Category Archives: Science News

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

Posted on April 2, 2012 by | 6 Comments

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

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The new face of transplant surgery, thanks to animal research

Posted on March 28, 2012 by | 1 Comment

Yesterday the University of Maryland Medical Center (UMM) announced most extensive full face transplant completed to date, including both jaws, teeth, and tongue. In a marathon 36-hour operation the surgical team led by Professor Eduardo Rodriguez were able to transplant a face of an anonymous donor onto their patient Richard Lee Norris, who had been injured in a gun accident 15 years ago.  The operation was the culmination of years of clinical and animal research undertaken at UMM under the leadership of Professor Stephen Bartlett, and funded by the Department of Defense and  Office of Naval Research due to its potential to help war veterans who have received serious facial injuries.

This successful operation, termed a vascularized composite allograft, was made possible not only by the selflessness of the family of the anonymous donor, but also by the years of animal research undertaken by Professors Rodriguez and Bartlett and colleagues. For example, a key factor in the success of this operation was that they transplanted high amounts of vascularized bone marrow (VBM), which came inside the transplanted jaw, a technique that was developed by the team after observing that tissue rejection following composite tissue allotransplantation in a cynomolgus monkeys was greatly reduced when VBM was included in the transplant. This discovery will also help to reduce the amount of immunosuppression that Mr. Norris and future patients require following facial transplants.

Of course this is far from the first contribution that animal research has made to transplant surgery, from the development of the techniques of kidney transplant through research in dogs by Joseph Murray and colleagues, to the careful experiments in dogs conducted by Norman Schumway and Richard Lower that led to the first successful heart transplants, to the studies in mice and rats that identified the immunosuppressive properties of the drug cyclosporin that transformed the transplantation field in the 1980′s, animal research has made a crucial contribution to this field. Indeed, in his 1990 Nobel Lecture Edward Donnall Thomas stressed the importance of animal research to his Nobel prize winning discoveries concerning bone marrow transplantation.

Finally, it should be noted that marrow grafting could not have reached clinical application without animal research, first in inbred rodents and then in outbred species, particularly the dog.”

Animal research continues to make key contributions to transplant science, and we have had several opportunities to discuss its role in the development of lab-engineered tissues for transplant, such as the artificial trachea and bladder, on this blog.

Yesterday’s news from the University of Maryland is another reminder that animal research is still crucial to advances in transplant surgery. It is also worth remembering that when animal rights groups attack animal research conducted by the Department of Defense, it is work such as that which led to yesterday’s breakthrough that they are attacking.

Paul Browne

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Of what use?

Posted on March 23, 2012 by | 5 Comments

By Isaac Asimov

One may detest nature and despise science, but it becomes more and more difficult to ignore them.  Science in the modern world is not an entertainment for some devotees.  It is on its way to becoming every-body’s business.  — Theodosius Dobzhansky, in The Biology of Ultimate Concern.

It is the fate of the scientist to face the constant demand that he show his learning to have some “practical use.”  Yet it may not be of interest to him to have such a “practical use” exist; he may feel that the delight of learning, of understanding, of probing the universe, is its own reward.  In that case, he might even allow himself the indulgence of contempt for anyone who asks more.

There is a famous story of a student who asked the Greek philosopher Plato, about 370 B.C., of what use were the elaborate and abstract theorems he was being taught.  Plato at once ordered a slave to give the student a small coin that he might not think he had gained knowledge for nothing, then had him dismissed from the school.

The student need not have asked and Plato need not have scorned.  Who would today doubt that mathematics has its uses? Mathematical theorems, which seem unbearably refined and remote from anything a sensible man can have any interest in, turn out to be absolutely necessary to such highly essential part of our modern life as, for instance, the telephone network that knits the world together.

This story of Plato, famous for two thousand years, has not made matters plainer to most people.  Unless the application of a new discovery is clear and present, most are dubious of its value.

A story about the English scientist Michael Faraday illustrates the point.  In his time, he was an enormously popular lecturer, as well as a physicist and chemist of the first rank.  In one of his lectures in the 1840s, he illustrated the peculiar behavior of a magnet in connection with a spiral coil of wire which was connected to a galvanometer that would record the presence of an electric current.

There was no current in the wire to begin with, but when the magnet was thrust into the hollow center of the spiral coil, the needle of the galvanometer moved to one side of the scale, showing that a current was flowing.  When the magnet was withdrawn from the coil , the needle flipped in the other direction, showing that the current was now flowing the other way.  When the magnet was held motionless in any position within the coil, there was no current at all, and the needle was motionless.

At the conclusion of the lecture, one member of the audience approached Faraday and said, “Mr. Faraday, the behavior of the magnet and the coil of wire was interesting, but of what possible use can it be?”  Faraday answered politely, “Sir, of what use is a newborn baby?”

It was precisely the phenomenon whose use was questioned so peremptorily by one of the audience that Faraday made use to develop the electric generator, which, for the first time, made it possible to produce electricity cheaply and in quantity.  That, in turn, made it possible to build the electrified technology that surrounds us today and without which life, in the modern sense, is inconceivable.  Faraday’s demonstration was a new-born baby that grew into a giant.

Even the shrewdest of men cannot always judge what is useful and what is not.  There never was a man so ingeniously practical in judging the useful as Thomas Alva Edison, surely the greatest inventor who ever lived, and we can take him as our example.

In 1868, he patented his first invention.  It was a device to record votes mechanically.  By using it, congressmen could press a button and all their votes would be recorded and totaled instantly.  There was no question that the invention worked; it remained only to sell it.  A congressman whom Edison consulted, however, told him, with mingled amusement and horror, that there wasn’t a chance of the invention being accepted, however unfailingly it might work.  A slow vote, it seemed, was sometimes a political necessity.  Some congressmen might have their opinions changed in the course of a slow vote, whereas a quick vote might, in a moment of emotion, commit the Congress to something undesirable.

Edison, chagrined, learned his lesson.  After that, he decided never to invent anything unless he was sure it would be needed and wanted and not merely because it worked.

He stuck to that.  Before he died, he had obtained nearly 1,300 patents — 300 of them over a four-year stretch, or one every five days, on the average.  Always he was guided by his notion of the useful and the practical.

On October 21, 1879, he produced the first practical electric light, perhaps the most astonishing of all his inventions. (We need only sit by candlelight for a while during a power breakdown to discover how much we accept and take for granted the electric light.)

In succeeding years, Edison labored to improve the electric light and, mainly, to find ways of making the glowing filament last longer before breaking.  As was usual with him, he tried everything he could think of.  One of his hit-or-miss efforts was to seal a metal wire into the evacuated electric light bulb, near the filament but not touching it, the two separated by a small gap of vacuum.

Edison then turned on the electric current to see if the presence of the metal wire would somehow preserve the life of the glowing filament.  It didn’t, and he abandoned the approach.  However, he could not help noticing that an electric current seem to flow from the filament to the wire across  the vacuum gap.

Nothing in Edison’s vast practical knowledge of electricity explained that phenomenon, and all Edison could do was to observe it, write it up in his notebooks, and, in 1884 (being Edison), patent it.  The phenomenon was called the “Edison effect,” and it was the inventor’s only discovery in pure science.  Edison could see no use for it.  He therefore pursued the matter no further and let it go, while he continued the chase for what he considered the useful and the practical.

In 1880s and 1890s, however, scientists who pursued “useless” knowledge for its own sake, discovered that subatomic particles (eventually called “electrons”) existed, and that electric current was accompanied by a flow of electrons.  The Edison effect was the result of the ability of electrons, under certain conditions, to travel unimpeded through as vacuum.

In 1904, the English electrical engineer John Ambrose Fleming (who had worked win Edison’s London office in the 1880s in connection with the developing electric-light industry) made use of the Edison effect and of the new understanding that the electron theory had brought.  He devised an evacuated glass bulb with a filament and a wire which would let the current through in one direction but not in the other.  The result was a “current rectifier.”

In 1906, the American inventor Lee De Forest made a further elaboration of Fleming’s device, introducing a metal plate that enabled it to amplify electric current as well as to rectify it.  The result is called a “radio tube” by Americans.

It is called that because only such as device could handle an electric current with sufficient rapidity and delicacy to make the radio a practical instrument for receiving and transmitting sound carried by the fluctuating amplitude of radio waves.  In fact, the radio tube made all of our modern electronic equipment possible — including television.

The Edison effect, then, which the practical Edison shrugged off as interesting but useless, turned out to have more astonishing results than any of his practical devices.  In a power breakdown, candles and kerosene lamps can substitute (however poorly) for the electric light, but what substitute is there for a television screen?  We can live without it (if we consider it only as an entertainment device, which does it wrong), but not many people seem to want to.

In fact, the problem isn’t a matter of showing that pure science can be useful.  It is much more difficult problem to find some branch of science that isn’t useful. Between 1900 and 1930, for instance, theoretical physics underwent a revolution.  The theory of relativity and the development of quantum mechanism led to a new and more subtle understanding of the basic laws of the universe and of the behavior of the inner components of the atom.

None of it seemed it seemed to have the slightest use for mankind, and the scientists involved — a brilliant group of young men — apparently had found an ivory tower for themselves that nothing could disturb.  Those who survived into later decades looked back on that happy time of abstraction and impracticality as a Garden of Eden out of which they had been evicted.  For out of that abstract work there unexpectedly came the nuclear bomb, and a world that now lives in terror of a possible war that could destroy mankind in a day.

But it did not bring only terror.  Out of that research also came radio-isotopes, which have made it possible to  probe the workings of living tissue with a delicacy otherwise quite impossible, and whose findings have revolutionized medicine in thousand ways.  There are also nuclear power stations, which, at present and in the future, offer mankind the brightest hope of ample energy during all his future existence on earth.

There is nothing, it turns out, that is more practical, more downright important to the average man, whether for good or for evil, than the ivory-tower researches of the young men of the early twentieth century who could see no use in what they were doing and were glad of it, for they wanted only to revel in knowledge of its own sake.

The point is that we cannot foresee the consequences in detail.  Plato, in demonstrating the theorems of geometry, did not envisage a computerized society.  Faraday knew that his magnet-induced electric current was a new-born baby, but he surely did not foresee our electrified technology.  Edison certainly didn’t foresee a television set when he puzzled over the electric current that leaped the vacuum, and Einstein, when he worked out the equation E = mc2 from purely theoretical considerations in 1905, did not sense the mushroom cloud as he did so.

We can only make the general rule that, though all of history, an increased understanding of the universe, however out-of-the-way a particular bit of new knowledge may seem, however ethereal, however abstract, however useless, has always ended in some practical application (even if sometimes only indirectly).

The application cannot be predicted, but we can be sure that it will have both its beneficial and its uncomfortable aspects.  (The discovery of the germ theory of disease by Louis Pasteur in the 1860s was the greatest single advance ever made in medicine and led to the saving of countless millions of lives.  Who can quarrel with that?  Yet it also has led , in great measure, to the dangerous population explosion of today.)

It remains for the wisdom of mankind to make the decisions by which advancing knowledge will be used well or not ill, but all the wisdom of mankind will never improve the material lot of man unless advancing knowledge presents it with the matters over which it can make those decisions.  And when, despite the most careful decisions, there come dangerous side-effects of the new knowledge, only still-further advances in knowledge will offer hope for correction.

And now we stand in the closing decades of the twentieth century, with science advancing as never before in all sorts of odd, and sometimes apparently useless, ways.  We’ve discovered quasars and pulsars in the distant heavens.  Of what use are they to the average man? Astronauts have brought back rocks from the moon at great expense.  So what? Scientists discover new compounds, develop new theories, work out new mathematical complexities.  What for?  What’s in it for you?

No one knows what’s in it for you right now, any more than Plato knew in his time, or Faraday knew, or Edison knew, or Einstein knew.

But you will know if you live long enough; and if not, your children or grandchildren will know.  And they will smile at those who say, “But what is the use of sending rockets into space?” just as we know smile at the person who asked Faraday the use of his demonstration.

In fact, 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.

—

From the introduction to “The greatest adventure: basic research that shapes our lives”, Eds. E. H. Kone and H. J. Jordan, Rockefeller University Press, 1974.

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Big Questions, but few answers from opponents of animal research

Posted on March 21, 2012 by | 4 Comments

A recent edition of the BBC1 Program called “The Big Questions” offered a brief debate on animal research. Among those discussing the issues was SR’s founder, Tom Holder. Within this post we will discuss some of the many issues which were touched upon, but barely explored in this brief debate.

Some of the questions centered on moral issues, other on scientific ones. At the beginning of the discussion Prof. John Stein of Oxford University explained his use of monkeys in studying Parkinson’s disease, after which he was asked if he would experiment on great apes.  He replied he would not, unless there was some extreme circumstance that required them.

“Where would you draw the line?” — countered the host.

Let us pause for a second here. This is an important question that is worth asking. But first let us consider – and reject all the theories that do not involve drawing any lines at all.  What theories are these?

One is the Cartesian view, which posits animals do not truly suffer, do not really have emotions, and do not really have interests of their own. Consequently, the Cartesian view is that humans can use animals as we please. We do not know any living scientist or philosopher that would seriously defend this view.

The other theory that does not draw any lines is the animal rights view, in which all living beings have the same basic rights to freedom and life as a normal human. Although most members of the public reject this view as making no sense at all, nobody in the panel cared to explain, nor did the host bother to ask, what justifies this stance.

What Prof. Stein articulated as a justification was a version of something called the sliding scale model.  Here, the moral weight of a living being’s interests depends on the individual’s degree of cognitive, affective and social complexity. Where we draw the line for different types of experiments in animals is a valid and important question, but we can only ask it that if we all agree with the notion of graded moral status.

Opponents of research reject such a theory.  Alistair Currie, from PeTA, stated:

Suffering is suffering.  We have a moral obligation not to impose it on anybody.”

We generally agree that unnecessary suffering should not be imposed on other living beings, and as Prof. Stein stressed, scientists work hard to ensure that suffering is eliminated or reduced to an absolute minimum in laboratory animals. We do not think there are absolute moral principles.  Even “thou shall not kill” permits exceptions, such as in the case of self defense. Another example is the infliction of harm to other human beings that was, for most of us, morally justified and necessary when it came to liberating the concentration camps in Nazi Germany.

If we truly had an absolute moral obligation to never impose suffering on anybody, as PeTA representative Currie suggests, liberating concentrations camps would be morally wrong. We might accept such a declaration from someone who is a declared pacifist, but we have plenty of evidence to suggest that PeTA is a far from being such an organization.  PeTA remains morally confused.

Invariably, when opponents of animal research fail to make an ethical case for their position, they attack the science. In this case, it was Kailah Eglington, representing the Dr Hadwen Trust, who was in charge of this strategy.

“Scientifically looking at the facts, the animal model is flawed.” — she declared without even blinking.

Wait a second. Where was she when Prof. Stein explained how he found an area of the brain that when inactivated could relieve the symptoms of Parkinson’s? How does she explain his success?  Or does she deny the benefits of the work?

Ms. Eglington also suggested that Prof. Stein could have used non-invasive methods in humans, such as MEG, suggesting the same information could be obtained by this techniques. As Prof. Stein pointed out in his response this is flatly wrong. Prof. Stein not only uses a range of such techniques, including MEG and fMRI alongside his studies in macaques, but with his colleagues at Oxford University pioneered the use of MEG as a research method in patients undergoing deep brain stimulation. However, none of the non-invasive methods can yield the same data that one obtains using micro-electrode recordings from the brain, as we discussed in an earlier post on the limitations of fMRI.

A quick visit to the Dr. Hawden Trust web-site reveals that they state with absolute certainty that:

Alternatives to animal experimentation are available in virtually every field of medical research.”

Wow…   Let’s be clear: this is complete utter nonsense that deserves to be filed here. Should we be surprised at the lack of sensible science by someone who, on the side, founded an organization which claims that “the power of positive thinking” can treat physically debilitating conditions.

Kailah Eglington furthered her pseudo-scientific nonsense by claiming that: “9 out of 10 drugs that are tested on animals successfully fail in humans“. The problem here is the mistaken blame on the animal model – these same drugs have already passed pre-clinical non-animal tests such as cell cultures and computer models; moreover, about 90% of drugs fail at every stage of development – meaning that 90% of those that pass early clinical trials in humans still fail to make it to market – this is not something we can blame the animal model for. We have previously written a full and clear rebuttal of the 90% claim – however it continues to be used by the animal rights community.

Such examples go to show a common problem for advocates of science – that it takes a lot longer to debunk junk science, than it does to make it up. While Tom Holder and Prof. Stein argued science’s case very well the debate highlighted some of the limitations of this format, though perhaps this is all we can expect from a format that tries to address Big Questions in 15 min of television programming.  It seems the goal here is more to get opposing sides to have a screaming contest rather than to provide an opportunity for thoughtful exploration of the questions at hand.

Speaking of Research

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Professor Doudet vindicated as investigation rejects animal rights allegations.

Posted on March 20, 2012 by | 2 Comments

Two weeks ago we discussed the targeting by Canadian animal rights group Stop UBC Animal Research (STOP) of University of British Columbia scientist Professor Doris Doudet. STOP alleged that Prof. Doudet had performed experiments on monkeys without the approval of the UBC Animal Care Committee, and then lied in a scientific paper to cover her tracks, though as we reported at the time their allegations of professional misconduct against her were based on a deliberate misrepresentation of the facts. We are now happy – though in the circumstances not very surprised – to learn that an independent investigation of Prof. Doudet’s work has dismissed the allegations made against her.

According to today’s report in the Vancouver Sun, the Canadian Council on Animal Care (CCAC) carried out a detailed review of the research undertaken by Prof. Doudet’s team, and found:

no evidence to support allegations of animal cruelty against a University of British Columbia research team related to the deaths of four macaque monkeys.”

An earlier report on CTV news adds that the CCAC investigation:

found no evidence to support allegations that UBC was subjecting monkeys to cruel research experiments that were not overseen by the UBC Animal Care Committee.”

The letter from the CCAC to STOP detailing the conclusions of their investigation can be read here.

We asked Prof Doudet her views about this week’s developments, welcoming the news she said:

It is distressing to be wrongly accused, but the truth prevailed and we are all grateful for it.  MPTP always had unexpected effects, not only in monkeys but in the humans who unknowingly injected themselves with it: Out of the more than 100 people who were exposed to the drug in the early 80s, only a handful developed severe parkinsonism and there is no way to predict who will have such a severe negative response. But the MPTP primate model and the knowledge gained from it have played an important part in the basic understanding of physiological mechanisms involved in the disease, and this has been key to the development of many therapies for Parkinson’s disease, including DBS and the current testing of many gene therapies.”

We too welcome this news, though we wonder whether a formal investigation was really required to confirm what had been patently obvious right from the start.

Speaking of Research

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Hypothermia in stroke: EuroHYP moves from rats to man

Posted on March 19, 2012 by | Leave a comment

Earlier today the BBC reported that European Stroke Research Network for Hypothermia (EuroHYP) has announced the launch of a major clinical trial – involving 1,500 patients in 15 centers across Europe – to evaluate whether cooling the body by 2 degrees can reduce the risk of death and disability in ischaemic stroke.

CT image of an ischemic stroke. The dark area in top left quadrant of brain shows the damaged brain area. Welcome Images.

The trial, known as EuroHPY-1, is being lead by Professor Malcolm McLeod of the University of Edinburgh, and its design is supported by very strong evidence from studies in animals – mostly rats -that we discussed on this blog just over a year ago, with the trial synopsis stating that:

Systematic review of animal studies modelling ischaemic stroke suggests that cooling is the most promising intervention identified to date. In these animal studies, cooling to 35˚C reduced infarct size by about one third, and cooling to 34°C by around 45%.”

We are very pleased to learn that this trial – which has the potential to radically alter and improve the way in which ishaemic stroke is treated – has now received sufficient funding to go ahead.

In another interesting report on the BBC today, scientists at the University of Colorado have reported that they have used studies of genetically modified mice to identify the mechanism through which the brain-derived neurotrophic factor (BDNF) interacts with other regulatory proteins to control appetite and body fat levels.  In some people with the genetic disorder WAGR syndrome it was observed that having only one copy of the gene encoding BDNF was associated with excessive appetite and obesity, but until now the mechanisms through which BDNF regulates appetite was not clear.

This research fills in another important gap in our understanding of how genetic differences between individuals influence the risk of becoming obese, and we know already that genetics makes a very large contribution to that risk. While the complex nature of the influence of genes on obesity means that it is rarely possible for a single medication to have a dramatic impact – though there are a few examples such as the treatment of leptin deficiency with recombinant leptin (following studies in the leptin-deficient Ob/Ob mouse) – increasing understanding of the influence of the impact of an individuals genetic makeup on their risks of becoming obese will aid the development of both new medicines to help combat obesity, and the development of more targeted lifestyle interventions that are more likely to be successful for that individual.

Taken together these two items reported in the BBC highlight the importance of animal research to medical progress, both as a way to uncover the processes involved in health and disease in basic research, and as a way to evaluate potential therapies in order to obtain sufficient information to proceed to trials in human patients.

Addendum:

More good clinical trial news that I missed earlier!

On Friday the Cystic Fibrosis Trust announced that thanks to major grants from the Medical Research Council (MRC) and National Institute for Health Research (NIHR) they will soon launch their clinical trial of non-viral gene therapy for Cystic fibrosis.

We briefly discussed the important role played by animal research in the development of this therapy in a blog post last August, and it is great to see that the UK Cystic Fibrosis Gene Therapy Consortium (UK CFGTC) has now raised sufficient funds to proceed with this exciting trial.

The UK CFGTC has also announced that it received a further £1.2 million fund research to develop a lentiviral vector for improved delivery of gene therapy in cystic fibrosis, much of which will like earlier work on this vector require the use of animal models.

Paul Browne

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The 21st Century Scientist

Posted on March 16, 2012 by | Leave a comment

Earlier today we discussed some of the characteristics of the animal rights crank, so it’s perhaps appropriate that an award announced earlier this week has highlighted the best qualities of the scientists who are really shaping 21st century medicine.

The Grete Lundbeck European Brain Research Foundation has awarded its 2nd €1-million Brain Prize to Professor Karen Steel of Cambridge University, founder of the Mouse Genetics Programme at the Wellcome Trust Sanger Institute, and Professor Christine Petit of the College de France, head of the Genetics and Physiology of Hearing laboratory at the Institut Pasteur in Paris, for:

their unique, world-leading contributions to our understanding of the genetic regulation of the development and functioning of the ear, and for elucidating the causes of many of the hundreds of inherited forms of deafness”

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A Brief History of Deep Brain Stimulation

Posted on March 15, 2012 by | 11 Comments

An on-going campaign against the use non-human primates to study Parkinson’s disease (PD) at the University of British Columbia prompted me to summarize some basic facts about the work and the history of a successful therapy was developed.

Why is the work done?

In the U.S. alone there are between 500,000 and 1 million people living with PD, with about 50 to 60 thousand new diagnoses every year.  The National Institutes of Neurological Disorders and Stroke (NINDS) estimates the cost to our society is at least $5.6 billion, including both direct medical expenses and indirect costs from lost income, disability payments and so on.  Moreover, the emotional toll of Parkinson’s on patients and families is enormous.

One of the most successful therapies developed for PD  involves the electrical stimulation of deep structures within the human brain — so called deep brain stimulation (DBS).  The technique works remarkably well for some patients.

How was the method developed?

Back in 1983 Langston and colleagues reported on a clinical case study of four patients that developed Parkinsonism after illicit drug use.  Analyses of the drugs they had taken via mass spectroscopy revealed primarily MPTP, but there were also traces of MPPP. They suggested MPTP might be the most likely culprit and suggested that:

“Given the pathologically studied case, the relative purity of the clinical syndrome seen in our patients, and its remarkable clinical resemblance to Parkinson’s disease, the drug [MPTP] may be of value in producing an animal model of Parkinson’s disease.”

In other words, a group of clinicians studied a handful of human patient cases, identified a potential link between MPTP toxicity and the development of PD, and proposed to follow up with animals studies.

In 1983, Burns and colleagues follow up on this idea by trying to replicate the disease in monkeys.  Indeed, intravenous administration of MPTP caused the animals to develop rigidity, postural tremor, eyelid closure, and many other symptoms of Parkinsonism.  Moreover, their symptoms could be relieved by the administration of L-dopa, exactly as it was the case with the Langston et al patients. The animal model also allowed them to characterize the selective destruction of dopaminergic neurons in the subtantia nigra and a marked reduction in the dopamine content of the striatum.  They offered MPTP treated monkeys as a model to explore therapies for PD.  How many animals were used?  Twelve.

Although these anatomical studies shed light into the brain areas that might be involved in PD it was unclear what functionally was causing the observed symptoms.  Subsequent work by Mitchell et al (1989) using single unit recordings and lesion studies in monkeys pointed to increased activity in the subthalamic nucleus (STN) as generating motor abnormalities.  How many monkeys were used?  Eight.

A natural question arose from these studies.  Would suppressing the activity of these hyperactive neurons help in alleviating the symptoms of the disease?

Two studies showed that lesions of the STN could reverse the effect of Parkinson symptoms in the monkey MPTP model, with studies by Bergman et al (1990) and Aziz et al (1991).  These studies not only began to dissect the functional connectivity within the basal ganglia-thalamocortical circuit, but also offered evidence that inactivation of the STN could work as a potential therapy for Parkinson’s.   How many monkeys were used in these two studies?  Four.

Shortly after, Benazzouz et al (1993) showed that instead of lessoning the STN one could use high frequency stimulation of the STN to alleviate the symptoms in MPTP treated monkeys.  Supposedly, the high frequency stimulation suppresses the activity of these cells acting as a “virtual lesion”.  How many monkeys were used here?  Two.

Indeed, Limousin et al (1995) successfully applied this method in three patients and concluded:

“In this study, bilateral subthalamic nucleus stimulation improved akinesia and rigidity in three patients with Parkinson’s disease.  This is in agreement with the results obtained in monkeys with MPTP-induced parkinsonism by lesions or stimulation of the sub-thalamic nucleus.”

Number of humans used?  Three.

And to dispel any remaining doubts he writes in a recent review that:

“The knowledge of the functional changes of basal ganglia activity in the parkinsonian state as it emerged from extensive experimental studies on animal models has provided the theoretical basis for surgical therapy in PD. The 6-hydroxydopamine (6-ODHA) rat model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of PD provided powerful research tools for uncovering the pathophysiology of changes in functional basal ganglia activity in PD.” 

And finally one may ask, ho many human patients have benefited from this type of work?

The answer is 80,000 and counting.

What do these patients think of such studies?

Here is one — please listen to him carefully.

And if you truly want to learn more here are some extra resources:

SfN brain briefing on PD discoveries.
The Michael J. Fox Foundation
Information from National Institutes of Neurological Disorders and Stroke.
Information from Understanding Animal Research.

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