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

Related Posts

• Wo(Man) & Machine

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.