The Departure of the Cranes

“Today, the solitary inventor, tinkering in his shop, has been overshadowed by task forces of scientists in laboratories and testing fields. In the same fashion, the free university, historically the fountainhead of free ideas and scientific discovery, has experienced a revolution in the conduct of research. Partly because of the huge costs involved, a government contract becomes virtually a substitute for intellectual curiosity. For every old blackboard there are now hundreds of new electronic computers. The prospect of domination of the nation’s scholars by Federal employment, project allocations, and the power of money is ever present — and is gravely to be regarded.” President Dwight D. Eisenhower in his 1961 farewell address (added 01/17/2011).

Grus grus.

I used to live near a region that was once known for its cranes (Grus grus). They were so abundant that the region took its name from them, and the lords who ruled this land adopted them as central theme in their coat of arms which today adorns the local pottery. The landscape is bucolic. Small villages and towns dot green rolling foothills rising toward distant altitude above the timberline. Modernity and history are interwoven here in natural growth. Below the picturesque castle of the ancient lords and attached medival town, the visitor may be surprised to find the facilities of a contemporary college with American accreditation.

The cranes have become a rare sight today and the region is better known for its cheese. Only the patient may notice a lonesome bird early in the morning standing tall and motionless in the shallow water near the reedy banks of a quiet pond. Over time, the observant develops a keen eye for these graceful creatures and may be able to spot them on occasion in passing from the window of a commuter train carrying people off to work. I have not been on that train in two decades. But according to the most recent check list, the cranes are still about.

The pottery.

Ever since I left that land, I have become familiar with a different kind of crane on my visits to academic institutions in this country. You can spot them easily from afar. These cranes are usually clustered around tall stately buildings under construction. In the past eight years, endowment portfolios at private research universities and medical schools accrued with solid gains. Intense fund raising swelled donations. Credit for new construction was cheap. The institutions embarked on a building spree.

A number of these edifices with facades of blue glass, white columns and brown stone tile are going to house academic medical centers. With the aging of the baby boomers, the demand on health care will amplify profoundly. According to the Health Work Force Institute, 2.5 million registered nurses will be needed in 2020. At present, new degree programs in affiliated health sciences are being created in great numbers across the U.S. In my area, nursing schools have doubled in two years. Local universities as Belmont University are expanding their health science programs. Doubtlessly, new health care facilities are necessary.

On the other end of the spectrum, I saw many construction projects that were slated for biomedical research laboratories. Despite the current funding crunch that I discussed in my post dated Oct. 1, universities and medical schools look fondly upon biomedical research because of its prestige and the money that it attracts. Research grants from federal agencies do not only cover laboratory supplies and equipment, but also a significant portion of faculty and staff salaries. That is why, medical schools can afford to maintain large faculties in excess of the demand of clinical service. For example, I counted 81 faculty members in Neurology at the University of Pennsylvania.

In addition to the direct cost for research, the federal agencies provide host institutions with a percentage of direct cost to help defray overhead expenses for infrastructure, administration and basic services like utilities and plant operations. The indirect cost recovery rate is negotiated with each institution. For example, the rate of the University of Pennsylvania was 59.5 percent in 1999, but could be 100 percent and more in other cases. Some institutions charged overhead excessively, were audited, and eventually fined (Federation of American Scientists Report #91095). The system was revised. Administrative cost was capped at 11 percent.

Overhead recovery rates that are representative for the country at present are hard to find. The University of Michigan currently recovers 54.5 percent. At a presumed rate of 60 percent, a medical school that attracts about 200 million dollars in direct cost for specific research from federal agencies annually (not an unheard-of amount), will receive another 120 million unspecified dollars for indirect cost recovery. This sum would approximately cover the investment for a new five-story research building. The more square feet of laboratory space a university adds, the more investigators can pursue federally funded research, the greater the returns for the institution, inviting yet another clone of a research building. I believe that this chain reaction fueled the current construction boom, boding ill for the future. The cranes may disappear soon.

First, federal funding for biomedical research has been eroding over the past 10 years in the face of a steadily rising number of applications. According to the National Institutes of Health Office of Extramural Research, the grand total average success rate of grant applications fell from 34.2 percent in 1997 to 24.4 percent in 2007 (see success rate table at NIH funding).

In addition, the investment portfolios of endowed research institutions shrank catastrophically in recent weeks and credit has all but dried up. American private universities are commercial enterprises. In his congressional hearing, the former CEO of Lehman Brothers, Richard Fuld, named the exposure to commercial mortgages as the prime cause of his bank's downfall. National Public Radio's All Things Considered broadcast this snippet of his testimony entitled "Lehman CEO Testies On Capitol Hill" on Oct. 6.

On top, private universities are linked into astronomical increases in college tuition and fees. According to Tamar Lewin's in The New York Times on Oct. 29 with the title "Downturn Expected to Drive Tuition up", tuition and fees are about to exceed $50,000.- per academic year for some institutions, forcing them to offer substantial financial aid to attract academically qualified students. If the portfolios of these universities do not recover soon, some may find themselves unable to service their debt.

When you are looking for a college these days, you may wish to read my post dated Jan. 24, 2008, and re-assure yourself that there are not too many cranes on campus.

Addenda

• Tamar Lewin filed a second report report on this issue with the title "Tough Times Strain Colleges Rich and Poor" in The New York Times today. It is quite consistent with the observations above (11/08/08).
• Charles Bagli aptly describes in his report with the title " As Vacant Office Space Grows, So Does Lenders' Crisis" in The New York Times today, the problems afflicting commercial mortgages that Mr. Fuld regretfully recognized in retrospect as lethal to his bank (01/04/09).
• Reuters Health and Science Editor Maggie Fox reported in her post with the title "U.S. hospital profits fall to zero: Thompson Reuters" today that, according to a recent Thomson Reuters Healthcare survey of more than 400 profit and non-profit U.S. hospitals, the examined institutions were not able to generate surplus revenue for new infrastructure expenditures already in the third quarter of 2008. Because of losses in investment portfolio and slowed medical insurance reimbursements, half of the hospitals were operating at loss. The study was discussed in Janet Babin's segment on National Public Radio's Marketplace with the title "Hospitals ailing with financial stress" on the same day (03/02/09).
• I just finished my walk around the campus of Vanderbilt University and counted among the university-owned real estate projects completed since my arrival in 1994: four complexes housing offices, hotels and/or retail, four apartment complexes, eight large multi-storied parking garages,  four large dormitories on a commons, three student centers, a baseball stadium, a totally refurbished football stadium, six large and three small research buildings, a new wing for the School of Engineering, a new School of Music, a new School of Law, a new School of Business, a new School of Nursing, two large and one small hospital buildings, plus one large outpatient clinic just completed. I neither counted major renovation projects, nor may my list be complete. The total of the investment may roughly amount to as much as 2.4 billion dollars. That is, the university spent the equivalent of its entire current endowment on the expansion of infrastructure (03/29/2009).
• National Public Radio's Market Place broadcast an interview of Kai Ryssdal with Chronicle of Higher Education reporter Paul Basken entitled "Stimulus creates application avalanche" today on the implications of this year's 10.4 billion dollar stimulus for the National Institutes of Health (NIH) to fund scientific research at academic institutions. About 115,000 grant applications were filed with the NIH so far this year, constituting a 1.5-fold increase over last year's 77,000. About 21,000 grant applications directly targeted the stimulus funds (06/09/09).
• Today Gina Kolata reports in her article for The New York Times entitled "Playing it Safe in Cancer Research" that the NIH may be able to fund roughly one percent of the applications for economic stimulus-financed grants known as challenge grants (06/27/09).
• As an example in support of my own impressions, Richmond Times Dispatch writer Karin Kapsidelis reports in her article with the title "Rising cost at Virginia’s universities mostly unrelated to instruction, study says" published online Jun 10, 2013, by the Daily Progress that Virginia public research universities have increased infrastructure spending over the past two decade, while investment in instruction declined (06/15/2013).

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Research Funding & Lost Treasures of the Mind

The Nobel Prize in Chemistry 2008 was awarded to Osamu Shimura, Roger Tsien and Martin Chalfie for the development of the use of green fluorescent protein as a genetic marker in molecular biology (see Kenneth Chang's article entitled "Three Chemists Win Nobel Prize" dated Oct. 8, 2008). The announcement brought about a peculiar revelation. The researcher who first sequenced and cloned the gene for the protein, Dr. Douglas Prasher, was not included in the prize. Dr. Prasher is battling depression and has left science. National Public Radio's Morning Edition broadcast an interview with Dr. Prasher by Dan Charles in a segment entitled "Glowing Gene's Discoverer left Out Of Nobel Prize" on Oct. 9. Kenneth Chang published an article entitled "Man Who Set Stage for a Nobel Now Lives a Life Outside Science" about him in The New York Times on Oct. 16.  Tara Parker-Pope took up the issue to discuss the impact of depression on our lives and careers in her column Well in The New York Times on Oct. 21. Her post entitled "Depression and the Nobel Prize" has received more than 150 comments.

The decisions of the Swedish Royal Academy of Sciences on who shall win the Nobel Prize have been rarely discussed in public. Deserved scientists have been left out in the past. Lise Meitner who conducted the first experiments demonstrating nuclear fission in Otto Hahn's laboratory is a famous example.

Skimming through the comments on Well, I noticed that there were about as many entries lamenting the insufficient support for scientific research in the U.S. as there are about ways to fight depression. Doubtlessly, the constant struggle for funding in scientific research in this country may easily overwhelm the mind, diverting precious energy and time from the experiments the researcher set out to do. Funding and outcome are mutually intertwined in a vicious cycle. Without results there will be no funding, and vice versa. Was it predisposition that led to Dr. Prasher's depression? Was it the stress of his work? Most likely both played a part.

I can affirm more assertively the precarious situation of research funding in this country. Wherever American scientists convene around a table these days, the discussion quickly veers from research to funding. As a result of half a century of monetary infusion from Federal agencies and the encouragement to include increasing percentages of salary in the grants, private American academic institutions depend mainly on these funds to survive today, reducing themselves to mere subcontractors of the government.

In the past eight years, this support has been eroding. As I reported in my post dated Oct. 1, the largest Federal funding agency for biomedical research in this country, the National Institutes of Health, currently funds less than 1 in 5 research proposals. Such stiff competition for scarce resources inevitably favors the applicants who are invited to sit on the study sections where applications of other colleagues are appraised. The very junior and very senior applicants are disadvantaged most in the decision process. First-time applicants do not have the credentials yet to qualify. The judgment on the quality of their research mainly relies on the reputation of the hosting institution. The chances of success are greatly enhanced, if this institution is among the top ten of US News & World Report's ranking of colleges and medical schools. The very senior applicants are more prone to fail with time because their supporters wither. 

In spite of the crunch, academic institutions do not compensate their scientists extravagantly for their efforts to attract Federal money. I recently attended a commemorative symposium. The chancellor of the university and the dean of the medical school gave opening remarks, followed by four internationally renowned scientists speaking about cutting edge research. One was Scientific Director of a National Institute of Health, another was Chairman of a Department at an Ivy League School. The other two held similarly senior positions. While I was listening to their presentations, the thought struck me that their salaries combined amounted to less than half of the income of the first two speakers. I concurred with the brightest undergraduate students I took care of that attending medical school was a smart choice. One is currently in residency training for Neurology at a school with a good reputation and still may become a scientist.

I believe that the struggle for funding in a ferocious climate unsupportive of fundamental research helped precipitate Dr. Prasher's depression. I wish him well and hope that he soon finds an occupation he is passionate about. In my opinion, he deserves a share in the Prize for his contribution.

Addendum

• Beryl Lieff Benderly provides an interesting point of view on science as a career in today's U.S. in her cover story with the title "The Real Science Gap" posted online Jun. 14, 2010, for Miller-McCune (11/02/10).

Brain-Machine Interfaces & Brain Plasticity

On Oct. 16, 2008, Julie Steenhuysen filed a report for Reuters entitled "Device helps monkeys move paralyzed wrists" describing a recent break through in fundamental research on brain-machine interfaces that considerably broadens avenues for the prosthetic control of limb movement. The findings are published in the journal Nature (Moritz and others, 2008). National Public Radio's Morning Edition provided an interview by Dan Charles entitled "Monkey Studies Could Help Paralyzed Humans" with the first author of the study. I have written about such interfaces in my post dated Jan 23, 2008.

The researchers at the University of Washington temporarily numbed nerves controlling arm movement in monkeys. Fine electrical leads were implanted into the area of cerebral cortex that controls limb movement known as motor cortex. The leads were used to record the electrical signals that nerve cells use to control skeletal muscle contraction. The signals were amplified, electronically transformed and fed into wire electrodes implanted into the muscles of the numbed arm. The monkeys learned to execute goal-directed movements with this limb. The results constitute a mile stone proving both the applicability of the electronic interface and the versatility of the motor system to utilize the new extraordinary tool in a meaningful fashion.

The nerve cells in our central nervous system that innervate the skeletal musculature are known as motor neurons. When peripheral nerve injury severs their axons, that is the nerve fibers that establish the connections with the muscle fibers, motor neurons can regenerate the disrupted connections. During this period, the cells are subjected to remarkable alterations. A glial reaction ensues in their vicinity. In my own experience, strong signs of the glial response can be detected on histological tissue sections within four days after nerve injury. The signs are visible on this micrograph from a transverse section through the brain stem of a rat.

microglia, courtesy of J.A. McKanna

The hypoglossal nerve, that is the twelfth cranial nerve innervating the muscles of the tongue, was damaged on the right side (left in the micrograph). The bodies of nerve cells are stained blue in the micrograph. Microglia are stained black. The cell bodies of the axotomized motor neurons (asterisk) are located left of the center of the section in an area called hypoglossal nucleus. Microglia (arrowhead) are gathered in great number among the axotomized motor neurons and wrap themselves around their bodies (arrow), detaching incoming nerve contacts known as synapses that convey command and control for muscle contraction from the fore brain. The motor neurons undergo chromatolysis and increase protein synthesis. David Bodian described the cellular changes using electron microscopy in great detail in the Johns Hopkins Hospital Bulletin (Bodian, 1964). Blinzinger and Kreutzberg (1968) were the first to identify the cells that insert themselves between the motor neuron and the synapses as microglia. After roughly two months the glial reaction ceases, the synapses re-attach to the cell bodies, and the motor neurons regain much of their original appearance. Major histo-compatibility complexes have been identified as one major group of signal molecules that control the observed glial and motor neuron responses to axotomy (Oliveira and others, 2004).

The ability of motor neurons to re-establish disrupted muscle innervation is a fascinating example of our brain's ability to recover from injury. However, it is important to note that the repair is imperfect. The novel innervation commonly remains below original strength and the endings of the motor neurons may not succeed in finding their original muscle fibers (Madaschi and others, 2003). Intriguingly, the nerve cells in the central nervous system are able to adjust to the altered peripheral innervation. Sprouting of novel connections has been proposed as mechanism (Fujito and Aoki, 2002). In fact, the plasticity of the motor system is so great that animals reportedly learn meaningful limb movements even after the surgical cross of nerves controlling antagonistic muscles [Sperry, 1941 (reviewed by Todman, 2008)].

Taking this enormous flexibility of the motor system into consideration, the directed arm movements of the interfaced monkeys Moritz and others (2008) observed may not entirely come as a surprise. Doubtlessly, the technology to transform the nerve cell signals recorded in the cerebral motor cortex into meaningful stimuli for the arm muscles is a daunting achievement. However, it is important to emphasize that the success of this method ultimately relies upon the nerve cells that alter their electrical discharges in order to produce the desired movement. As pointed out on the National Public Radio broadcast, the fascinating discovery is the rapidity with which the nerve cells learn to direct a movement under extraordinary experimental conditions. The question remains to be answered whether special cells or a special ensemble of cells is needed to produce fine-grain limb control.

Addendum

• On Feb. 10, 2009, Pam Belluck reported in her post entitled "In New Procedure, Artificial Arm Listens to Brain" for The New York Times on a promising variation of this idea published in The Journal of the American Medical Association (JAMA 301(6):619-628). With the new procedure, Kuiken and others (2009) planted wire electrodes over functional muscle groups that a patient with a lost limb can control. The electrical nerve signals recorded from the electrodes when the patient is using the underlying muscles are subsequently employed to steer a prosthesis replacing the missing limb. With practice, the patients learn to substitute the contractions of the intact muscles with prosthetic limb movements to the extent that they feel the limb manipulated when the skin over the muscles is touched (02/11/2009).

References

• Blinzinger K, Kreutzberg G (1968) Displacement of synaptic terminals from regenerating motoneurons by microglial cells. Cell Tissue Res 85: 145-157.
• Bodian D (1964) An electron-microscopic study of the monkey spinal cord. I. Fine structure of normal motor column. II. Effects of retrograde chromatolysis. III. Cytological effects of mild and virulent poliovirus infection. Bull Johns Hopkins Hosp 114: 13-119.
• Fujito Y, Aoki M (2002) Distal forelimb cross-innervation effectively induces formation of corticorubral synapses. Neuroreport 13: 2121-2124.
• Kuiken TA, Li G, Lock BA, Lipschutz RD, Miller LA, Stubblefield KA, Englehart KB (2009) Targeted muscle reinnervation for real-time myoelectric control of multifunction artificial arms. JAMA 301: 619-628.
• Madaschi L, Di Giulio AM, Gorio A (2003) Muscle Reinnervation and IGF-I Synthesis Are Affected by Exposure to Heparin: An Effect Partially Antagonized by Anti-Growth Hormone-Releasing Hormone. Neurochem Res 28: 163-168.
• Moritz CT, Perlmutter SI, Fetz, EE (2008) Direct control of paralysed muscles by cortical neurons. Nature 456: 639-642.
• Oliveira AL, Thams S, Lidman O, Piehl F, Hökfelt T, Kärre K, Lindå H, Cullheim S (2008) A role for MHC class I molecules in synaptic plasticity and regeneration of neurons after axotomy. Proc Natl Acad Sci U S A 101: 17843-17848.
• Sperry RW (1941) The effect of crossing antagonistic muscles in the hind limb of the rat. J Comp Neurol, 75: 1-19.
• Todman, D (2008) History of Neuroscience: Roger Sperry (1913-1994), IBRO History of Neuroscience

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Gingko & Stroke

Today, Oct. 10, 2008, Tara Parker-Pope informs us in a post under her New York Times health column Well on recent research suggesting that Ginkgo tree extracts may reduce brain damage after stroke. The study is published in the journal Stroke. The researchers affiliated with Johns-Hopkins University and La Fondation Ipsen temporarily blocked the middle cerebral artery in mice to induce an ischemic stroke. In mice treated with Ginkgo extract, the volume of brain tissue affected by the stroke was only about half that observed in untreated mice. The extract had no effect in mice that lacked heme oxygenase 1, an enzyme known to reduce oxidative stress caused by free radicals. These findings may encourage further basic research, ultimately opening a path for future pre-clinical and clinical trials.

I developed a liking for Ginkgo trees ever since I saw my first one on a high school visit to Heidelberg. The tree stood in the park outside the castle, solemnly holding its own one of a kind. They are not native to Germany. A lord long gone had purchased a seedling from China and planted it as a curiosity.

Ginkgo biloba is a species of ancient plants. Herbivorous dinosaurs already dieted on their broad leaves. The leaves are misleading. The trees are more closely related to conifers than to broad-leafed trees. Ginkgos are abundant in the Southeastern United States where I live. The leaves add a wonderful bright yellow to the panoply of foliage colors in the fall.

The leaves' peculiar shape caught the eye of the eminent German poet scientist J.W. von Goethe two centuries ago. Eternalized in a remarkable poem, Goethe calls to our attention the fact that the observer cannot tell from the leaves' shape whether they constitute one leaf split into two or two leaves fused into one. I quote "...Eins und doppelt bin."

This notion of ambiguity applies immediately to the discussed stroke research. As long as we do not know precisely which substances in the Ginkgo extract affect the ischemic brain tissue and what underlying molecular mechanisms reduce the impact of the stroke, medication with Ginkgo extracts is ill-advised. Particular prudence should be exercised, because the extracts are known to diminish blood clotting, exposing patients on blood thinners to additional risk.

Free Will Exists

Helen Musyoka (1:01'10",2) and John Mwangangi (52'08",2) both from Kenya, won the 75^th race from Morat to Fribourg, Switzerland, last Sunday. The distance is 10.48 miles. The race commemorates a mile stone in the struggle for self-determination. Read more here. Free will exists!

P.S: I still run regularly, inspired by the encouragement of loved ones, "The Penguin",and Joschka Fischer's book.I saw him often playing soccer in a park on Saturdays while returning from my duties as a bat warden at the Institute of Zoology. These days I am running on Spiras.

Social Data Mining: Misperceptions of the Mind

Demographic data mining is a recent enterprise in social networking on the internet and appears to be still in its infancy. Social web sites commonly ask the user to create a profile to help them find friends, that is the like-minded they wish to communicate with. The collected personal information is used to define the users' context of life and attempt to match it against that of other users. In my experience, the most widely-applied data mining strategies quarry only the simplest information, e.g. residence, school or employer, and only the most fundamental personal characteristics are examined. That is, age, gender and marital status are used to draw conclusions about the interests and preferences of the profiled.

In addition to providing matches for users, these data are used to steer advertisements to the users' web pages that inform on products and services they may be interested in. This seems only fair, because the service on the web site is provided free of charge. However, the conclusions drawn from the users' profile seem at times unrefined and presumptuous, painting a startling image of the average person.

I am 53, male and married. I provide these demographics in my profiles. On my page on one popular social network site, I recently found advertisements of services entitled "Dating for Seniors" and "Meet Married Women in your Neighborhood". Welcome to the real world? A look at my profile however suggests that I am not a likely consumer of these services. Such misguided targeting may only convince users to develop avartars, i.e. virtual cyberspace personalities, bearing little resemblance with their actual lives. Credibility suffers, while professional advertising agencies must be interested in finding true clients for their customers. Obviously, there is ample space for improvement. Until more suitable targeting has been developed, we must tolerate these inconveniences with a . They are minor compared with the great opportunities social sites offers.

Fundamental Research & Fragile X Syndrome

On Sep. 23, 2008, National Public Radio's Morning Edition aired a report on progress in research on Fragile X syndrome or FXS for short. You may listen to the podcast here. In FXS, the gene Fmr1 is not expressed in nerve cells. This gene encodes a messenger RNA-binding repressor protein known as fragile X mental retardation protein, or FMRP for short. The protein hinders the translation of the genetic code into protein in protein synthesis. Recent studies in the laboratory of Mark Bear, director of the Picower Institute at M.I.T., suggest that a specific type of receptor for the excitatory neurotransmitter glutamate plays a crucial role in the synthesis of FMRP. Neurotransmitters are molecules that convey information from one nerve cell to another across the synaptic cleft. The synapse constitutes the contact between the nerve cells. Glutamate and its receptors are instrumental in the strengthening of synapses. 

Mark Bear is fundamentally interested in the development of the cerebral cortex. As I summarized in my post dated Aug. 14, 2008, the strengthening of glutamatergic synapses is understood today as the basic mechanism underlying brain plasticity, learning and memory. The stabilization of synapses profoundly affects cortical development. Perturbation of synaptic growth and pruning is suspected to be involved in the development of mental disorders like autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), and manic depression.

I met Mark and his family for the first time when I was visiting Wolf Singer's laboratory at the Max-Planck-Institute for Brain Research where Mark was staying as a postdoctoral fellow. The Max-Planck Society funds 80 research establishments covering a broad range of topics from art, law and anthropology to biology, medicine, chemistry, material sciences and physics. The MPI for Brain Research comprised three laboratories at the time. The facilities were located in a cluster of brick-tiled buildings on the opposite bank of the Main in Frankfurt.

Mark proudly drove a very used green BMW 2000Ti and lived with wife and daughter in a small apartment in the western suburb of Schwanheim across the river from a huge chemical plant. Frankfurt's air quality was not as good as today. The river's water was pitch black. A subsidiary of the conglomerate Hoechst AG, Messer Griesheim, was still in full operation. On rainy days the air smelled like in Philadelphia when you pass the refineries.

I remember vividly one occasion on which Mark tried hard with little success to convince his Frankfurter colleagues of the refined taste of the All-American soul food: peanut butter-and-jelly sandwiches. His wife had prepared plates piled high with more than enough for everybody. Not unlike Frankfurt's Aeppelwoi, peanut butter-and-jelly sandwiches are an acquired taste. Only those who have raised children on them will fully appreciate the profound usefulness and true satisfaction they deliver.

By contrast, Mark's work with Wolf Singer and colleagues was a convincing success. The team showed with elegant experiments published in the journals Nature (Bear and Singer, 1986) and Science (Kleinschmidt and others, 1987) and Nature that glutamate and the neuromodulators acetyl choline and norepinephrine play fundamental roles in the plasticity of domains of ocular dominance in visual cortex during postnatal development. The discovery of ocular dominance plasticity had won D.H. Hubel and T.N. Wiesel the Nobel Prize half a dozen years earlier (Hubel and Wiesel, 1998).

After his return to the U.S., Mark continued to investigate the role of glutamate in the organization of nerve cell circuits in cerebral cortex. In a long series of studies, he and his colleagues examined long-term potentiation (LTP) and long-term depression (LTD) as mechanisms for cortical plasticity. The elucidation of the underlying molecular mechanisms led to the G-protein-coupled metabotropic glutamate receptor mGluR5. By contrast to ionotropic receptors that regulate ion fluxes across cellular membranes important to electrical nerve cell signaling, metabotropic receptors regulate cell protein activity and homeostasis. The mGluR5-receptor appears to play a major role in FXS and autism. I have written about this in my post dated April 1, 2008. Designing antagonists against the receptor's actions promises a treatment. Mark points out in his interview with NPR that he was not planning on finding a cure for mental disorders. Things came together serendipitously. It was only with the support and encouragement of the Fragile X Research Foundation (FRAXA) that the work on a potential treatment began.

The National Institutes of Health (NIH) provide most funding for biomedical research in the U.S. Measured in inflation-adjusted dollars, the NIH have seen their budget erode in the past 8 years. By contrast, the number of applications for research grants has doubled. As consequence according to the NIH online report, the success rate of competitive grant applications diminished from 32 percent in fiscal year (FY) 2000 to 21 percent in FY 2007. The NIH were able to award about 41 percent of the total cost to new investigator-initiated applications (R01). These are proposals for projects that scientists submit based on their most recent findings. They advance the most innovative ideas and are most likely to lead to new discoveries. The success rate of R01 applications decreased to 19 percent in FY 2007 from 26 percent in FY 2000. The mounting budgetary constraints inevitably result in increasingly conservative funding decisions. Under these circumstances, it is not surprising that Mark Bear and his colleagues sought funding outside government for their novel ideas.

Addenda

• First federal funds for research dry up. Now nonprofit private support evaporates. Read here (12/21/08).
• Brain plasticity and memory share similar underlying molecular mechanisms. Recent studies have provided evidence that the brain-specific protein-phosphorylating enzyme protein kinase Mzeta (PKMzeta) is necessary to sustain LTP (Sacktor, 2008). Such enzymes commonly upregulate the activity of other enzymes. An increase in enzyme activity resulted in the doubling of postsynaptic glutamatergic ionotropic AMPA receptors, augmenting synaptic transmission in rodents. Inhibiting PKMzeta disrupts long-term memory (Serrano and others, 2008). Benedict Carey published an article entitled "Brain Researchers Open Doors to Editing Memory" in The New York Times on this research and its potential implications for future medical treatments today (04/05/08).
• According to Lauran Neergaard's report for Associated Press with the title "Experiment Takes Aim at Genetic Learning Disorder" published online in The New York Times today, the first clinical trials to treat FXS in adults with mGluR5 antagonists are underway at five medical centers (02/01/10).
• According to Gardiner Harris' report with the title "Promise Seen in Drug for Retardation Syndrome" for the New York Times dated Apr. 29, 2010, Novartis completed its first double blind study using its mGluR5 drug on adults with FXS with encouraging results. Details of the study were not disclosed (05/01/10).
• In her report with the title "Special Report: new drugs, fresh hope for autism patients" published online on Reuters today, Julie Steenhuysen informs us how the search for new drugs to treat FXS and ASD has been shaping up. The article's focus is on the use of derivatives of the established psychoactive compound baclofen. Seaside Therapeutics Inc., co-founded by Mark Bear, is testing arbaclofen (STX209) in clinical trials. The compound acts as an agonist of the inhibitory neurotransmitter gamma-aminobutyric acid, or GABA for short. Baclofen binds to G-protein-coupled metabotropic GABA_B-receptors and has traditionally been used to relieve skeletal muscle spasms. In contrast to the compounds acting on mGluR5-receptors discussed in the post, this drug modulates the effects of glutamate indirectly (Fejgin and others, 2009). Considering that more than 100 genes have been identified to play a role in autism, Dr. Edwin Cook's claim in Julie Steenhuysen's report that “many of the genes related to autism are right in the same pathway that has been implicated and worked out in Fragile X” does not come as a surprise (05/31/2012).
• Two studies of note have been published online in Science Translational Medicine yesterday. Henderson and others (2012) showed in a fragile X mouse model, that The GABA_B-receptor agonist arbaclofen alleviated known biochemical (basal protein synthesis), molecular (AMPA-receptor internalization), and cellular (dendritic spine density) manifestations of the disorder. In addition, Barry-Kravis and others (2012) report first encouraging results for arbaclofen in phase II clinical trials. The drug seems to improve social function (09/20/2012).

References

• Bear MF, Singer W (1986) Modulation of visual cortical plasticity by acetylcholine and noradrenaline. Nature 320: 172-176.
• Berry-Kravis EM, Hessl D, Rathmell B, Zarevics P, Cherubini M, Walton-Bowen K, Mu Y, Nguyen DV, Gonzalez-Heydrich J, Wang PP, Carpenter RL, Bear MF, Hagerman RF (2012) Effects of STX209 (Arbaclofen) on Neurobehavioral Function in Children and Adults with Fragile X Syndrome: A Randomized, Controlled, Phase 2 Trial. Sci. Transl. Med. 4, 152ra127.
• Fejgin K, Erik Pålsson E, Wass C, Finnerty N, Lowry J, Klame D (2009) Prefrontal GABA_B Receptor Activation Attenuates Phencyclidine-Induced Impairments of Prepulse Inhibition: Involvement of Nitric Oxide. Neuropsychopharmacol 34: 1673–1684.
• Henderson C, Wijetunge L, Kinoshita MN, Shumway M, Hammond RS, Postma FR, Brynczka C, Rush R, Thomas A, Paylor R, Warren ST, Vanderklish PW, Kind PC, Carpenter RL, Bear MF, Healy AM (2012) Reversal of Disease-Related Pathologies in the Fragile X Mouse Model by Selective Activation of GABA_B Receptors with Arbaclofen. Sci. Transl. Med. 4, 152ra128.
• Hubel DH, Wiesel TN (1998) Early Exploration of the Visual Cortex. Neuron 20: 401-412.
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