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.

Whiz kids are not a solution.

Pharma hires another academic whiz kid to head up neuropsychiatric drug discovery.  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.

What’s the appeal, and what’s the reality?

Pharma is led by business folk; it is a business after all.  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…  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.  In most businesses, new ideas become products in a couple of years.  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
anything in your overall stats.  Still, we drag in the new shooting star – who’s probably worked 15 years to build up
their own special knowledge and viewpoint in, say, basketball – and expect them to become .400 hitters in a year or two. 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.

I’m not totally surprised that business people turn to outside whiz kids to fix things.  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.  Heard repeatedly, it would be difficult not to view these ‘explanations’ as platitudes, excuses,
or a lack of expertise within the Neuroscience group.  

So, Pharma needs new idea guys (no gender implied), but what do they need to do?  We generally need new ideas related to classes of drug targets, how to assay their activity, and how to investigate disorders with unmet needs. 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
anyway.  Yet we put them in charge, managing activities that they are unfamiliar with, confusing everyone.  Instead, let’s have them take a sabbatical from their present, generally academic, position for two years.   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.  This keeps the engine running developing new therapeutics while it gives the whiz kid a well-defined transition process – slip back into their academic
position with some fabulous information/experience to dole out to their colleagues, or choose to stay within pharma.

Re: Desperately seeking solutions

The pharmaceutical industry is not producing new treatments fast enough.  Not fast enough to justify the hype around the long list of “omics”.  Not fast enough to continue as highly profitable companies. These headlines are
everywhere.  One immediate reaction to these headlines is to affirm that the pharmaceutical business is not a hype industry.  Ethical medicines do not meld well with ASAP.  However, this fact does not help us to improve and invigorate the pharmaceutical business.

Research and development of new treatments is a difficult business – and, indeed, is difficult as the basis of a business.  With the rapidly increasing number of potential drug targets, and our greater understanding of the numerous ways drugs can interact with their targets – competitive, noncompetitive, use-dependent,
allosteric, etc. – the search for the best new chemical entity becomes more involved, slowing the process even more than in previous years.

Basic research, generally the purview of academic and individual investigators, is necessary to uncover the new diamonds in the rough.  But, as noted by Sharon Begley & Mary Carmichael in their article in Newsweek,
academic researchers are not prepared, or rewarded, for the “time-consuming drudgery” required to take an idea into drug development. 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 Science Citation Index). 

Perhaps more troubling is the rush to fund translational studies in the clinical setting.  At present the vast majority of clinical studies are run through pharmaceutical companies, directly or via clinical contract research organizations (CRO’s).  A critical factor governing these studies is the palpable fear of being spotlighted for scrutiny by the FDA.  Beyond the standard approval process, FDA scrutiny can fatally delay a project, be very expensive, and produce negative publicity.  Companies, certainly those that have been in business a while, work very hard to ensure their protocols align with FDA guidelines.  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. 

Now, we are seeing a trend towards pushing more of the early clinical development work into medical centers.  The goal is to get more potential treatments examined and hopefully translated sooner into new and better therapeutics.  At face value, this trend seems reasonable since medical centers are often where clinical trials are carried out.  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.  And,
while medical center staffs (nurses, etc.) carry out the studies, they do so at the command of the funding pharmaceutical company.

Medical centers are still often run as feudal societies, nobility (read physicians and other lettered professionals) and staff (read serfs).  We give physicians a lot of leeway in treating patients because they may have to make life and death decisions.  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.  And, physicians are trained to expect their plans to be carried out.  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.  Given this polarity, it is difficult to imagine that there is not a tragedy in the making.

NIH’s CTSA centers and the ROADMAP in general are based on a no- repercussions philosophy, one that permeates medical centers and universities.  However, they are moving that into the realm of public safety.  It is clearly true that changes are critically needed to enhance the flow of good, novel therapeutics into the public health sector.  However, it is only pharmaceutical companies that have the experience, skills, and mindset (“fear of the FDA”) to carry this out.  I believe that NIH should be working to set up pharmaceutically-guided research institutes, not presuming that inexperienced (but really smart…) non-pharmaceutical investigators can pick up that role.  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.

Managing new discoveries

Managing new discoveries.

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.   As discussed in my last (first!) blog, the lack
of information about reproducibility is a huge problem for anyone needing to prioritize new ideas for follow up.

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.  These gentlepeople scientists often hired a person to manage the daily research operations of the lab.  And often this lab research manager was to become the next shining light in scientific research.   This type of manager position could be one solution to our present problem of substantiating new discoveries.  However, very few labs today have the luxury of such a hands-on research manager.  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.  Finding the lab’s leader requires scheduling meetings even just to talk; only rarely to actually help learning techniques.

Postdocs try their hands at a number of different techniques – funding agencies don’t favor one-technique wonders –

and publish a series of papers giving them enough material for a good interview presentation.  They are then thrown into an assistant professor position for which they generally aren’t ready.  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.  Larger labs may even have more than one to provide skill and experience with disparate techniques within the lab.  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).  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.  They would also guide/manage grad students and postdocs, including helping them learn techniques from the lab manager.  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.  They would learn how to manage obtaining supplies for the lab.  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.  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.

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.  It also ensures smooth, continued research progress for the lab chief.  Brilliant scientists are too often called or lured away to administrative positions leaving their labs to languish.  With
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. 

Translationing new ideas into novel drugs

Re: The Importance of New Companies for Drug Discovery:”

A recent report published in Nature finds that a majority of novel drugs are the result of research at universities and new biotechs.  This is good news, showing that the system is working.  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.  The only problem with this finding is that this isn’t the problem.  It is critical that universities continue to receive sufficient funding to allow for a broad range of new ideas to be followed up.  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.  In fact, the volume is overwhelming!  And what makes this a particularly acute problem is the minimal depth of information available about these new ideas and novel targets.  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.

The byword in the drug discovery and development business is robustness, specifically reproducibility.  Unfortunately reproducing research findings is almost a curse for academic and many biotech investigators.  A graduate student or postdoc who has gotten some new exciting data doesn’t immediately set up to run the experiment again.  What they do is run to publish it, and also to use some additional technique to approach the same question.  Of course, it is important to make data public, and as soon as reasonable.  It is important for graduate students and postdocs to gain working knowledge and experience with multiple techniques.  But often, very often, the original data cannot be easily reproduced.  Often, there are unrecognized experimental conditions or details that render reproduction tedious at best.  And yet, without reproducibility there can be no drug discovery project.  The FDA, at least, frowns on results that were only observed once.

And yet, it isn’t the perceived role of the basic science investigator to demonstrate exactly how to reproduce their results.  This is left to other investigators in other labs who may want to follow up on the original exciting results.  The primary job of the discoverer, the explorer, is to instigate new studies.  Responsibility for getting things right is not a part of basic science.  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.  No, I don’t mean they can make results up. But, their perceived role is to publicize new data, new ideas, and new hypotheses;  not to show that they can get the same result over and over again.

Unfortunately this leaves pharmaceutical/translational scientists in a lurch.  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.  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.  This took a lot of my time, took it away from ongoing discovery projects, and certainly made no friends among the academic stars.

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.  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.  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.  Assays must be consistent in the results they give and they need to be sensitive to specific challenges – gold standard compounds, for example.  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.  Or there needs to be a translational institute that focuses on reproducing results.  Nothing less should be acceptable.

So, how do pharmaceutical companies decide what new ideas to follow up on.  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.  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.

A new type of research organization needs to come into existence.  At one time, pharmaceutical companies with “money to burn” could allow research departments to take a lot of chances on new ideas.  Those days are gone.  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.  Being funded by multiple entities would reduce the financial risk for all.  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.   Anyone who has been in the pharma business more than five years knows this argument is a crock…   Companies want to work on ideas they believe others also see as valuable – robust.   Value comes from the unique properties of specific compounds each company finds.  And, companies have different strengths, in biology and chemistry, and so each project will really only appeal to a fairly small number of companies.