How to move forward - published results don't replicate

Powering better drug discovery research(ers):

Most people working in and around the pharmaceutical industry agree that it must become more efficient, more effective, and less costly.  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.  Another view is that stand-alone pharmaceutical companies must retain strong internal research groups (see John LaMattina).  Both sides agree that a primary goal is to lower the cost of products going to the market.
There is little doubt that novel drug discovery must be grounded in unfettered academic-type research.  The question is how best to apply those findings to drug discovery.  I’ve written previously that a primary hurdle lies in the evaluation of which early stage findings to follow up on.  Academic research has no incentive to provide replication of findings or presumes that other researchers will provide for replication.  Those of us in pharmaceutical research know that replication of published biological results is not common.  This leads pharmaceutical researchers to using gut instincts, read subjective preferences, to decide which new ideas to follow up.  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! 
The situation makes it impossible for pharmaceutical companies to efficiently, cost-effectively, start drug discovery programs.  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.  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.  Information that a result cannot be replicated is primarily carried word-of-mouth and is not directly verifiable.  The presumption by academics that replication will occur elsewhere is, in reality, nowhere.
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.  It is a dead-end approach.  It is true that development and sales companies cannot afford to add to the consumer price of drugs by footing large, permanent research groups.  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.  However, even these groups will be overloaded by the number of novel ideas that ought to be evaluated.
Still, the bigger issue is how to breech the grand canyon between novel ideas and exploratory drug discovery projects.  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.  Much money and other resources have been made available to facilitate this path.  There are at least two gigantic faults with this approach.  One, many excellent scientists simply have no interest in taking this route, preferring to continue basic research, teaching, etc.  Their ideas may simply be lost.  The other fault is that the academic scientists who do form a start-up must now convert themselves into pharmaceutical scientists, without training.  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.  I conclude, simplistically, but truthfully, that this is primary a waste of time and money.  The graveyard of genomics start-ups is a testament to this opinion.  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.
Moreover, this approach distracts academics from their role of digging up new ideas.  And, the breech between academic ideas and pharmaceutical exploratory programs is, very often, a matter of whether to believe results are reproducible and generalizable.  Replication of results needs to become a standard expectation from academic laboratories.  Results should, first of all, be repeated by the original investigator/postdoc, but in a blinded fashion.  The dividends this will pay in the education of new investigators are enormous, if initially painful.  Secondly, someone else in the same lab (graduate student, junior postdoc) should repeat the findings, in a blinded fashion.  Again, this provides specific training to these less experienced researchers, as well as experience with equipment and procedures used in the lab.  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.
The gap between one-publication new ideas and exploratory drug projects must be bridged!  Pharmaceutical companies and/or NIH could form institutes whose goal is to replicate published results.  However, the multitude of new publications every day would quickly overwhelm such efforts.  Much better that young investigators and their lab chiefs, universities and journals, take on the responsibility of replicating their own results.  Huge benefits would accrue to the development of new drugs, and in increased trust and communication between companies and academic investigators.  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.

Accuracy in advertising

Accuracy in advertising

Truth in advertising is an important requirement to help protect citizens from overzealous claims and characterizations of
products.  Potential customers must be allowed to judge their purchases against some objective standards presented in
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
serious, adverse effects that have been observed in clinical trials and post-approval use.  The verbalized lists,
or even written ones presented over a few second period, are simply too long for a consumer to recall.  About seven
numbers is what most people can recall and that’s when they are attending.  After hearing more than a couple ads for
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
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)
directly compared between products in a statistically relevant manner. 

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. 

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. 

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.

I would prefer to watch the Super Bowl, for example, without hearing about nausea and drowsiness and whatever else has been reported.

 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.

National Center for Advancing Translational Sciences

National Center for Advancing Translational Sciences

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.  As presently configured, the pharmaceutical industry cannot support the cost and time required for new drug discovery.  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.  This new Center sounds exactly like the right kind of approach.

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.  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.  Who carries out this role now?   Who has experience?  Well, mainly a large number of un/underemployed pharmaceutical industry scientists and managers.

Will this new Center bring in these experienced professionals?  While this should be a no-brainer, I expect this new and critical part of drug discovery will be staffed by academic-type investigators. The only justification for this that I can imagine would be that the present process of drug discovery and development is wrong, broken.  I don’t believe this!  It is costly, time-consuming, and has a fairly low success rate, but much of that is because the end-products are ethical pharmaceuticals.  These require enormous attention to detail and to safety. As I’ve mentioned earlier, this is not, and I believe should not, be the main charge of academic research. Academic research can be non-generalizable (read, not reproducible) because its function is to stimulate further research, not make a product.  Furthermore, I believe that there are a large number of novel ideas, novel targets that could be worked on.  The bottleneck is providing tools (compounds)
and information (reproducibility, efficacy, safety, among others) in order for drug discovery and development to be objectively triggered.  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.  Who will teach them?  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
industry saying that it doesn’t have the information it needs to start programs.  What will be next, a National Center for the Development, Manufacture, and Sales of Medicines?  Far-fetched?  I sure hope so.

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…  They can probably be snatched up for 70-80c on the dollar…   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.

I call for more pharmaceutical professionals for this important Center for another reason, success. The NIH Genome project was touted to provide a plethora of new medicines.  With the huge, possibly unnecessary, outlay of Federal funds, the medicines are yet to come.  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.  This type of effort was going on, slowly, in some academic labs, and, in a much higher throughput manner in some companies.  Belatedly, NIH started
programs like KOMP, the knock-out mouse project.  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. 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 –
almost no one – has worked with enough KO mice to understand the real hurdles.  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.  However, the industry is built on years of experience with rats.  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!]

I fully believe in and support the need for a Center for Advancing Translational Sciences.  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.

Women's tears

Women’s tears

“I heard the news today, oh boy…”   We’ve all been affected by women’s tears.  I have to specify women because the recent study published in Science Express only involved tears from women.  The TV news reporter said that these tears
were a turnoff to men.  Turnoff?  Yep, make men less interested.  That didn’t resonate with me, so I looked at a few     write-ups about this study.  There the headline was that “Women’s tears lowers testosterone in men”.  That alters things a lot.  Still, a quote from one of the authors was that tears “was one way of saying ‘no, I am not interested.’”  Really?! 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…  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.

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.  Testosterone is strongly associated with aggressive behavior and thoughts and so it makes sense to try to lower it for self-protection.  And, maybe turn aggression towards something
that is hurting the person crying.

So, these results are pretty exciting!  The results suggest that tears contain a chemical that can reduce testosterone levels, and possibly reduce or redirect aggression.  The authors’ mention using this chemical to reduce testosterone levels in conditions such as prostate cancer.  A worthy goal, but appears to overlook the direct effect noted in the study – reduction of sexual, aggressive arousal.  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.

As for the sound bites of TV news...  you get what you pay for.

A real science of mind. Really?!

A Real Science of Mind.  Really?!

Dr. Tyler Burge is not a fan of babble.  Neither am I.  His opinion in The New York Times Opinionator smacked of babbling.

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,
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.

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
(brain).  Of course these studies, such as those by Broca and others, have been very successful in noting examples of
specific deficits in mental processes that correlate with damage to specific areas of the brain.  Nevertheless these
studies are correlative and are grounded on damaged, abnormal brains. 

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.

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
to examine this paradigm are well underway.  Trained as a physiological psychologist, I am somewhat envious of the
newbies who get to study normal brains with fMRI’s and other advanced technologies.  But, I am very content to
discover new therapeutics.

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.
Burge’s admiration, perceptual psychology, is playing a significant role.  As we better define the results and limits of
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.

Transported to ecstasy

Transported to ecstasy

The pharmaceutical industry relies on the discovery of new, or de-orphaning of recognized, targets. 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.  The various techniques to identify GPCR agonists are still not easy or general, but they are making inroads into a number of novel targets.  Ion channels
are also a rich source of pharmaceuticals.  Huge strides have been made to increase the thruput of ion channel
screening.  However, the speed and efficiency are very much behind that of GPCR’s and enzymes.

Another source of pharmaceutical agents are transporters.  SSRI’s, SNRI’s, and mixed amine uptake inhibitors for major depression are one very strong example.  Dopamine transporter inhibitors – amphetamine, methylphenidate, cocaine – constitute another.  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.  However, as yet there are no good technologies to de-orphan transporters.  This is extremely unfortunate since measuring transport activity –
tagged substrates – can be accomplished in a high-throughput manner, equivalent to GPCR’s and enzymes.

Does this lack of techniques belie some special problems with transporters or just the lack of strong efforts?                           I feel it is primarily the latter while acknowledging that much exploratory work must still be done.  It is unreasonable to tag (³H-labelled for example) thousands of different compounds to apply to a concentrated group of transporters.  And, obtaining a rich source of transporters in closed-off membranes (synaptosomes, vesicles, black lipid membranes) also has its difficulties.  Finally, transport requires energy, in the form of ATP hydrolysis, in order to run.  That’s a pretty big list
of problems to be solved, but, I believe the end result will be much greater than the effort expended.

Many transporters contain cotransport for ions, in particular chloride.  Although this cotransport may be small per transporter, it is likely that it could be detected from a rich source of transport activity.  And, I hope and believe, that further study of transporters will provide evidence for additional cotransporters.  Perhaps even ATP hydrolysis itself could
provide a measure of transport activity.  Detection of coexisting activities will likely require rich sources of transporters.  While one can imagine single transporter recordings, it is more difficult to visualize this being high throughput.  

Rich sources will likely mean recombinantly expressing transporters.  This is highly feasible.  The real problems are transporter orientation and energy.  If transporters are randomly oriented in membranes, then overall transport will be zero.  However, application of putative substrates to one side of a membrane should initially produce transport primarily in one direction.  And that interval of one-sided transport may be extendable if the concentration of substrate on the
initial side is kept much higher, for example, by dilution, than on the second side.  Other means, directing the
orientation of membrane insertion or deactivation of transporters from one face, may also be discovered.  Similar
issues will revolve around providing energy to power transport, but I believe these can also be dealt with.

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.  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.

Lost in translation

Lost in translation. 

Pharma is broken.  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.  Yet, a blanket statement solution characterizes the new drug discovery and development and clinical trials initiative from on high.  For one, the Clinical Translational Science Award Centers.  The original notions initiating a call for reform were the high cost of medicine and low novelty of NCE’s coming from Pharma.  The notion was to stop depending on Pharma to come up with the new ideas for targets and to more quickly move compounds into
clinical trials.  There is no doubt that basic target and drug discovery is too risky, too expensive for Pharma to
do.  New, seemingly crazy, ideas may best be carried out in universities and medical centers.  Wow, so a conclave of scientists with pharmaceutical experience and those with academic/medical center experience could really turn this into a golden reality! 

And there’s the rub – where are the pharmaceutical scientists in all this?  Pointedly ignored and left out!  It seems we are
destined to rediscover the light bulb, going through the 1,000 failures to find a useful filament.  It is appalling and galling

to watch NIH and various academic centers once again throw money, rather than expertise, at a critical need.  The solution pointedly, if not explicitly, says that the whole R&D enterprise within Pharma is broken.   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. 

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.  It’s broken because the timelines to making a profitable pharmaceutical product force foolish
reprioritizations into the discovery and development process.  Development of drugs takes many years – that’s a fact of the processes and needed regulations.   But, financial considerations – read salaries, resources, and shareholders – require the process to complete in, at most, a couple of years.  The answer is to separate drug discovery and early development from the costs and resources of clinical development, manufacturing, marketing and sales. 

It should be a mandate that pharmaceutically-trained scientists and drug development managers be front and center in this new roadmap.  They are the only ones who have ever had to talk the talk and walk the walk.  Maybe Pharma needs to take a more active role here, forming their own independent discovery and training center(s), if nothing else, to embarrass
this high-foolishness being touted as the answer to the high cost of medicines.  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.

This new initiative must fail, in part because there’s no requirement to make it work.  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.  I’m sure the FDA will happy to approve the new medicines created by those who don’t have to take responsibility.