sales companies cannot afford to add to the consumer price of drugs by footing large, permanent research groups.<span style="mso-spacerun: yes;"> </span>However, they must have experienced pharmaceutical scientist-consultants who can, in their own labs or by contract, efficiently validate (replicate and more) novel ideas and findings.<span style="mso-spacerun: yes;"> </span>However, even these groups will be overloaded by the number of novel ideas that ought to be evaluated.<o:p></o:p></span><br />
<span style="font-family: Calibri;">Still, the bigger issue is how to breech the grand canyon between novel ideas and exploratory drug discovery projects.<span style="mso-spacerun: yes;"> </span>One way novel ideas progress to a stage that they can be assessed by companies is for an individual scientist to start a company to gather more information about their idea.<span style="mso-spacerun: yes;"> </span>Much money and other resources have been made available to facilitate this path.<span style="mso-spacerun: yes;"> </span>There are at least two gigantic faults with this approach.<span style="mso-spacerun: yes;"> </span>One, many excellent scientists simply have no interest in taking this route, preferring to continue basic research, teaching, etc.<span style="mso-spacerun: yes;"> </span>Their ideas may simply be lost.<span style="mso-spacerun: yes;"> </span>The other fault is that the academic scientists who do form a start-up must now convert themselves into pharmaceutical scientists, without training.<span style="mso-spacerun: yes;"> </span>Notwithstanding that these scientists are all the smartest people in the room, the conversion to pharmaceutical researcher has as much to do with weltanschauung and experience as intelligence.<span style="mso-spacerun: yes;"> </span>I conclude, simplistically, but truthfully, that this is primary a waste of time and money.<span style="mso-spacerun: yes;"> </span>The graveyard of genomics start-ups is a testament to this opinion.<span style="mso-spacerun: yes;"> </span>It is only the fact that these costs are not directly factored into the overall price of a drug that makes this a viable path.<o:p></o:p></span><br />
<span style="font-family: Calibri;">Moreover, this approach distracts academics from their role of digging up new ideas.<span style="mso-spacerun: yes;"> </span>And, the breech between academic ideas and pharmaceutical exploratory programs is, very often, a matter of whether to believe results are reproducible and generalizable.<span style="mso-spacerun: yes;"> </span>Replication of results needs to become a standard expectation from academic laboratories.<span style="mso-spacerun: yes;"> </span>Results should, first of all, be repeated by the original investigator/postdoc, but in a blinded fashion.<span style="mso-spacerun: yes;"> </span>The dividends this will pay in the education of new investigators are enormous, if initially painful.<span style="mso-spacerun: yes;"> </span>Secondly, someone else in the same lab (graduate student, junior postdoc) should repeat the findings, in a blinded fashion.<span style="mso-spacerun: yes;"> </span>Again, this provides specific training to these less experienced researchers, as well as experience with equipment and procedures used in the lab.<span style="mso-spacerun: yes;"> </span>If these two levels of replication cannot be met, the results should not be published. This scenario obviously leads to young investigators staying longer in their training lab, but the benefits that can occur – more time to learn how to write successful grant applications, taking on the role of lab manager and learning how to manage a lab, etc. – will pay off greatly in terms of new faculty better able to adjust to having their own position, their own lab, etc.<o:p></o:p></span><br />
<span style="font-family: Calibri;">The gap between one-publication new ideas and exploratory drug projects must be bridged!<span style="mso-spacerun: yes;"> </span>Pharmaceutical companies and/or NIH could form institutes whose goal is to replicate published results.<span style="mso-spacerun: yes;"> </span>However, the multitude of new publications every day would quickly overwhelm such efforts.<span style="mso-spacerun: yes;"> </span>Much better that young investigators and their lab chiefs, universities and journals, take on the responsibility of replicating their own results.<span style="mso-spacerun: yes;"> </span>Huge benefits would accrue to the development of new drugs, and in increased trust and communication between companies and academic investigators.<span style="mso-spacerun: yes;"> </span>In addition, I strongly believe that the lessons learned, and new wisdom developed, from the experience of non-replication will lead to tremendous progress in all of biological research.<o:p></o:p></span><br />
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</div>Tomhttp://www.blogger.com/profile/01214880769550787697noreply@blogger.com0tag:blogger.com,1999:blog-3730411677427158594.post-77750066123823912092011-02-02T00:50:00.000-08:002011-02-02T00:50:37.099-08:00Accuracy in advertising<p$1><p$1><p$1><div class="MsoNormal" style="margin: 0in 0in 10pt;"><p$1><b><span style="font-family: Calibri;">Accuracy in advertising</span></b></p$1><p$1><p$1><p$1></p$1></p$1></p$1></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><p$1><span style="font-family: Calibri;">Truth in advertising is an important requirement to help protect citizens from overzealous claims and characterizations of<br />
products. Potential customers must be allowed to judge their purchases against some objective standards presented in<br />
a standard format designed to facilitate comparison. Still, truth does not need to involve stunningly detailed accuracy in cases where the consumer is not the person who chooses which products to try and not try. I’m addressing television and radio ads for prescription medicines, ads that must provide a listing of most of the reported mild side-effects and<br />
serious, adverse effects that have been observed in clinical trials and post-approval use. The verbalized lists,<br />
or even written ones presented over a few second period, are simply too long for a consumer to recall. About seven<br />
numbers is what most people can recall and that’s when they are attending. After hearing more than a couple ads for<br />
medicines, I’m very sure that the consumer is not specifically attending to the laundry list of side- and adverse effects, unless perhaps there is one they have had trouble with. And what would consumers do with the list even if they could remember them? Almost all chemical compounds can produce life-threatening reactions, allergic reactions if nothing else. Will a consumer not mention a new, to them, drug because the list contained life-threatening? And, if they<br />
don’t recall exactly what the conditions leading to life-threatening are, they are probably more likely to confuse rather than inform their physician. In addition, I feel it is doubtful they would compare the list between possible medicines for their ailments, and such comparisons would be incorrect anyway because they weren’t (in most cases)<br />
directly compared between products in a statistically relevant manner. </span></p$1><p$1><p$1><p$1></p$1></p$1></p$1></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><p$1><span style="font-family: Calibri;">In this case, truth is overwhelmed by detailed accuracy, in a manner largely useless to the consumer. It is useful to present approved medicines so that people can ask their physicians’ about whether ailments they have (seem to have) might be reduced pharmacologically and/or whether a new medicine might be more effective than ones they have been using. But, the consumer does not, cannot, choose the medicinal product. Only certified physicians can do that! The physician must be allowed the data by which to make their own judgments about the usefulness of medicines for their patients, and which medicines are likely to be best tolerated by their patients’ with specific histories of diseases and concomitant medicine use. </span></p$1><p$1><p$1><p$1></p$1></p$1></p$1></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><p$1><span style="font-family: Calibri;">The FDA has, as always, erred on the side of safety. However, advertisements for medicines aimed at general, non-prescribing, audiences are not made safer by listing all/most/many of the side-effects and adverse effects reported. I fully believe that these listings are simply tuned out, and even if attended to, would be of little value to the potential consumer – the consumer is not the person who will, must, evaluate the product and make the choice to use it. </span></p$1><p$1><p$1><p$1></p$1></p$1></p$1></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><p$1><span style="font-family: Calibri;">Truth would be well served by carefully stating the use which the FDA approved, and not overstepping that boundary, coupled with a statement that one’s physician will judge the product against the side- and adverse-effects that have been observed in people and their relevance to a particular patient. Advertising to the general public in no way reduces physicians’ obligations to make these choices. They must consult with the patient to ensure they have considered the patient fully, but the patient does not have any right to self-prescribe prescription medicine.</span></p$1><p$1><p$1><p$1></p$1></p$1></p$1></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><p$1><span style="font-family: Calibri;">I would prefer to watch the Super Bowl, for example, without hearing about nausea and drowsiness and whatever else has been reported. </span></p$1><p$1><p$1><p$1></p$1></p$1></p$1></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><p$1><span style="font-family: Calibri;"> I am not the first to voice this opinion, and am not likely to be the last… still, accuracy can overwhelm truth in advertising, and in so doing, reduce the critical value of the truth. And that's an important truth to tell.</span></p$1></div><p$1><p$1></p$1></p$1></p$1></p$1></p$1>Tomhttp://www.blogger.com/profile/01214880769550787697noreply@blogger.com0tag:blogger.com,1999:blog-3730411677427158594.post-8404306264830186042011-01-24T10:05:00.001-08:002011-01-24T10:05:55.339-08:00National Center for Advancing Translational Sciences<div class="MsoNormal" style="margin: 0in 0in 10pt;"><b><span style="font-family: Calibri;">National Center for Advancing Translational Sciences</span></b></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">Finally the wraps are off and we can assess how the Federal government intends to address the apparent – real – decline in the number of new medicines.<span> </span>As presently configured, the pharmaceutical industry cannot support the cost and time required for new drug discovery.<span> </span>Drug developers and manufacturers need an ally who can evaluate novel potential drug targets and provide enough information for pharmaceutical companies to invest in drug development.<span> </span>This new Center sounds exactly like the right kind of approach.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">In order for National Center the Advancing Translational Sciences (CATS?) to be successful, it must be able to take naked discoveries from academic investigators and fill out their resume enough that pharmaceutical companies can evaluate their feasibility as products.<span> </span>This should mean taking scientists and managers, and leaders, who are already experienced in this art and putting them into this less financially volatile (hopefully) institute.<span> </span>Who carries out this role now?<span> </span>Who has experience?<span> </span>Well, mainly a large number of un/underemployed pharmaceutical industry scientists and managers.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">Will this new Center bring in these experienced professionals?<span> </span>While this should be a no-brainer, I expect this new and critical part of drug discovery will be staffed by academic-type investigators.<span> </span>The only justification for this that I can imagine would be that the present process of drug discovery and development is wrong, broken.<span> </span>I don’t believe this!<span> </span>It is costly, time-consuming, and has a fairly low success rate, but much of that is because the end-products are ethical pharmaceuticals.<span> </span>These require enormous attention to detail and to safety.<span> </span>As I’ve mentioned earlier, this is not, and I believe should not, be the main charge of academic research.<span> </span>Academic research can be non-generalizable (read, not reproducible) because its function is to stimulate further research, not make a product.<span> </span>Furthermore, I believe that there are a large number of novel ideas, novel targets that could be worked on.<span> </span>The bottleneck is providing tools (compounds)<br />
and information (reproducibility, efficacy, safety, among others) in order for drug discovery and development to be objectively triggered.<span> </span>I don’t believe it is reasonable to ask academic or internal NIH scientists to learn to become pharmaceutical scientists overnight, or even over a 5-10 year period.<span> </span>Who will teach them?<span> </span>Are they expected, allowed, to learn from personal experience?! Staffing this new Center with academic investigators and managers will also set the stage for a politically charged battle between this Center, claiming that it has great things for pharma to invest in, and the<br />
industry saying that it doesn’t have the information it needs to start programs.<span> </span>What will be next, a National Center for the Development, Manufacture, and Sales of Medicines?<span> </span>Far-fetched?<span> </span>I sure hope so.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">One of the best things about staffing this Translational Sciences Center with a goodly percentage of pharmaceutical research professionals is that so many are currently very available…<span> </span>They can probably be snatched up for 70-80c on the dollar…<span> </span>On the other side, Federal stimulus funds have allowed many universities to hire more assistant professors and postdocs so that the academic community doesn’t have as strong a need for new positions.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">I call for more pharmaceutical professionals for this important Center for another reason, success.<span> </span>The NIH Genome project was touted to provide a plethora of new medicines.<span> </span>With the huge, possibly unnecessary, outlay of Federal funds, the medicines are yet to come.<span> </span>Even at the time of the Genome project it was clear that determination of physiological function would be necessary in order to prioritize gene products as potential drug targets.<span> </span>This type of effort was going on, slowly, in some academic labs, and, in a much higher throughput manner in some companies.<span> B</span>elatedly, NIH started<br />
programs like KOMP, the knock-out mouse project.<span> </span>But, again, the reality is that huge sums of money were spent for KO mice that in many cases already existed, delaying any chances for success stories for years.<span> </span>Sure, there are lots of reasons for why NIH had to reinvent the wheel, but I maintain that those reasons were/are mainly hypothetical as no one –<br />
almost no one – has worked with enough KO mice to understand the real hurdles.<span> </span>If NIH, and friends, have to reinvent translational sciences, it is likely that a large amount of money will be needlessly spent, and the delay to real successes will be long. [As an aside, KO mice, mice in general could provide a very nice, and presumably less costly, vehicle for most pharmaceutical testing.<span> </span>However, the industry is built on years of experience with rats.<span> </span>Let NIH, and industry, work to either solidify KO rats as a general tool, or build up a large amount of disease model and toxicology data on mice!]</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">I fully believe in and support the need for a Center for Advancing Translational Sciences.<span> </span>I only hope that it will provide answers and not just a call for a National Center for Developing, Manufacturing, and Selling Medicines in a couple of years.<o:p></o:p></span></div>Tomhttp://www.blogger.com/profile/01214880769550787697noreply@blogger.com0tag:blogger.com,1999:blog-3730411677427158594.post-84788115016194754762011-01-07T09:02:00.000-08:002011-01-07T09:02:28.003-08:00Women's tears<div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">Women’s tears</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">“I heard the news today, oh boy…”<span> </span>We’ve all been affected by women’s tears.<span> </span>I have to specify women because the recent study published in Science Express only involved tears from women.<span> </span>The TV news reporter said that these tears<br />
were a turnoff to men.<span> </span>Turnoff?<span> </span>Yep, make men less interested.<span> </span>That didn’t resonate with me, so I looked at a few write-ups about this study.<span> </span>There the headline was that “Women’s tears lowers testosterone in men”.<span> </span>That alters things a lot.<span> </span>Still, a quote from one of the authors was that tears “was one way of saying ‘no, I am not interested.’”<span> </span>Really?!<span> </span>If you, you man-thing, speak to a woman in a bar and she starts crying, you’ve probably got a lot more to worry about than her not being interested…<span> </span>Or, in fact, that might be a good sign to crank up your protective, white knight skills – presuming that you aren’t the reason she’s crying.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">My immediate thought is that this effect is more related to aggression, that tears may soften a man, reduce his aggressive behavior and thoughts, by reducing testosterone.<span> </span>Testosterone is strongly associated with aggressive behavior and thoughts and so it makes sense to try to lower it for self-protection.<span> </span>And, maybe turn aggression towards something<br />
that is hurting the person crying.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">So, these results are pretty exciting!<span> </span>The results suggest that tears contain a chemical that can reduce testosterone levels, and possibly reduce or redirect aggression.<span> </span>The authors’ mention using this chemical to reduce testosterone levels in conditions such as prostate cancer.<span> </span>A worthy goal, but appears to overlook the direct effect noted in the study – reduction of sexual, aggressive arousal.<span> </span>I hope that the industry will rapidly look to identify this chemical and evaluate whether it can be a lead to a new anti-aggression therapy.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">As for the sound bites of TV news...<span> </span>you get what you pay for. <o:p></o:p></span></div>Tomhttp://www.blogger.com/profile/01214880769550787697noreply@blogger.com0tag:blogger.com,1999:blog-3730411677427158594.post-48754781148929604892010-12-27T11:22:00.000-08:002010-12-27T11:23:13.590-08:00A real science of mind. Really?!<p$1><div class="MsoNormal" style="margin: 0in 0in 10pt;"><p$1><span style="font-family: Calibri;">A Real Science of Mind. Really?!</span></p$1></div><p$1><div class="MsoNormal" style="margin: 0in 0in 10pt;"><p$1><span style="font-family: Calibri;">Dr. Tyler Burge is not a fan of babble. Neither am I. His opinion in The New York Times Opinionator smacked of babbling.</span></p$1></div><p$1><div class="MsoNormal" style="margin: 0in 0in 10pt;"><p$1><span style="font-family: Calibri;">First, there are the points where I believe we agree. Images of fMRI scans appear everywhere, flashy color images that tout the location of brain functions nee mental processes. They are, simply, too much. They are exploratory science,<br />
often not much more than case studies. They seem to offer explanations of everything including our most cherished emotions such as love. They do not.</span></p$1></div><p$1><div class="MsoNormal" style="margin: 0in 0in 10pt;"><p$1><span style="font-family: Calibri;">They are also necessary. Dr. Burge seems to have forgotten Kuhn’s exhortations that these types of studies are a central part of normal science. They are puzzle-solving, examining the wide range of mental functions looking to verify the applicability of the paradigm that the brain/nervous system is a necessary substrate for mental processes. As such, they represent a quantum leap forward in the neurobiology of mental processes. Physiologists like von Helmholtz had earlier demonstrated that basic mental processes, psychophysics really, like perception correlated with the structure – length of nerves – of the nervous system. For the more hard-core mental processes, such as language and emotions, psychology and neurobiology has had to work from instances of brain damage to investigate the relationship of mind to body<br />
(brain). Of course these studies, such as those by Broca and others, have been very successful in noting examples of<br />
specific deficits in mental processes that correlate with damage to specific areas of the brain. Nevertheless these<br />
studies are correlative and are grounded on damaged, abnormal brains. </span></p$1></div><p$1><div class="MsoNormal" style="margin: 0in 0in 10pt;"><p$1><span style="font-family: Calibri;">Functional MRI studies allow psychologists and neurobiologists to evaluate normal functioning brains! With this technology we can, are, exploring the range of mental processes and their relationship to specific brain areas. This cataloging will take a long time, the activities in many regions will overlap and we will learn to further subdivide mental processes. And, we will learn to distinguish among many processes that we now call by single words, like love, that we know have numerous facets to them. And, we will learn to better probe mental functions, emotions, and mental disorders as we learn about the various brain regions and circuits modulated during them. We will make many missteps, studies that seem brash or sophomoric, but we will discuss and debate our methods, and we will better our understanding of ourselves. Does this excuse overstating the aims and findings from such exploratory cataloging? No, but neither does it require lambasting.</span></p$1></div><p$1><div class="MsoNormal" style="margin: 0in 0in 10pt;"><p$1><span style="font-family: Calibri;">I feel that Dr. Burge is setting up a rearguard action, an attempt to reinstate the mind-body distinction. If this is the case, he has already lost. The necessity of brain/nervous system to the expression of many mental processes is well-documented and cannot be wished away. The paradigm underlying most neurobiologists’ studies are that all mental processes require the nervous system for their expression, and the arduous, and sometimes simplistic efforts<br />
to examine this paradigm are well underway. Trained as a physiological psychologist, I am somewhat envious of the<br />
newbies who get to study normal brains with fMRI’s and other advanced technologies. But, I am very content to<br />
discover new therapeutics.</span></p$1></div><p$1><div class="MsoNormal" style="margin: 0in 0in 10pt;"><p$1><span style="font-family: Calibri;">The place where Dr. Burge might still open a debate is the question of whether the nervous system is sufficient for mental processes; I believe that the necessity of the nervous system for mental processes is a forgone conclusion and a resounding yes! Yet, no technologies that I am aware of allow us to formally address the question of sufficiency. We are clearly determining the processing that neurons and neuronal circuit can carry out. It is here that the object of Dr.<br />
Burge’s admiration, perceptual psychology, is playing a significant role. As we better define the results and limits of<br />
our perceptions, then we will better be able to ask whether the processing powers of neurons are sufficient to carry this out. Moreover, the studies and results of perceptual psychology are a wonder unto themselves. And yes, the results should be given more publicity. In my own teaching, I specifically warn students not to put too much into the glossy, colorful fMRI images and to look more to the effects of visual illusions in their own perceptions to deal with their daily lives. However, none of this overshadows the work of neurobiologists using fMRI’s and other real-time technologies to probe the brain-mental process connection. <o:p></o:p></span></p$1></div><p$1></p$1></p$1></p$1></p$1></p$1></p$1></p$1></p$1>Tomhttp://www.blogger.com/profile/01214880769550787697noreply@blogger.com0tag:blogger.com,1999:blog-3730411677427158594.post-29298118790126593112010-12-20T13:25:00.000-08:002010-12-20T13:25:47.453-08:00Transported to ecstasy<div class="MsoNormal" style="margin: 0in 0in 10pt;"><b><span style="font-family: Calibri;">Transported to ecstasy</span></b></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">The pharmaceutical industry relies on the discovery of new, or de-orphaning of recognized, targets.<span> </span>Tremendous effort has been directed at the de-orphaning of GPCRs since they are the targets for numerous therapeutic agents and there are a large number still needing to have native agonists identified.<span> </span>The various techniques to identify GPCR agonists are still not easy or general, but they are making inroads into a number of novel targets.<span> </span>Ion channels<br />
are also a rich source of pharmaceuticals.<span> </span>Huge strides have been made to increase the thruput of ion channel<br />
screening.<span> </span>However, the speed and efficiency are very much behind that of GPCR’s and enzymes.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">Another source of pharmaceutical agents are transporters.<span> </span>SSRI’s, SNRI’s, and mixed amine uptake inhibitors for major depression are one very strong example.<span> </span>Dopamine transporter inhibitors – amphetamine, methylphenidate, cocaine – constitute another.<span> </span>And now that we recognize transporters on numerous membranes – synaptic vesicles, mitochondria, etc. – the scope of their potential uses as pharmaceutical agents becomes very diverse.<span> </span>However, as yet there are no good technologies to de-orphan transporters.<span> </span>This is extremely unfortunate since measuring transport activity –<br />
tagged substrates – can be accomplished in a high-throughput manner, equivalent to GPCR’s and enzymes.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">Does this lack of techniques belie some special problems with transporters or just the lack of strong efforts?<span> </span></span><span style="font-family: Calibri;">I feel it is primarily the latter while acknowledging that much exploratory work must still be done.<span> </span>It is unreasonable to tag (<sup><span style="font-size: x-small;">3</span></sup>H-labelled for example) thousands of different compounds to apply to a concentrated group of transporters.<span> </span>And, obtaining a rich source of transporters in closed-off membranes (synaptosomes, vesicles, black lipid membranes) also has its difficulties.<span> </span>Finally, transport requires energy, in the form of ATP hydrolysis, in order to run.<span> </span>That’s a pretty big list<br />
of problems to be solved, but, I believe the end result will be much greater than the effort expended.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">Many transporters contain cotransport for ions, in particular chloride.<span> </span>Although this cotransport may be small per transporter, it is likely that it could be detected from a rich source of transport activity.<span> </span>And, I hope and believe, that further study of transporters will provide evidence for additional cotransporters.<span> </span>Perhaps even ATP hydrolysis itself could<br />
provide a measure of transport activity.<span> </span>Detection of coexisting activities will likely require rich sources of transporters.<span> </span>While one can imagine single transporter recordings, it is more difficult to visualize this being high throughput.<span> </span></span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">Rich sources will likely mean recombinantly expressing transporters.<span> </span>This is highly feasible.<span> </span>The real problems are transporter orientation and energy.<span> </span>If transporters are randomly oriented in membranes, then overall transport will be zero.<span> </span>However, application of putative substrates to one side of a membrane should initially produce transport primarily in one direction.<span> </span>And that interval of one-sided transport may be extendable if the concentration of substrate on the<br />
initial side is kept much higher, for example, by dilution, than on the second side.<span> </span>Other means, directing the<br />
orientation of membrane insertion or deactivation of transporters from one face, may also be discovered.<span> </span>Similar<br />
issues will revolve around providing energy to power transport, but I believe these can also be dealt with.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">In summary, I believe that the ability to efficiently de-orphan transporters should be a major goal for neurobiology because several of our most powerful drugs affect transport.<span> </span>While, the road to making this a reality will be arduous, I believe the end result will be a spectacular opening up of new avenues for discovering novel therapeutics.<o:p></o:p></span></div>Tomhttp://www.blogger.com/profile/01214880769550787697noreply@blogger.com0tag:blogger.com,1999:blog-3730411677427158594.post-34760740136406112192010-12-17T08:18:00.000-08:002010-12-17T08:18:03.350-08:00Lost in translation<div class="MsoNormal" style="margin: 0in 0in 0pt;">Lost in translation.<span> </span></div><br />
<div class="MsoNormal" style="margin: 0in 0in 0pt;">Pharma is broken.<span> </span>This statement is very true – on so many levels -but blanket statements like this don’t really inform on the structure of a relief plan.<span> </span>Yet, a blanket statement solution characterizes the new drug discovery and development and clinical trials initiative from on high.<span> </span>For one, the Clinical Translational Science Award Centers.<span> </span>The original notions initiating a call for reform were the high cost of medicine and low novelty of NCE’s coming from Pharma.<span> </span>The notion was to stop depending on Pharma to come up with the new ideas for targets and to more quickly move compounds into<br />
clinical trials.<span> </span>There is no doubt that basic target and drug discovery is too risky, too expensive for Pharma to<br />
do.<span> </span>New, seemingly crazy, ideas may best be carried out in universities and medical centers.<span> </span>Wow, so a conclave of scientists with pharmaceutical experience and those with academic/medical center experience could really turn this into a golden reality! </div><div class="MsoNormal" style="margin: 0in 0in 0pt;">And there’s the rub – where are the pharmaceutical scientists in all this?<span> </span>Pointedly ignored and left out!<span> </span>It seems we are<br />
destined to rediscover the light bulb, going through the 1,000 failures to find a useful filament.<span> </span>It is appalling and galling </div><div class="MsoNormal" style="margin: 0in 0in 0pt;">to watch NIH and various academic centers once again throw money, rather than expertise, at a critical need. <span> </span>The solution pointedly, if not explicitly, says that the whole R&D enterprise within Pharma is broken.<span> </span><span> </span>So, to replace that we will have a wholly new set of translators, ones that don’t know the syntax of the language they need to be speaking, ones who will develop a new language from scratch. </div><div class="MsoNormal" style="margin: 0in 0in 0pt;">One can certainly fault some pharmaceutical people and practices for not getting it right, but it's not broken because they are deaf, dumb, and blind.<span> </span>It’s broken because the timelines to making a profitable pharmaceutical product force foolish<br />
reprioritizations into the discovery and development process.<span> </span>Development of drugs takes many years – that’s a fact of the processes and needed regulations.<span> </span>But, financial considerations – read salaries, resources, and shareholders – require the process to complete in, at most, a couple of years.<span> </span>The answer is to separate drug discovery and early development from the costs and resources of clinical development, manufacturing, marketing and sales. </div><div class="MsoNormal" style="margin: 0in 0in 0pt;">It should be a mandate that pharmaceutically-trained scientists and drug development managers be front and center in this new roadmap.<span> </span>They are the only ones who have ever had to talk the talk and walk the walk.<span> </span>Maybe Pharma needs to take a more active role here, forming their own independent discovery and training center(s), if nothing else, to embarrass<br />
this high-foolishness being touted as the answer to the high cost of medicines.<span> </span>A place where academic and medical scientists can work with experienced drug developers to work very hard at bringing new ideas to fruition, at least to decision points, without the financial deadlines so critical to paying employees and stockholders.</div><div class="MsoNormal" style="margin: 0in 0in 0pt;">This new initiative must fail, in part because there’s no requirement to make it work.<span> </span>We’ll get a lot of great publications, that the authors can walk away from at the end if they don’t really work out.<span> </span>I’m sure the FDA will happy to approve the new medicines created by those who don’t have to take responsibility. </div>Tomhttp://www.blogger.com/profile/01214880769550787697noreply@blogger.com0tag:blogger.com,1999:blog-3730411677427158594.post-78933791034043255372010-12-13T09:31:00.000-08:002010-12-13T09:31:37.097-08:00Whiz kids are not a solution.<div class="MsoNormal" style="margin: 0in 0in 0pt;">Pharma hires another academic whiz kid to head up neuropsychiatric drug discovery.<span> </span>It doesn’t matter whether this occurred a month ago or a year ago, this approach has been tried over and over, and it very rarely (ever?) works. </div><div class="MsoNormal" style="margin: 0in 0in 0pt;">What’s the appeal, and what’s the reality?</div><br />
<div class="MsoNormal" style="margin: 0in 0in 0pt;">Pharma is led by business folk; it is a business after all. <span> </span>And business folks know you have to stay at least one step ahead of the competition, have the newest technology, the newest gizmo, the newest…<span> </span>And, they have been taught, and may even have supporting personal experience, that a company needs to have a new idea about every 3-4 years.<span> </span>In most businesses, new ideas become products in a couple of years.<span> </span>In Pharma, 3-4 years is like the first inning in baseball – you have to play it, it may set up opportunities and challenges for the rest of the game, but it sure doesn’t win the game, doesn’t count as<br />
anything in your overall stats.<span> </span>Still, we drag in the new shooting star – who’s probably worked 15 years to build up<br />
their own special knowledge and viewpoint in, say, basketball – and expect them to become .400 hitters in a year or two.<span> </span>It’s a bad situation for Pharma, because it rarely develops a new product, and it’s bad for the whiz kid because they’re thrown into the lion’s den, with no training or mentor.</div><br />
<div class="MsoNormal" style="margin: 0in 0in 0pt;">I’m not totally surprised that business people turn to outside whiz kids to fix things.<span> </span>Too often neuropsychiatric drug discovery and development is slow, and numerous explanations such as the difficulty of the BBB and poor animal models are presented as reasons.<span> </span>Heard repeatedly, it would be difficult not to view these ‘explanations’ as platitudes, excuses,<br />
or a lack of expertise within the Neuroscience group.<span> </span></div><div class="MsoNormal" style="margin: 0in 0in 0pt;">So, Pharma needs new idea guys (no gender implied), but what do they need to do? <span> </span>We generally need new ideas related to classes of drug targets, how to assay their activity, and how to investigate disorders with unmet needs.<span> </span>What we don’t have is time for the whiz kid to become pharmaceutical scientists or managers; this takes years and they may not be suited for it<br />
anyway.<span> </span>Yet we put them in charge, managing activities that they are unfamiliar with, confusing everyone.<span> </span>Instead, let’s have them take a sabbatical from their present, generally academic, position for two years.<span> </span>Position them as Chief Scientific or Technology Consultant, let them interact with staff and make changes in processes and viewpoints, but still have a pharmaceutical director in charge of target and drug discovery and development.<span> </span>This keeps the engine running developing new therapeutics while it gives the whiz kid a well-defined transition process – slip back into their academic<br />
position with some fabulous information/experience to dole out to their colleagues, or choose to stay within pharma.<o:p></o:p></div><br />
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</div>Tomhttp://www.blogger.com/profile/01214880769550787697noreply@blogger.com0tag:blogger.com,1999:blog-3730411677427158594.post-12366941394175370702010-12-09T09:37:00.000-08:002010-12-09T09:37:44.197-08:00Re: Desperately seeking solutions<div class="MsoNormal" style="margin: 0in 0in 0pt;"><br />
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</div><div class="MsoNormal" style="margin: 0in 0in 0pt;"><span style="font-family: "Microsoft Sans Serif","sans-serif";">The pharmaceutical industry is not producing new treatments fast enough.<span> </span>Not fast enough to justify the hype around the long list of “omics”. <span> </span>Not fast enough to continue as highly profitable companies. These headlines are<br />
everywhere.<span> </span>One immediate reaction to these headlines is to affirm that the pharmaceutical business is not a hype industry.<span> </span>Ethical medicines do not meld well with ASAP.<span> </span>However, this fact does not help us to improve and invigorate the pharmaceutical business.<o:p></o:p></span></div><br />
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</div><div class="MsoNormal" style="margin: 0in 0in 0pt;"><span style="font-family: "Microsoft Sans Serif","sans-serif";">Research and development of new treatments is a difficult business – and, indeed, is difficult as the basis of a business.<span> </span>With the rapidly increasing number of <i>potentia</i>l drug targets, and our greater understanding of the numerous ways drugs can interact with their targets – competitive, noncompetitive, use-dependent,<br />
allosteric, etc. – the search for the best new chemical entity becomes more involved, slowing the process even more than in previous years.<o:p></o:p></span></div><br />
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</div><div class="MsoNormal" style="margin: 0in 0in 0pt;"><span style="font-family: "Microsoft Sans Serif","sans-serif";">Basic research, generally the purview of academic and individual investigators, is necessary to uncover the new diamonds in the rough. <span> </span>But, as noted by Sharon Begley & Mary Carmichael in their article in <i>Newsweek</i>,<br />
academic researchers are not prepared, or rewarded, for the “time-consuming drudgery” required to take an idea into drug development.<span> </span>Academic researchers are rewarded for publications and funded grants; their results don’t even have to be able to be replicated as long as they stimulate research and publications by others (see <i>Science Citation Index</i>).<span> </span><o:p></o:p></span></div><br />
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</div><div class="MsoNormal" style="margin: 0in 0in 0pt;"><span style="font-family: "Microsoft Sans Serif","sans-serif";">Perhaps more troubling is the rush to fund translational studies in the clinical setting.<span> </span>At present the vast majority of clinical studies are run through pharmaceutical companies, directly or via clinical contract research organizations (CRO’s).<span> </span>A critical factor governing these studies is the palpable fear of being spotlighted for scrutiny by the FDA.<span> </span>Beyond the standard approval process, FDA scrutiny can fatally delay a project, be very expensive, and produce negative publicity.<span> </span>Companies, certainly those that have been in business a while, work very hard to ensure their protocols align with FDA guidelines.<span> Of course, following FDA guidelines and approval is simply making sure the best and safest drugs are approved, but fear of the FDA is a quick way to put that into one's daily mindset. </span><o:p></o:p></span></div><br />
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</div><div class="MsoNormal" style="margin: 0in 0in 0pt;"><span style="font-family: "Microsoft Sans Serif","sans-serif";">Now, we are seeing a trend towards pushing more of the early clinical development work into medical centers.<span> </span>The goal is to get more potential treatments examined and hopefully translated sooner into new and better therapeutics.<span> </span>At face value, this trend seems reasonable since medical centers are often where clinical trials are carried out.<span> </span>BUT, when generated by pharmaceutical companies and CRO’s, clinical studies are carried out with full knowledge that the companies’ bottom lines are critically dependent on meeting FDA standards.<span> </span>And,<br />
while medical center staffs (nurses, etc.) carry out the studies, they do so at the command of the funding pharmaceutical company.<o:p></o:p></span></div><br />
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</div><div class="MsoNormal" style="margin: 0in 0in 0pt;"><span style="font-family: "Microsoft Sans Serif","sans-serif";">Medical centers are still often run as feudal societies, nobility (read physicians and other lettered professionals) and staff (read serfs).<span> </span>We give physicians a lot of leeway in treating patients because they may have to make life and death decisions.<span> </span>However, this can play out that it is difficult for staff to question physicians’ directives; physicians can change treatment regimens with little or no explanation.<span> </span>And, physicians are trained to expect their plans to be carried out.<span> </span>So, now, you have a situation where you have the FDA that expects to review and give consent on clinical trial protocols and changes to them before they are put into place, and physicians who expect to improve treatment as needed.<span> </span>Given this polarity, it is difficult to imagine that there is not a tragedy in the making.<o:p></o:p></span></div><br />
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</div><div class="MsoNormal" style="margin: 0in 0in 0pt;"><span style="font-family: "Microsoft Sans Serif","sans-serif";">NIH’s CTSA centers and the ROADMAP in general are based on a no- repercussions philosophy, one that permeates medical centers and universities.<span> </span>However, they are moving that into the realm of public safety.<span> </span>It is clearly true that changes are critically needed to enhance the flow of good, novel therapeutics into the public health sector.<span> </span>However, it is only pharmaceutical companies that have the experience, skills, and mindset (“fear of the FDA”) to carry this out.<span> </span>I believe that NIH should be working to set up pharmaceutically-guided research institutes, not presuming that inexperienced (<i>but really smart</i>…) non-pharmaceutical investigators can pick up that role.<span> </span>Drug discovery and development are simply outside the ken of those who have not personally experienced success and failure as part of pharmaceutical discovery and development.<o:p></o:p></span></div>Tomhttp://www.blogger.com/profile/01214880769550787697noreply@blogger.com0tag:blogger.com,1999:blog-3730411677427158594.post-83321906313279248242010-12-05T23:50:00.000-08:002010-12-05T23:50:27.104-08:00Managing new discoveries<div class="MsoNormal" style="margin: 0in 0in 10pt;"><b><span style="font-family: Calibri;">Managing new discoveries.<o:p></o:p></span></b></div><br />
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<div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">One major disconnect between new ideas discovered by university scientists and their translation into drug discovery projects is the paucity of data characterizing the new discovery.<span> </span>As discussed in my last (first!) blog, the lack<br />
of information about reproducibility is a huge problem for anyone needing to prioritize new ideas for follow up.<o:p></o:p></span></div><br />
<div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">My understanding of the early days of scientific research is that it was generally carried out by people with independent means who funded their own lab.<span> </span>These gentlepeople scientists often hired a person to manage the daily research operations of the lab.<span> </span>And often this lab research manager was to become the next shining light in scientific research.<span> </span>This type of manager position could be one solution to our present problem of substantiating new discoveries.<span> </span>However, very few labs today have the luxury of such a hands-on research manager.<span> </span>Many labs are mish-mashes of siloed graduate students and postdocs scaring up enough supplies to run their experiments, and hoping the ‘senior postdoc’ (if there is one) has the time and inclination to help them get up and running.<span> </span>Finding the lab’s leader requires scheduling meetings even just to talk; only rarely to actually help learning techniques.<o:p></o:p></span></div><br />
<div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">Postdocs try their hands at a number of different techniques – funding agencies don’t favor one-technique wonders – </span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">and publish a series of papers giving them enough material for a good interview presentation.<span> </span>They are then thrown into an assistant professor position for which they generally aren’t ready.<span> </span>So, I propose that instead of sending promising postdocs out to sink or swim, let’s reinstate high status to the concept of assistant research professor.<span> </span>Larger labs may even have more than one to provide skill and experience with disparate techniques within the lab.<span> </span>After some time as a successful postdoc and promising researcher, these people would remain in their present labs for say, up to six years (the time generally given to new assistant professors to obtain tenure or move on).<span> </span>During this time they would continue to carry out their own research program without being fettered to the faculty committees and such that can overwhelm a new assistant professor.<span> </span>They would also guide/manage grad students and postdocs, including helping them learn techniques from the lab manager.<span> </span>The lab manager would work closely with the lab chief to write funding grants for the lab and their own projects – RO1’s etc., not postdoc fellowships.<span> </span>They would learn how to manage obtaining supplies for the lab.<span> </span>And, for me and my drug discovery needs, they would assign newer grad students and undergraduates to learn a technique, e.g. prepulse inhibition, running it until they obtained consistent results and consistent effects of standard pharmacological agents, and then (and only then) seek to reproduce the novel findings of the lab manager and other postdocs and graduate students.<span> </span>The lab manager would also need to lecture for some courses in order to have that experience, but also as a set of lectures they could use to teach a course once in their own position.<o:p></o:p></span></div><br />
<div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">This structure allows for clean transfer of and consistency in techniques in the laboratory, ensures training and proper use of lab devices, ensures reproducibility of new findings, and gives the lab manager the training and experience necessary to jump into setting up and running their own lab.<span> </span>It also ensures smooth, continued research progress for the lab chief.<span> </span>Brilliant scientists are too often called or lured away to administrative positions leaving their labs to languish.<span> </span>With<br />
their additional experience and skills, lab managers could move straight into (provisional) associate professorships – maybe a one-year probation on tenure to ensure that they continue their high level of activity.<span> </span><o:p></o:p></span></div>Tomhttp://www.blogger.com/profile/01214880769550787697noreply@blogger.com1tag:blogger.com,1999:blog-3730411677427158594.post-26087924975960335072010-12-03T10:37:00.000-08:002010-12-03T21:22:09.711-08:00Translationing new ideas into novel drugs<div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">Re: The Importance of New Companies for Drug Discovery:”</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">A recent report published in Nature finds that a majority of novel drugs are the result of research at universities and new biotechs.<span style="mso-spacerun: yes;"> </span>This is good news, showing that the system is working.<span style="mso-spacerun: yes;"> </span>Academic researchers with more freedom to follow the road less traveled, and the biotechs that often spring from their discoveries, are responsible for many or most of the novel therapeutic agencies.<span style="mso-spacerun: yes;"> </span>The only problem with this finding is that <u>this isn’t the problem</u>.<span style="mso-spacerun: yes;"> </span>It is critical that universities continue to receive sufficient funding to allow for a broad range of new ideas to be followed up.<span style="mso-spacerun: yes;"> </span>But the critical issue in translating new ideas into new therapies isn’t the lack of new ideas. The volume of new research findings is astounding.<span style="mso-spacerun: yes;"> </span>In fact, the volume is overwhelming!<span style="mso-spacerun: yes;"> </span>And what makes this a particularly acute problem is the minimal depth of information available about these new ideas and novel targets.<span style="mso-spacerun: yes;"> </span>There is still too much basic translational work to be done to separate the wheat from the chaff, and besides being a very expensive process, it also means that promising ideas can go overlooked for years.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">The byword in the drug discovery and development business is robustness, specifically reproducibility.<span style="mso-spacerun: yes;"> </span>Unfortunately reproducing research findings is almost a curse for academic and many biotech investigators.<span style="mso-spacerun: yes;"> </span>A graduate student or postdoc who has gotten some new exciting data doesn’t immediately set up to run the experiment again.<span style="mso-spacerun: yes;"> </span>What they do is run to publish it, and also to use some additional technique to approach the same question. <span style="mso-spacerun: yes;"> </span>Of course, it is important to make data public, and as soon as reasonable.<span style="mso-spacerun: yes;"> </span>It is important for graduate students and postdocs to gain working knowledge and experience with multiple techniques.<span style="mso-spacerun: yes;"> </span>But often, very often, the original data cannot be easily reproduced.<span style="mso-spacerun: yes;"> </span>Often, there are unrecognized experimental conditions or details that render reproduction tedious at best.<span style="mso-spacerun: yes;"> </span>And yet, without reproducibility there can be no drug discovery project.<span style="mso-spacerun: yes;"> </span>The FDA, at least, frowns on results that were only observed once.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">And yet, it isn’t the perceived role of the basic science investigator to demonstrate exactly how to reproduce their results.<span style="mso-spacerun: yes;"> </span>This is left to other investigators in other labs who may want to follow up on the original exciting results.<span style="mso-spacerun: yes;"> </span>The primary job of the discoverer, the explorer, is to instigate new studies. <span style="mso-spacerun: yes;"> </span>Responsibility for getting things right is not a part of basic science. <span style="mso-spacerun: yes;"> </span>One has only to look at many of the most published psychopharmacologists to see that their batting record isn’t necessarily so high; their value was in inspiring more people to join the new game.<span style="mso-spacerun: yes;"> </span>No, I don’t mean they can make results up. But, their perceived role is to publicize new data, new ideas, and new hypotheses; <span style="mso-spacerun: yes;"> </span>not to show that they can get the same result over and over again.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">Unfortunately this leaves pharmaceutical/translational scientists in a lurch.<span style="mso-spacerun: yes;"> </span>How can one prioritize which, among the huge number of exciting new ideas and data, to assign limited resources to follow up when robustness has not been demonstrated.<span style="mso-spacerun: yes;"> </span>I can vividly recall reading through 20-30 new idea statements each month from brilliant scientists at a world-renowned university, and generally have to tell them that there wasn’t enough information to follow up on.<span style="mso-spacerun: yes;"> </span>This took a lot of my time, took it away from ongoing discovery projects, and certainly made no friends among the academic stars.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">An interim function needs to be installed; one whose goals involve standardizing some assays enough so that they are carried out essentially the same in every lab and in setting out to reproduce potentially exciting results in these standardized tests.<span style="mso-spacerun: yes;"> </span>Some effort in this direction has been ongoing, most critically in the realm of standard behavioral pharmacology assays, but this needs to become one of the highest priorities in pharma and in academic centers.<span style="mso-spacerun: yes;"> </span>No longer can an expert electrophysiologist decide one day that they need to run the Morris water maze and expect anyone to accept their single study results.<span style="mso-spacerun: yes;"> </span>Assays must be consistent in the results they give and they need to be sensitive to specific challenges – gold standard compounds, for example.<span style="mso-spacerun: yes;"> </span>A new and exciting result needs to be reproduced by the original investigator, but now blinded to conditions, and then by another lab member, that is, using the same set-up, and also blinded to conditions.<span style="mso-spacerun: yes;"> </span>Or there needs to be a translational institute that focuses on reproducing results.<span style="mso-spacerun: yes;"> </span>Nothing less should be acceptable.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">So, how do pharmaceutical companies decide what new ideas to follow up on.<span style="mso-spacerun: yes;"> </span>Well, they either work on second- and third-generation projects related to drugs already known to work, reproducibly, or they find new uses for known compounds. <span style="mso-spacerun: yes;"> </span>Or they go with their gut… and then suffer their departments being right-sized or given “new direction” after two or three years without clear progress.</span></div><div class="MsoNormal" style="margin: 0in 0in 10pt;"><span style="font-family: Calibri;">A new type of research organization needs to come into existence.<span style="mso-spacerun: yes;"> </span>At one time, pharmaceutical companies with “money to burn” could allow research departments to take a lot of chances on new ideas.<span style="mso-spacerun: yes;"> </span>Those days are gone.<span style="mso-spacerun: yes;"> </span>Perhaps what is needed is a multi-company reproducibility/research organization that can plow through a large number of new ideas, while also working to standardize certain assays.<span style="mso-spacerun: yes;"> </span>Being funded by multiple entities would reduce the financial risk for all.<span style="mso-spacerun: yes;"> </span>One might snipe at this saying that companies only want to work on novel ideas, ones that aren’t being worked on by other companies. <span style="mso-spacerun: yes;"> </span>Anyone who has been in the pharma business more than five years knows this argument is a crock…<span style="mso-spacerun: yes;"> </span>Companies want to work on ideas they believe others also see as valuable – robust.<span style="mso-spacerun: yes;"> </span>Value comes from the unique properties of specific compounds each company finds.<span style="mso-spacerun: yes;"> </span>And, companies have different strengths, in biology and chemistry, and so each project will really only appeal to a fairly small number of companies.<span style="mso-spacerun: yes;"> </span></span></div>Tomhttp://www.blogger.com/profile/01214880769550787697noreply@blogger.com0