Monthly Archives: April 2012

The Golden Goose Awards

Politicians sometimes deride research based on the what they perceive as being “silly” titles of federal funded grants.  If they spot a title that deals with “games”, for example, they may assume it deals with some sort of amusement of little value to society, instead of a deep, powerful branch of mathematics that describes the behavior of competing rational agents with much relevance to voting, economics, cooperation, and so on.  Animal rights activists also enjoy the hobby.  The latest example is IDA’s list of “ridiculous research” ,whose claims were sadly repeated by far too many news journalists who were clearly too lazy check if they were accurate.  There were some honorable exceptions, notably an excellent editorial entitled “When the facts ruin a good spin” in the Times Union, which discusses a project on the role of music as a conditioning stimulus for drug use ends with a statement with which we heartily agree:

What’s “ridiculous,” to borrow the press release’s language, is that we fall for it, over and over, egged on by politicians eager to score easy points. And what’s “wasteful” is the time and energy that could be so much better spent on something other than a cheap shot.”

Back in 1976 the House Committee on Appropriations asked the National Science Foundation “Why does the Foundation persist in supporting research whose results have no apparent value to the American people?”  The NSF responded in part that:

Basic research seeks an understanding  of the laws of nature  without  initial  regard  for specific  utilitarian  value. Ultimately, however, it  is of the  most important  practical significance, because in a broad sense it is the foundation upon  which rests  all technological development.  Applied research builds on the results of basic research, seeking detailed  information  about  a specific situation  whose general laws have  been  discovered by  basic  research.  The  final step  toward  utilization  of research-development is  the systematic  application  of knowledge to  the  design  of  end products. […]

As we  increase  our  knowledge  of nature  and  mankind,  in order  to adjust  nature  to our survival, safety,  comfort and convenience, we must  depend  upon  scientific research  to clarify the  relationships  of many, many things.  Thus,  we study  atoms,  even  though  they  will never  be seen  by an  unaided  human  eye.  We study  stars  too  faint  to  be  seen without  a  telescope  and  with  wavelengths  which  can  only be  detected  with  radio  receivers  or  photographic  plates. To  understand  geology, we must  look  at  geologic formations  and processes in many  parts  of the world where different  conditions have existed.  To understand  more about the  phenomena  of life, we must  study  the  behavior  of viruses,  single  cells,  plants,  and  animals  of  many  species.

A book was compiled covering various areas of research with Isaac Asimov writing an essay defending the value of basic research.

Thus, it was with some surprise and delight that we read in the news about Rep. Jim Cooper (D-Tenn) understanding the value of basic research.  The Washington Post reports that:

On Wednesday afternoon, Cooper rose to the defense of taxpayer-funded research into dog urine, guinea pig eardrums and, yes, the reproductive habits of the parasitic flies known as screwworms–all federally supported studies that have inspired major scientific breakthroughs.

Together with two colleagues he created the Annual Golden Goose Awards to honor federally funded research  “whose work may once have been viewed as unusual, odd, or obscure, but has produced important discoveries benefiting society in significant ways.”

Studying dog urine, among other stuff deem crazy by animal rights cranks, led to major medical discoveries

The article goes on to describe how research on dog urine led to an understanding of the effects of hormones on the human kidney, how studies in the guinea pig led to a treatment for hearing loss in infants, and how studies on the screwworm led to the effective control of the a deadly parasite that targets cattle.  All these provide additional examples refuting the notion that learning about life processes from animals cannot yield knowledge applicable to human health.

The Golden Goose Award has the backing of the American Association for the Advancement of ScienceAssociation of American Universities (who in 2011 published a series of “Scientific Inquirer” articles skewering dubious politically-motivated attacks on basic science) and the Progressive Policy Institute, who are to be congratulated for this excellent initiative to highlight the importance of basic research.

At the press conference to launch the award Rep. Robert Dold told reporters that “When we invest in science, we also invest in jobs. Research and development is a key part to any healthy economy,” while  Rep. Charlie Dent (R-Penn.) added “It’s critical, and the federal government has an important role to play,” who went on to describe how injecting horses with snake venom might “seem peculiar” but led to the discovery of the first anti-venom.

Taking us, once again, to the concluding words of Asimov’s essay:

Unless we continue with science and gather knowledge, whether or not it seems useful on the spot, we will be buried under our problems and find no way out.  Today’s science is tomorrow’s solution — and tomorrow’s problems , too — and, most of all, it is mankind’s greatest adventure, now and forever.

Restoring vision in night blindness: Mice point way to stem cell therapy

Impaired vision and blindness are leading causes of disability, affecting over 3 million people in the USA today, so it’s no surprise that biomedical scientists are working hard to develop therapies to improve and restore vision.  Over the past few years we have discussed several therapies that have been developed to treat different types of vision loss, including anti-angiogenic therapies to treat wet age related macular degeneration, a leading cause of severe, irreversible vision loss in the elderly,  and gene therapy to treat Leber congenital amaurosis, an inherited disease characterised by progressive degeneration of the retina. Speaking of Research committee member Dario Ringach has also written on the Opposing Views website on the very promising research now underway to develop electronic prosthesis to restore vision in blind people.

In another important development in this field Professor Robin Ali* and his team at the UCL Institute of Ophthalmology have announced the first demonstration that transplanted retinal rod cells can improve vision in mice with night-blindness, publishing the results of their study in the prestigious science journal Nature1. Rod cells are photoreceptor cells in the retina of the eye that function well in low light conditions, and an absence of rod cells leads to night blindness. Mutations in the gene GNAT1 cause congenital night blindness in humans, and mice in which the Gnat1 gene has been knocked out are night blind.  In the video below Professor Ali show that by transplanting rod cell precursors into the retina of Gnat1 knockout mice his team was able to restore vision – albeit  not fully.

It’s a fascinating piece of work, though as Professor Ali makes clear in comments to the Guardian newspaper last week there is still a lot of work to do before this can be evaluated in humans.

Now we’ve discovered we can restore vision, it gives us impetus to go on and make the process better”

As both the video and Guardian article indicate an important step will be identifying suitable sources of cells for transplantation, with both embryonic stem cells and induced pluripotent stem (iPS) cells under consideration.  This may not take as long as one might think, as we discussed last November a clinical trial was recently launched to assess the potential for transplantation of another retinal cell type, retinal epithelial cells derived from human embryonic stem cells , to improve vision in patients with  Stargart’s Macular Dystrophy, an inherited form of blindness.

The work of Professor Ali and his colleagues at UCL is moving us closer to an effective treatment – and perhaps it is not unrealistic to talk about a cure – for night blindness. Their work will also no doubt drive research on protoreceptor cell transplantation in other forms of blindness, such as dry age related macular degeneration – the most common cause of vision loss in people aged over 50 – which is characterised by loss of both rod and cone photoreceptor cells.

Paul Browne

*        Professor Ali also played a leading role in the development of gene therapy for Leber congenital amaurosis, and led the first clinical trial of this technique.

1)      Pearson RA, Barber AC, Rizzi M, Hippert C, Xue T, West EL, Duran Y, Smith AJ, Chuang JZ, Azam SA, Luhmann UF, Benucci A, Sung CH, Bainbridge JW, Carandini M, Yau KW, Sowden JC, Ali RR. “Restoration of vision after transplantation of photoreceptors.Nature. 2012 Apr 18. doi: 10.1038/nature10997.

Straight from the animal rights book

It is that time of the year when animal rights activists, will show up at our workplaces dressed in their favorite animal costumes to spread more nonsense and misinformation about the nature of biomedical research.

One of their favorite claims is that the scientific community treats animals like any other piece of disposable, laboratory equipment — such as a Petri dish or a test tube.

Has anyone wondered where do they come up with such an idea?

The notion comes straight from the animal rights books that provide the theoretical foundation for animal rights theory while rejecting more nuanced positions.

A living being is said to have moral status if we are morally obliged to give weight to its interest independent of their utility to us. But what exactly is the moral status of non-human animals? Among the various positions one can take the two extremes are the easiest to describe.

At one end of the spectrum, we find the argument that animals do not truly experience pain, do not have emotions, they do not have interests of their own, and thus they lack moral status.  According to this view humans can do with animals as we please. Given what is known presently about animal cognition and behavior, it would be difficult to find anyone who would seriously defend the Cartesian position.

At the other end of the spectrum, we find those who hold that the moral status of some animals must equal to that of humans. These theories posit that if a living being has some basic properties (such as a minimum level of sentience according Gary Francione, or being the “subject-of-life criterion” according to Tom Regan) they attain the same moral status as that of a normal human: our moral consideration for a mouse, or a dog, or a child, ought to be exactly the same.

And let me assure you — when they say exactly the same, they mean it.

It is evident that most members of the public, including scientists that work with animals in medical research, prefer to position themselves somewhere between the two extremes. These more nuanced positions can be considered to represent different versions of “animal welfarism” which are based on the notion of graded moral status.  In these theories animals would certainly have higher moral status than inanimate laboratory equipment, but not that of humans. Animal anti-cruelty laws, the Animal Welfare Act, and the NIH guidelines as examples of how rules and regulations were established to acknowledge the moral standing of animals (establishing the “forbidden zone” in the spectrum of positions above).

Prominent animal rights philosophers, however, are not happy with shades of gray in moral decision making and attempt to rob others of adopting nuanced positions.

For example, Elizabeth Harman writes:

We have no reason to posit such degrees of moral status, so we can conclude that moral status is not a matter of degree but is rather on/off: a being has moral status or lacks it.

The idea is to reject the concept of graded moral status.

Gary Francione, agrees:

We have two choices – and only two – when it comes to the moral status of animals.

Tom Regan also concurs writing terms of the “inherent value” of animals:

Two options present themselves concerning the possession by moral agents of inherent value. First, moral agents might be viewed as having this value to varying degrees, so that some may have more of it than others. Second, moral agents might be viewed as having this value equally. The latter view is rationally preferable. […] We must reject the view that moral agents have inherent value in varying degrees. All moral agents are equal in inherent value, if moral agents have inherent value.

These philosophers want to force everyone to choose among the two extreme positions — either we accept the animal rights view or we must be cartesians that assign no moral status to the animals.

Thus the activists claim “If you disagree with us then you must be treating the animals as you treat a Petri dish”.

Nonsense.  It is the extreme views that must be rejected instead.

And the above also explains the need for the costumes, the scary masks, the blood-stained coats, the screams and insults, the misinformation and the lies. For these animal rights activists have neither solid philosophical nor scientific arguments to enter into a serious and civil debate on the role of animals in research and how the work has benefited mankind generation after generation.

Mouse study points to effective treatment of Fragile X syndrome

Fragile X syndrome is the most common genetic causes of intellectual disability, affecting about 1 in 4,000 people with more males affected than females, and also the most common genetic cause of autism, being responsible for 2-6% of all cases of autism. While no drugs have yet been approved to treat Fragile X syndrome, there is considerable interest in the biomedical research community in this condition, since as well as being a significant cause of disability in its own right it is a condition whose study may well help medical science to develop effective therapies for other forms of autism.

GM mice have made crucial contributions to our understanding of Fragile X syndrome. Image courtesy of Understanding Animal Research.

Fragile X syndrome is caused by mutations that silence the Fragile X (FMR1) gene and lead to a reduction –or absence – of the fragile X mental retardation protein (FMRP) and by knocking out the corresponding Fmr1 gene in mice and other organisms scientists have been able to generate models for the evaluation of potential therapies for autistic spectrum disorders , such as the drug Arbaclofen whose development we discussed briefly in 2010.

While it was clear quite early on that FMRP plays an important role at the synapse  – the structure that allows nerve signals to be passed from one neuron to another  – the nature of that role was not obvious, though a series of experiments in a variety of animal models had indicated that a class of proteins known as the metabotropic glutamate receptors might be involved.  A key discovery was made by Professor Mark Bear at MIT, who demonstrated that FMRP acted as a counterbalance to metabotropic glutamate receptor sub-type 5 (mGluR5). mGluR5 increases protein synthesis at the synapse as a means to facilitate signal transmission through the brain, and FMRP acts to reduce protein production. In the absence of FMRP signaling at the synapse goes awry, leading to the symptoms observed in fragile X syndrome.  This key scientific breakthrough was made in 2007 by Prof. Bear by genetically engineering Fmr1 knockout mice to halve the production of mGluR5, resulting in a significant reduction in fragile X symptoms in these mice. This linking of alteration in the expression of the gene to changes in fragile X symptoms was an important result, indicating that it may be possible to treat Fragile X by reducing the amount or the activity of mGluR5.

However, using gene modification to knock-down mGluR5 activity in people with Fragile X syndrome is not a practical option at this time, so attention turned to identifying drugs that could block mGluR5.  Last week in a paper in the journal Neuron Prof. Bear’s team, working in collaboration with scientists at the Swiss healthcare company Roche ,announced another major breakthrough. This study used an experimental  mGluR5 inhibitor known as CTEP which had recently been shown in animal studies  to be far more selective for mGlu5 than previous mGluR5, as well as having a longer half-life in vivo making it an ideal candidate for studies where mGLuR5 activity needed to be suppressed for extended continuous periods. They showed that CTEP treatment could not only stop the worsening of the condition but actually reversed the symptoms in FMR1 knockout mice with established Fragile X syndrome (1), including hearing sensitivity, learning and memory, suggesting that the defects in Fragile X syndrome are not irreversible and that it may be possible to effectively treat the cognitive and behavioral disabilities by pharmacological inhibition of mGluR5.

While CTEP is not currently being developed for clinical use, the result of this trial adds further weight to the evidence in favor of mGluR5 inhibition as a means to treat Fragile X syndrome. Two other mGluR5 antagonists – Fenobam and STX 107 – are already being evaluated in early clinical trials following successful evaluation in Fmr1 knockout mice, and this most recent result should encourage further investment in this approach.

The discovery that symptoms can be reversed in established disease in a model of Fragile X syndrome that accurately models the disorder in humans is a major advance, suggesting that the impairments associates with autistic spectrum disorders may not always be permanent  – a result with profound implications for the future of treatment of these disorders.

Paul Browne

1)      Michalon A, Sidorov M, Ballard TM, Ozmen L, Spooren W, Wettstein JG, Jaeschke G, Bear MF, Lindemann L. “Chronic Pharmacological mGlu5 Inhibition Corrects Fragile X in Adult Mice.” Neuron. 2012 Apr 12;74(1):49-56. PubMed 22500629

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Benefits of Animal Research, Right Down to the Letter

It’s always exciting, in this day and age, to get a letter that isn’t spam. Even more exciting when the letter is from another continent. And even more when it’s a letter as supportive and insightful as this one (full text below).

Dear Tom Holder:

I am a freshman studying at Orange County High School of the Arts. In my literature class, I recently gave a political speech addressing the benefits of animal research. I understand that your organization strongly encourages animal research. Allow me to thank you for actively supporting the use of animals in biomedical research by inspiring students and scientists to speak out in favor of animal research.

With animal testing, the world’s life expectancy is remarkably high. From the eradication of polio and small pox to breast cancer treatments, animal research has proved to be fundamental to the well being of this species. Viruses, diseases, and illnesses should never get in the way of our country’s success. By means of animal research, we have several vaccines and prescriptions available to the country to prevent these. Conventional wisdom states that animal testing implies animal abuse. But in reality, most scientists build up strong attachments to the animals they use in their experiments. Public misconceptions about alternatives to animal testing remain high, In vitro testing, MRI scanning, computer modeling and micro dosing are al vital, but these aspects of medicine simply compliment animal testing. One cannot purely find a replacement to animal research. Animal research should therefore not only be allowed, it must be strongly encouraged.

Animal research is irreplaceable and crucial to medical progress. Thus, thank you for standing up for science by founding several organizations similar to Speaking of Research. Please continue inspiring others and encouraging students, like me, to speak out for the benefits of animal research.

Sincerely

Momachi Pabrai
(reprinted with permission of author)

I congratulate Momachi for standing up among her colleagues to tell them of the benefits of animal research. Her letter shows that she has clearly thought through this controversial issue. Momachi hits upon the key ideas of why animal research is done. Namely:

  1. It is crucial to medical development; and
  2. It is currently irreplaceable

She includes examples such as the polio vaccine and breast cancer treatments (e.g. Herceptin) to back up her arguments. This is an example of how anyone, no matter what their scientific background, can make the case for animal research.

On behalf of Speaking of Research I wish Momachi all the best in the rest of her freshman year.

Cheers

Tom Holder

Objections to the Marginal Case Argument

Scientists are often challenged with the so-called marginal case argument.

We are asked to spell out the criteria that make our experiments justifiable in animals but not in humans with comparable abilities and therefore comparable interests. These criteria, we are told, must be evaluated for each individual separately (so-called moral individualism). The resulting argument against animal research consists in pointing out that no matter what criteria are selected, it is always possible to find some humans (e.g., the senile, the cognitively impaired or the comatose patient) who should also be candidates for invasive research. According to this line of reasoning, logical consistency demands that we conduct experiments with these human patients along or instead of using animals.  If we are unwilling to do so, then we must be guilty of speciesism.

Same moral status?

Let me bring up a few objections to this argument.

First, it seems clear (to me at least) that the intrinsic properties of an individual cannot possibly be all that matters in assessing moral status of living beings.  If such properties were all that mattered, then we should feel comfortable granting a rock, a dead cat, and human remains the same moral consideration since they can all be classified as inanimate objects with no interests of their own.  And yet, while nobody will object to a child playfully kicking a rock, most will not feel comfortable with him kicking a dead cat for his or her amusement or using human remains in an art project for school.  The suffering such acts will inflict on others must count as well.  Thus, we must reject moral individualism. Once that premise is gone, the entire marginal case scenario falls apart.

Second, even if for the sake of argument one accepts moral individualism, the resulting moral theory is impractical. Are we prepared to evaluate every single individual we encounter in life to decide on his or her moral status?  Should we assess the cognitive abilities of the child now crossing the street? The dog walking with her? The squirrel that just rushed in front of our moving car?  On one hand, consistency demands that we do so, but applicability demands that we come up with a more practical approach. Indeed, our ability to function in daily life is aided by organizing the world into different categories (or kinds) of living beings and making broad assessments of their interests and moral status. Our brain’s ability to quickly recognize species membership facilitates this. It enables us to determine that the squirrel running in front of our car is a living creature and to swerve to avoid running it over—unless doing so would endanger the child crossing the street. In most situations, we can assess the interests of living beings based on the normal life of the members of that species. We have no need to assess the specific interests and moral status of this particular squirrel and this particular child.

Third, the marginal case scenario is nearly always posed by using an impaired human and a non-human animal, rather than a normal human and a non-human animal with super-natural abilities. Why? Because there is a clear difference between these two situations.  On one hand, should an ape appear in front of us, such as in Kafka’s “Report to the Academy”, speaking in fluent English, asking to be treated as a peer, it seems difficult to think we could refuse on any grounds, even if it represents an extraordinary case.  On the other hand, when human patients are impaired from their normal state, in most cases, we have no absolute certainty the condition is permanent.  A cure for Alzheimer’s or autism may possibly be developed in the future and their mental capacities restored.  Moreover establishing the lack of cognitive function with confidence may be more difficult than we have anticipated, with new studies showing that patients in vegetative state may retain some cognitive function. And, as I mentioned earlier, even in cases were science tell us there is no hope for recovery on the horizon, harming these patients would cause suffering in others that must also be taken into consideration.

Finally, there is also a scientific objection: Even if one were to accept on principle the suggestion by animal philosophers and activists that if we experiment on animals we ought to be experimenting on impaired human patients, that population would not be best suited for scientific studies. Patients with pre-existing conditions have a wide range of abnormalities and individual differences that would make it extremely difficult to conduct properly controlled scientific studies.  Thus, in addition to moral considerations, there are valid scientific reasons to reject the proposal of using impaired humans rather than animal subjects in most studies.

Good, bad, useful? Reflections on animal models for Parkinson’s disease research

Parkinson’s disease is a relentless, ruthless neurodegenerative disorder that often strikes in the early “golden years”, around 60 years of age, but sometimes much earlier.  It progressively robs its victims of every capability that makes life enjoyable, from their ability to move, talk, eat by mouth, and in the worst cases, decreasing their cognitive abilities.

In the sixties, pioneering work in animal models, primarily rats, led to the discovery of a “pill” that transformed the lives of many patients by restoring their ability to move and allowing them to perform daily tasks, often continuing to work, travel, and to enjoy sports and family time.  In research that earned him a Nobel prize many years later, Arvid Carlsson and colleagues reproduced in these rats the main chemical deficit that exists in patients, and found that administration of l-dopa (sinemet) could greatly improve the motor deficits of PD patients.

Subsequent work, always based on generating a “model” of the disease in animals by destroying the neuronal cells that also die in patients, have led to refinement of this treatment; additional advances have led to surgical methods (deep brain stimulation) that further improved quality of life for many patients.

Why should we continue to use animals to study this disorder?

First, as any patient will tell you, the available treatments do not work on all the symptoms they experience, such as depression, sleep disorders, and digestive problems that plague their lives often even more deeply than their motor disorders. Second, the current treatments do not cure the disease, and their benefits do not last forever. In time, the treatments progressively lead to side effects, for example uncontrolled movements or spasms that leave the patient to chose between not moving at all or moving too much. Today’s medications do not stop the progressive loss of nerve cells in the brain, which will ultimately lead to disability and death.

A real treatment for the disorder will have to address its root cause and stop its process, perhaps even reverse them. This is where a lot of confusion on the utility and value of the animal models arises. In the press and even the scientific literature there are statements expressing concern that there is “no good model” of Parkinson’s disease, and sometimes that existing models are useless because some drugs that work in animals fail in the clinic.  It is a complex issue that is a source of debate among scientists and lay people alike. However, one has to examine the roots of the problem.

Models are only as good as our understanding of a human disease at a given time. Science is an evolving process and so are our models of disease. There was a time when we did not understand why some people would die from blood transfusion and others did not, because blood types had not yet been discovered. In the case of Parkinson’s disease, we have known for about a century which cells die in the brain of patients but we still do not know why. The early models, those that led to the major breakthroughs in treating some of the symptoms of the disease, reproduce this loss of cells but do not address its mechanism. We now know more about this mechanism because of research on the causes of rare cases of the disease that have a genetic component and run in families. We also know that even though most cases of Parkinson’s disease do not have a clear genetic component, the mechanisms may be the same. New understanding has led to a new generation of models, in which defective genes are introduced in mice to reproduce the mechanisms thought to cause the disease in people.

GM mice help to uncover the processes of Parkinson's disease. Image courtesy of Understanding Animal Research.

Are those models perfect?

No model is perfect. No model can be expected to reproduce all the symptoms that occur in patients. Even if similar, the brain and nervous system of mice are not identical to those of a human, who walks on two legs, not four paws, and can live up to a hundred years rather than two. Yet, a lot of the general functions that are affected by the disorder in humans are present to some extent in the mouse model.

More importantly, only in an animal can one examine the very beginning of the disease process. Many studies in humans have now shown that diseases like Parkinson’s begin to affect a person’s body decades before they even know it. The disease causes subtle changes that are not even perceived as abnormal but have long-term consequences, just as a minute water leak can over years rot a wooden beam and lead to a roof collapse. As the disease progresses, it can manifest itself with minor troubles, so unremarkable that they are not recognized as related to Parkinson’s disease, for example problems with sleep and smell, that are very common and have many different causes.

Thus, in a human, we will never be able to understand the beginning of the disease, the water leak, because we do not know in which individuals they are occurring. This is where animal models are the most useful. By reproducing anomalies, such as the overexpression of the protein alpha-synuclein, that cause the disease in people, we can study the mechanisms from the beginning and find ways to stop the damage as early as possible.

Why then are people writing that animal models of Parkinson’s disease did not accurately predict whether a new treatment can be effective in patients? For one thing, those drawbacks were largely based on old models, which were – and still are – useful for some things (developing treatments for symptoms and evaluating new approaches to restoring lost function such as gene therapy) but were only minimally productive in developing treatments to halt the development of Parkinson’s disease because of our limited knowledge of mechanisms at the time.

Will the new models be better at predicting drug efficacy in the clinic? It is too early to tell because none of the new compounds developed and currently being tested in these models has yet been tested in patients. Should these animal models be replaced by computer modeling of the disease?  Probably, but this is years in the future. The science of modeling all the molecular interactions that take place within a cell, and of all the connections this cell establishes with other cells in a complex organism in a way that could illuminate a disease process and make sound predictions leading to effective treatments is in its infancy. In the meantime, patients are diagnosed, grow worse, and die every day.

We cannot wait. Just as previous models, although imperfect, led to transforming discoveries that bought years of functioning to patients who otherwise would have been locked in a chair and condemned to an early death, the new models continue to lead every day to discoveries that bring us closer to an effective treatment. Nothing can replace them at the moment.

Marie-Francoise Chesselet, M.D., Ph.D.
Charles H. Markham Professor of Neurology
University of California, Los Angeles