Category Archives: Science News

Jeffrey Kahn’s Odd Views on Animal Research

Professor Jeffrey Kahn visited UW Madison to discuss the use of monkeys in medical research.

He is the Robert Henry Levi and Ryda Hecht Levi Professor of Bioethics and Public Policy and the Deputy Director for Policy and Administration at the Johns Hopkins Berman Institute of Bioethics.

Professor Kahn has participated in numerous federal panels and chaired the influential Institute of Medicine (IoM) committee on the Use of Chimpanzees in Biomedical and Behavioral Research, which recommended that the NIH phase out most biomedical research on chimpanzees.

Because he is respected and listened to by those in charge of making policy decisions on matters of important medical research and public health issues, his talk at UW Madison drew much attention.

During his comments Prof. Kahn raised several objections about how animal research is regulated in the United States that deserve closer scrutiny.

Unfair application of the principles of utilitarian philosophy

Professor Kahn objected to justifying research based on utilitarianism on the grounds that it is unfair to consistently harm one group (non-human animals) for the benefit of another (humans).

However, the notion that pure utilitarianism forms the basis for an ethical defense of biomedical research is incorrect.

For example, a pure utilitarian view would also call for doing invasive experiments in mentally disabled human beings whose cognitive capabilities are comparable to those of animals used in research, or demand we forcefully harvest the organs of a potential human donor to save the lives of several others.

Of course, we don’t do any of these things. So it was perplexing to hear him state that utilitarianism is “how the system is set up.” 

No, it is definitely not.

Medical research with human and non-human animals is not based on a pure, utilitarian view.  Instead, it is partly based on a graded moral status perspective that posits we owe moral consideration to all living beings, but not to the same degree that we owe consideration to the lives of fellow humans. It is also partly based in our mutual recognition of equal, basic rights for all members of the human family.

These ethical considerations are embedded in federal regulations and NIH guidelines that call for minimizing the number of animal subjects used in any one study, the amount of suffering involved, and require the use the “lowest” species that can be expected to yield meaningful scientific answers.  It is also reflected in specific federal programs aimed at developing alternatives to animal use and, of course, in protections for human subjects.

It is true that NIH has never made explicit the ethical and philosophical principles underlying its research.  Nevertheless, the ethical principles etched in these regulations should be clear to anyone who spend the time to become familiar with them.

A misguided notion of scientific necessity

Professor Kahn views the “scientific necessity” of the work as inextricably linked to the ethics. His views are aligned with the conclusions of the panel that he chaired on chimpanzee research.  Within this framework a project would be morally justified only if all the following three conditions were met:

  1. No suitable alternative is available
  2. The work cannot be performed ethically on human subjects
  3. The work is required in order to accelerate the prevention, control and treatment of life-threatening or debilitating diseases

A large class of studies readily meet the first two requirements. When we seek information about the cellular and molecular mechanisms in a living organism, the technologies available to us at the present are invasive, and the work cannot be performed ethically in human subjects. If we could observe and manipulate molecular pathways and cells in living humans without jeopardizing their well being, then the work would be done in humans. But we don’t yet have such tools. No computer simulation, no in-vitro system, no MRI, no organs-on-a-chip currently available, provide an adequate alternative to animal studies.

The crux of the matter then boils down to the third condition, and therein lies the rub. When you are talking about the process of scientific discovery, this third condition is meaningless when applied to individual scientific projects. Science, as Professor Kahn himself points out, is not necessarily a predictable linear path from point A to point B, because it involves the exploration of the unknown. Science cannot promise that any one experiment can lead to a cure, nor can researchers know ahead of time which specific experiment or line of research will lead to a breakthrough. In Professor Kahn’s own words, “we call it research because we don’t know what the answer is.”  Why does he not realize that demanding a specific outcome in advance is out of the question?  One can only evaluate outcomes in retrospect, as Peter Singer has done offering in his approval for monkey studies in Parkinson’s research. Unfortunately, scientists on NIH study sections do not have the luxury of an oracle that can guide their decisions.

Instead, researchers understand that without animal studies we will not be able to develop new therapies and cures. Our expert scientific opinion is that were we to suspend animal research, most fields of biomedical research would come to a full stop. Meanwhile, patients and their families would pay the price of more human suffering.

Thus, the ethical question should be reframed as not whether one individual study is required but, in the case at the heart of this debate, whether the use of animal models is required to understand the molecular pathways underlying mental disorders so that we can  develop new treatments and cures for them.  Or more generally, if animals are required at all to advance medical knowledge and human health.  The scientific consensus in this matter, as indicated by a recent Nature magazine poll,  is overwhelming:

 

Bonus points should go to UW Professor Eric Sandgren who was nevertheless able to use Professor Kahn’s framework to explain, point by point, why he feels the studies under discussion can be justified. You may agree or disagree with his justification, but you cannot say he did not offer one. In contrast, Professor Kahn simply stated that he was “deeply skeptical” of the necessity of the work, despite acknowledging a lack of familiarity with the details of the study, nor bothering to explain the rationale for this view.

Given that the research at the center of this debate is aimed directly at anxiety disorders, a specific neurological condition that affects millions of humans, one might safely assume that Professor Kahn would express even graver doubts about basic research in animal subjects. He would have likely have rejected outright the research on olfactory cells that eventually allowed paralyzed people (and dogs) to walk again, among numerous advances in knowledge that have led to medical breakthroughs.

Professor Kahn ought to be reminded that the mission of the NIH is “to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability,” and try to understand better the inherent uncertainty and necessity of scientific research.

Do IACUCs and NIH study sections fail to evaluate scientific necessity?

Given his misguided view of necessity, it should not be surprising Professor Kahn believes that neither IACUCs nor NIH study sections are able to assess the scientific need for specific studies. He harshly criticized such committees for taking the claims of any one proposal at “face value.

That is a very strong statement… and a decidedly incorrect one, too.

First, the overall scientific direction of medical research in the country is established by our medical and scientific leadership. In the neurosciences, scientists are guided in their research by NIH’s Neuroscience Blueprint. Among the important scientific directions relevant to this particular discussion—ones that Professor Kahn should have known about—were the Blueprint Neurotherapeutics Network (to advance the development of new drugs for nervous system disorders) and the Blueprint Non-Human Primate Brain Atlas (to provide comprehensive data on gene expression in the rhesus macaque brain , from birth to four years old). Such work is expected to aid research on human brain development and its disorders.

Second, NIH study sections diligently assess proposals with an eye to which studies stand a better chance of advancing our knowledge of function and disease and therefore may have the greatest potential to lead to new cures or fundamentally advancing a field of study. In making their assessments, scientists who participate in study sections use their expertise to assess which research directions and pilot data look most promising. There is never a guarantee that any one study will produce a breakthrough. If there is any one premise it is that animal research has led to numerous advancements in knowledge and medicine that has benefited human and non-human animals alike. This is not taken at face value, rather, it is an indisputable fact of medical history.

Third, once the scientific merit of a proposal has been established, IACUCs provide an additional layer of local scrutiny and compliance oversight. It is perfectly reasonable for IACUCs to ensure the work at the institution maximizes the welfare of the animal subjects in each study, and NIH requires such an assurance for institutions that receive federal funding. (For the small minority of projects that have not yet received NIH review, the IACUCs seek local expertise to evaluate the scientific merit of the study.)

Is funding “unnecessary” research a waste of resources?

Another miscalculation derived from Professor Kahn’s flawed view of “necessity” is the claim that if research is “unnecessary” according to his definition, then it is also unethical, especially considering the limited funding resources we have available at the moment.

It is perfectly legitimate for a society to assess how it distributes its resources, but in doing so the entire budget ought to be considered.

One may ask, for example, how Professor Kahn feels about resources spent on drones for the military, the Hubble telescope, unmanned trips to Mars, funding for theoretical physics, game theory, or the Arts.

Or, more to the point, one could ask for a more detailed justification of why society should spend its resources on philosophers and bioethicists?

Should society prioritize the support of bioethics over the development of a vaccine for Ebola or a cure for cancer, Alzheimer’s or Parkinson’s?

Which is one more crucial to our social welfare and which is more “unnecessary”?

Who will direct medical research?

Scientists must participate more in public life because social policies need to be decided on the basis of rational grounds and facts. These include important issues ranging from climate change, to the goals of the space program, to the protection of endangered species, to the use of embryonic stem cells or animals in biomedical research.

When scientifically inaccurate statements emanate from someone who has demonstrable influence on public policy decisions, scientists have a duty to speak up and correct the mistakes.

Animal research poses a legitimate moral dilemma. Decisions to pursue different lines of research that are perceived as controversial — be it research involving animals subjects or embryonic stem cells — cannot be assessed fairly without the active participation of scientists, physicians, patients and their families, because all are stakeholders in the work.

Unless these stakeholders get involved in such debates, we may find that their interests are not taken into account when the future direction of medical research is determined.

Dario Ringach

 

Paralyzed man walks again after olfactory cell transplant, thanks to animal research

Today, almost 30 years after Prof. Geoffrey Raisman first identified their potential to repair nerve damage in mice, the BBC reports that olfactory ensheathing cell transplantation has been successfully used to enable Darek Fidyka, who was paralyzed from the chest down in a knife attack in 2010, to walk again.

The paper reporting the transplant, which was carried out by surgeons in Poland and  led by Geoffrey Raisman of the UCL Institute of Neurology, is published today in the journal Cell Transplantation (5). The technique involves taking specialized cells known as olfactory ensheathing cells (OECs) from the patient’s own patient’s olfactory bulbs, and then grafting these cells at the site of injury, where they promote nerve cell growth to bridge the gap and restore function. An added advantage in using the patient’s own cells is that it avoids the problem of rejection by their immune system.

Speaking earlier today Geoffrey Raisman described the results as “more impressive than man walking on the moon”. He’s not to far wrong, this achievement shows what is possible for regenerative medicine, and is the result of decades of basic and translational research. Indeed, whereas only 12 people have  walked on the moon, this new technique has the potential to help many thousands of people to walk again here on earth.

2014 has been an extraordinary year of progress restoring function after spinal injury, in May we saw how epidural stimulation allowed 4 paralyzed men in the US to move their legs again, while scientists at Newcastle University in the UK used closed loop electrostimulation to restore voluntary movement in temporarily paralyzed monkey arms. These techniques, and now OEC transplantation, show that many cases of paralysis are potentially reversible. Not every technique will be appropriate for every patient, and it will take much additional research before they are widely available, but together they represent a huge advance.

Darek Fidyka learns to walk again following OEC transplantation. Image BBC News.

Darek Fidyka learns to walk again following OEC transplantation. Image BBC News.

In each case it is an advance that rests on many decades of careful research in both animals and in human subjects, in particular basic research that uncovered the role of specialized cells and provided scientists with the knowledge about organization and function of the brain and spinal cord that enabled these pioneering therapies to be developed.

In a post in 2012 I discussed how Geoffery Raisman’s research led to the successful testing of olfactory ensheathing cells in injured dogs, and I’m reposting that article here:

Paralysed dogs walk again thanks to nasal cell transplants…and Professor Raisman’s rats. (published 19 November 2012)

This morning the BBC News carried a report on a medical breakthrough – and it is not a term I use lightly – that has enormous implications for people who have been paralyzed following spinal cord injuries. A team at the University of Cambridge led by Professor Robin Franklin Department of Veterinary Medicine, along with colleagues at the MRC Centre for Regenerative Medicine in Edinburgh succeeded in restoring the ability to walk with their hind legs to dogs which had been paralyzed by spinal injury. To do this they removed a special type of cell called the olfactory ensheathing cell (OEC) from the nasal passageways of the dogs, grown them in culture until a sufficient number had been produced, and then transplanted them at the site of injury. Many of the dogs which received the transplant were subsequently able to walk with their hind legs if supported by a harness, and some even able to walk without being supported by a harness, whereas dogs which received a control injection did not recover the ability to move their hind legs.

This is a major medical advance, and the first time that cell transplantation has been demonstrated to reverse paralysis in a real-life situation where the injury involves a combination of damage to the nerve fibre and to surrounding tissues, and there is a significant delay between injury and treatment, and while the therapy did not completely restore function it marks a very significant step towards a therapy that can be evaluated in a human clinical trial. It also of course is a very promising therapy for dogs that have suffered spinal injuries, for example after being hit by a car, and as such is an excellent example of the One Health concept which seeks a closer integration of human and veterinary medicine.

As with many breakthroughs this one did not happen overnight, indeed it is the result of decades of research. The story really begins in 1985 when Professor Geoffrey Raisman at University College London (for a good overview of his work see the UCL spinal Repair Group homepage) was studying the unique ability of nerve fibres in the olfactory system to grow and make the connections with central nervous system – an ability that other adult nerve cells lack and which is probably retained in the olfactory system due to the importance of preserving the ability to smell despite exposure of nerve cells in the nasal passages to toxins in the environment (a good sense of smell being crucial to survival for many mammalian species). He found that in a part of the brain termed the olfactory bulb of mice and rats a specific type of glial cell, cells that act to support and regulate the activity of the nerve cells along which nerve impulses travel , were responsible for creating the pathway along which the olfactory nerve fibres could regenerate (1).

Studies in rats were key to unlocking the potential of olfactory ensheathing cells in repairing spinal injuries. Image courtesy of Understanding Animal Research

This discovery suggested that if these specialized olfactory ensheathing cells (OECs) were transplanted at the site of spinal cord injury they might promote the growth of a bridge of nerve cells that would reconnect the severed pathway and restore function. In a series of experiments in rats Professor Raisman and colleagues demonstrated that OEC transplantation could repair a variety of different types of spinal cord injury, in order to restore function, for example to improve the ability to breath and climb following spinal cord injury (2) and to restore the ability of rat paws to grasp in order to climb following lesion of the spinal nerve that runs from the spinal cord down through the arm (3). Other scientists provided additional key information, for example scientists at the University of New South Wales in Australia demonstrated that OECs could be isolated from the nasal mucosa as well as from the olfactory bulb (4), and that these can also repair spinal cord injuries, an important step since obtaining OECs from the nasal mucosa is far more straightforward and safer than harvesting them from the brain. These discoveries, and the refinement of OEC transplant techniques over the past 2 decades by scientists such as Prof. Raisman, paved the way for the “real life” veterinary study reported today. A human clinical trial of this technique cannot be far off, though it is worth noting Prof. Raisman’s words of caution to the BBC concerning what has been achieved and what is still to be done:

“This is not a cure for spinal cord injury in humans – that could still be a long way off. But this is the most encouraging advance for some years and is a significant step on the road towards it…This procedure has enabled an injured dog to step with its hind legs, but the much harder range of higher functions lost in spinal cord injury – hand function, bladder function, temperature regulation, for example – are yet more complicated and still a long way away.”

In this respect it is worth noting the other approaches to repairing spinal cord injury, for example using other glial cell known as astrocytes and the use of electrical stimulation have produced promising outcomes in animal studies and early human clinical trials. Indeed, a clinical study of electrostimulation that we discussed last year reported “improved autonomic function in bladder, sexual and thermoregulatory activity that has been of substantial benefit to the patient”. In the future these different approaches may be combined to maximize the benefit to the patient, but it is still far too early to say which techniques will best complement each other. One thing we can be sure of is that turning these very promising technologies into effective treatments – perhaps even cures – for paralysis will require further research, both in the lab and in the clinic.

Paul Browne

1) Raisman G. “Specialized neuroglial arrangement may explain the capacity of vomeronasal axons to reinnervate central neurons.” Neuroscience. 1985 Jan;14(1):237-54. PubMed: 3974880

2) Li Y, Decherchi P, Raisman G. Transplantation of olfactory ensheathing cells into spinal cord lesions restores breathing and climbing.” J Neurosci. 2003 Feb 1;23(3):727-31. 12574399

3) Ibrahim AG, Kirkwood PA, Raisman G, Li Y. “Restoration of hand function in a rat model of repair of brachial plexus injury.” Brain. 2009 May;132(Pt 5):1268-76. Epub 2009 Mar 13. PMID: 19286693

4) Lu J, Féron F, Mackay-Sim A, Waite PM. “Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord.” Brain. 2002 Jan;125(Pt 1):14-21. PMID: 11834589

5) Tabakow P et al. “Functional regeneration of supraspinal connections in a patient with transected spinal cord following transplantation of bulbar olfactory ensheathing cells with peripheral nerve bridging” Cell Transplantation, published online 20 November 2014 http://www.ingentaconnect.com/content/cog/ct/pre-prints/content-CT-1239_Tabakow_et_al

Stem cell therapy allows blind to see again, thanks to animal research

A team of scientists led by stem cell pioneer Professor Robert Lanza has reported today in the Lancet (1) the first evidence for the long-term safety of  retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs) in patients who took part in a trial undertaken in four centres in the US. substantial improvements in vision were also recorded in almost half the treated patients, compared to no improvement in untreated patients.

This is the first time that clinical benefits have been demonstrated in the medium to long term in patients with any disese treated with hESC-derived cells, and is a major milestone in the development of the field of regenerative medicine. It’s an achievement that is due to many years of animal research.

Image:UCL/PA

Image:UCL/PA

The trial focused on 18 patients with two different types of macular degeneration,  Stargardt’s macular dystrophy and nine with dry atrophic age-related macular degeneration, that are common causes of blindness in adults and children and for which no effective treatments are currently available.

Nine patients with Stargardt’s macular dystrophy and nine with dry atrophic age-related macular degeneration received injections of 50,000 to 150,000 RPE cells behind the retina of their worst-affected eye. Robert Lanza, adjunct Professor at the Institute for Regenerative Medicine, Wake Forest University School of Medicine and Chief Scientific Officer at Advanced Cell Technology who funded the trial, describes the results:

The vision of most patients improved after transplantation of the cells. Overall, the vision of the patients improved by about three lines on the standard visual acuity chart, whereas the untreated fellow eyes did not show similar improvements in visual acuity. The patients also reported notable improvements in their general and peripheral vision, as well as in near and distance activities”

Professor Steven Shwartz, who led the team at the Jules Stein Eye Institute that took part in this trial, noted how important this result is to both the patients in this trial and the field of hESC-derived stem cell medicine.

Our results suggest the safety and promise of hESCs to alter progressive vision loss in people with degenerative diseases and mark an exciting step towards using hESC-derived stem cells as a safe source of cells for the treatment of various medical disorders requiring tissue repair or replacement,

You can listen to interviews with Steven Schwartz and several of the participants in this clinical trial in an NPR broadcast here.

In 2011 we discussed the launch of trials of these hESC-derived RPE cells, including some of those whose results are reported today,  at Moorfields Eye Hospital in London and the Jules Stein Eye Institute at UCLA. A paper published in the Journal Stem Cells in 2009 showed how studies in rodent models retinal degerneration paved the way for these trials by demonstrating that RPE cells derived from hESCs were safe and could restore vision:

Assessments of safety and efficacy are crucial before human ESC (hESC) therapies can move into the clinic. Two important early potential hESC applications are the use of retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration and Stargardt disease, an untreatable form of macular dystrophy that leads to early-onset blindness. Here we show long-term functional rescue using hESC-derived RPE in both the RCS rat and Elov14 mouse, which are animal models of retinal degeneration and Stargardt, respectively. Good Manufacturing Practice-compliant hESC-RPE survived subretinal transplantation in RCS rats for prolonged periods (>220 days). The cells sustained visual function and photoreceptor integrity in a dose-dependent fashion without teratoma formation or untoward pathological reactions. Near-normal functional measurements were recorded at >60 days survival in RCS rats. To further address safety concerns, a Good Laboratory Practice-compliant study was carried out in the NIH III immune-deficient mouse model. Long-term data (spanning the life of the animals) showed no gross or microscopic evidence of teratoma/tumor formation after subretinal hESC-RPE transplantation. These results suggest that hESCs could serve as a potentially safe and inexhaustible source of RPE for the efficacious treatment of a range of retinal degenerative diseases.”

This work – and earlier studies of RPE cells derived from ESCs – built on decades of basic stem cell research, starting with the pioneering work of Gail Martin, Matthew Kaufman and Martin Evans in mice, and the subsequent derivation of ESCs in macaques and then humans by James Thompson and colleagues at the university of Wisconsin- Madison.

Laboratory Mice are the most common species used in research

The humble mouse has played a key role in the development of stem cell medicine.

Today’s announcement is a major milestone in regenerative medicine, and one that id justifiably being celebrated, but we should also remember the many years of careful research that has led up to this moment. As with many medical advances much of the early research on embryonic stem cells was undertaken without any immediate clinical application in mind, but it nevertheless created the knowledge that is now driving an important emerging field of medicine. This is a lesson we need to remember when we donate to charities, when we discuss the importance of research with others, and most of all when we go to the ballot box!

Paul Browne

1) Schwartz SD et al. “Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies” Lancet published onlin3 15 October 2014. Link.

2) Lu B et al. “Long-term safety and function of RPE from human embryonic stem cells in preclinical models of macular degeneration.”
Stem Cells. 2009 Sep;27(9):2126-35. doi: 10.1002/stem.149.

Nobel Prizewinner John O’Keefe warns of threat to science from overly restrictive animal research and immigration rules

In an interview with the BBC yesterday 2014 Nobel laureate  John O Keefe has warned of the dangers posed by regulations that restrict animal research and the free movement of scientists across borders.

“It is an incontrovertible fact that if we want to make progress in basic areas of medicine and biology we are going to have to use animals.

“There is a worry that the whole regulatory system might begin to be too difficult, it might be constrictive.”

Professof John O'Keefe, 2014 Nobel Laureate in Medicine or Physiology. Image: David Bishop, UCL.

Professof John O’Keefe, 2014 Nobel Laureate in Medicine or Physiology. Image: David Bishop, UCL.

His concerns are well founded. Our post yesterday discussed the key role of recordings of single neuron activity in rats to the discoveries made by John O’Keefe, May-Britt Moser and Edvard Moser. The post also discusses two other advances made through basic research in animals whose impact in medicine has been recognized by awards, deep brain stimulation in Parkinson’s disease, and infant massage in preterm babies. Nevertheless in many countries around the world there is increasing pressure from animal rights groups on politicians to restrict, and even ban, animal research. Scientists have a key role to play in ensuring that important basic and translational research, and we welcome John O’Keefe’s statement,  it’s an example that scientists around the world should follow.

The issue of immigration is another important one for science, and John O’Keefe knows this better than most. Born in New York, he completed his PhD at the University on Montreal under the supervision of renowned Psychologist Ronald Melzack, before moving to the UK to undertake a postdoctoral fellowship, and credits the research environment in the UK and at UCL for giving him the opportunity to make his discoveries, and later May-Britt and Edvard Moser spent time as postdoctoral researchers at his laboratory.  For science to flourish scientists must be free to travel to centres of excellence in other countries, to learn skills and establish collaborations that are key to success in many fields of research in the 21st century. This freedom is under threat from narrow-minded isolationism in many countries, for example earlier this year Switzerland found its position as a leading scientific nation undermined by a new immigration law that threatens its ability to recruit talented scientists from abroad, and has disrupted its participation in a key EU research programmes.

John O’Keefe’s warning is a reminder that the threats to scientific research can come from many directions, and of the need for supporters of science to be ready to take action to defend the freedoms on which science is built.

Speaking of Research

Nobel Prize 2014: Fortune favours the prepared mind

Speaking of Research congratulates John O’Keefe, May-Britt Moser and Edvard I. Moser on being awarded the 2014 Nobel Prize in Physiology or Medicine “for their discoveries of cells that constitute a positioning system in the brain”.

Noble_med_medal_intro

By recording the activity of individual nerve cells within the brains of rats that were moving freely through their environment, they have shown how specialised nerve cells work together to execute higher cognitive processes.

In 1971 John O’Keefe identified the first component of the system, by identifying cells in the hippocampus that were only activated when a rat was in a certain position in its environment. These cells were activated when the rat visited the same location, but different nerve cells were activated when the rat visited a new location, these “place cells” were not merely registering visual input, but were building up an inner map of the environment. John O’Keefe is now a professor at University College London, where he studies the neural basis of cognition and memory in humans and animals.

Professor John O'Keefe UCL Institute of Cognitive Neuroscience. Image: David bishop, UCL

Professor John O’Keefe, UCL Institute of Cognitive Neuroscience. Image: David Bishop, UCL

In 2005 May-Britt Moser and Edvard I. Moser identified a second part of the system, a group of nerve cells in the an area of the brain adjacent to the hippocampus named the entorhinal cortex which were activated when a rat passed multiple locations arranged in a hexagonal grid. Each of these “grid cells” was activated in a unique spatial pattern and together they allow the rat form mental representation of a coordinate system that allows the rat to navigate through space. If you would like to learn more about their work at the Norwegian University of Science and Technology in Trondheim, Alison Abbott has written an excellent article in Nature News on the studies that led to the discovery of grid cells and their ongoing research in this field.

May-Britt Moser, Edvard Moser, and the rats that they use in their groundbreaking neuroscience research. Image Geir Mogan/ NTNU

May-Britt Moser, Edvard Moser, and the rats that they use in their groundbreaking neuroscience research. Image Geir Mogan/ NTNU

These place and grid cells have since been found to be present in all mammals, including humans, and equivalents are present in other vertebrates. In humans, the hippocampus and entorhinal cortex are frequently affected in the early stages of Alzheimer’s Disease, and it is hoped that understanding how the positioning system discovered by this year’s Nobel laureates in Physiology or Medicine will help us to understand the mechanism underpinning the loss of spatial memory that often leaves patients unable to recognize and navigate through familiar environments.

This year’s Nobel Prize highlights once again the continuing importance of animal research in pushing the frontiers of Neuroscience, and in particular the critical importance of techniques that use implanted electrodes to record the activities of individual nerve cells.

In an interview following the Nobel Prize announcement John O’Keefe stressed the continuing importance of animal research and warned of the danger to science from excessively strict animal research regulations.

Lasker Awards recognize pioneers of Deep Brain stimulation

The Nobel Prize is of course not the only award that recognizes excellence in scientific and medical research, and since the 1940’s the Lasker Foundation has granted awards to recognize excellence in basic and clinical medical research. In 2014 the Foundation has awarded its Lasker-DeBakey Clinical Medical Research Award to Alim Louis Benabid and Mahlon R. DeLong for “the development of deep brain stimulation of the subthalamic nucleus, a surgical technique that reduces tremors and restores motor function in patients with advanced Parkinson’s disease.”.

Lasker_2014_illustration_clinical_1

The development of deep brain stimulation of the subthalamic nucleus is a classic example of the intellectual cross fertilization between laboratory and clinical research that drives medicine forward, as Dario Ringach described on this blog a couple of years ago in “A Brief History of Deep Brain Stimulation”.

In the award description the Lasker Foundation again highlights the synergy between animal and clinical research.

First it looks at how Mahlon DeLong recognized the significance of the accidental discovery that a chemical called MPTP could induce Parkinson’s disease like symptoms, a discovery that would allow him to resolve long-standing questions concerning the role of different regions of a part of the brain known as the basel ganglia in Parkinson’s disease.

DeLong seized upon the opportunity. A part of the basal ganglia called the subthalamic nucleus drives the inhibitory output signal, and in 1987, DeLong reported that MPTP triggers neurons in the subthalamic nucleus of monkeys to fire excessively. Perhaps, DeLong reasoned, the overexuberant signals quash motor activity in PD. If so, inactivating the subthalamic nucleus might ameliorate some of the illness’s worst symptoms.

Next, he did an experiment that would transform PD treatment. He administered MPTP to two monkeys; as usual, they gradually slowed down until they sat motionless, their muscles stiffened, and they developed tremors. DeLong then injected a second toxic chemical that inactivated the subthalamic nucleus. Within one minute, the animals began to move. Gradually, their muscles loosened and the tremors ceased. These findings strongly supported the hypothesis that hyperactivity in the subthalamic nucleus underlies PD symptoms.”

On the other side of the Atlantic in Grenoble, Alim-Louis Benabid realized that DeLong’s findings could used to greatly improve a new therapy for Parkinson’s disease that he had pioneered.

Although the technique quelled tremors, Benabid knew that this symptom was not the one that most debilitated people with PD. Perhaps high-frequency stimulation of brain areas other than the thalamus (i.e., the subthalamic nucleus) would alleviate the more troublesome aspects of the illness such as slowness of movement and rigidity, he reasoned.

In this state of mind, Benabid read DeLong’s report that damage to the subthalamic nucleus wipes out multiple symptoms of PD in animals. This site was not an attractive target: Lesioning procedures and spontaneous lesions had established decades earlier that, when things went wrong, violent flailing could result. By that time, however, Benabid had performed high-frequency stimulation of the thalamus and other brain regions’ in more than 150 patients. He was confident that he would cause no harm in the subthalamic nucleus; if necessary, he could remove the electrode.

In 1995, Benabid reported results from the first humans who received bilateral, high-frequency stimulation of the subthalamic nucleus—three people with severe PD. The treatment suppressed slowness of movement and muscle rigidity.”

While DBS of the subthalamic nucleus is not a cure for Parkinson’s disease, it can relieve many of the major symptoms, and has benefited tens of thousands of patients around the world whose symptoms are not adequately controlled by first-line therapies. Currently DBS is also being explored as a therapy for several other neurological conditions, including depression and chronic pain.

From Golden Gongs to Golden Geese

What would you think if you read that scientists had received tens of thousands of taxpayer dollars to massage newborn rat pups?

You might think that it is exactly the sort of research that opponents of basic science like to parade as examples when accusing the NIH of wastefulness. However, as usual the truth turns out to be quite different.

In September the 18th Saul Schanberg, Tiffany Martini Field, Cynthia Kuhn and Gary Evoniuk ,  were among the 8 recipients of the Golden Goose Award at a ceremony at the Library of Congress in Washington, D.C., an award established “to demonstrate the human and economic benefits of federally funded research by highlighting examples of seemingly obscure studies that have led to major breakthroughs and resulted in significant societal impact”.

The work began in 1979 with a problem. Cynthia Kuhn and Gary Evoniuk needed to separate newborn rat pups from their mothers as part of their NIH funded research project to investigate the factors influencing two key growth markers, ornithine decarboxylase and growth hormone , but they found that despite being kept fed and warn the pups failed to thrive. What happened next was a classsic example of how careful observation and outside-the –box thinking advances science:

A series of experiments ruled out factors such as nutrition, body temperature and maternal pheromones. The researchers then made the key observation: the rat mothers spent a great deal of time grooming and vigorously licking their pups. Wondering whether the act of stimulation through licking was making the difference, the researchers simulated the mother’s tongue with a small brush and stroked up and down the rats’ tiny backbone. This was the missing link. Enzyme and growth hormone levels rose and the rat pups thrived again.

Field, a psychologist at the University of Miami Medical School who was conducting her own research on how to help premature infants survive and grow, learned of Schanberg’s groundbreaking work and wondered whether it had implications for human infants. In 1986, Field published her own landmark study drawing from Schanberg, Kuhn and Evoniuk’s work with rat pups. Funded by the National Institute of Mental Health (part of NIH), Field’s study demonstrated that using similar tactile stimulation in preterm human infants had immediate positive effects. Premature infants who were massaged for 15 minutes three times a day gained weight 47 percent faster than others left alone in their incubators (standard practice at the time), were more alert and responsive, and were released from the hospital an average of six days sooner than the premature babies who were not massaged.”

Since their discovery tactile stimulation of preterm babies, in the form of infant massage, has become standard practice in many neonatal intensive care units around the world. It has been demonstrated to greatly improve the outcome for babies born prematurely millions of lives around the world, and saved billions of dollars in healthcare costs in the United States alone.

It’s yet another example of how “Off the wall” scientific research can deliver the goods!  Spending on basic scientific research is a crucial long-term investment, one whose precise outcomes are never certain, but which will pay off in both advancing knowledge and improving our future health, well-being and prosperity!

Paul Browne

Crash course in medical history

Opponents of animal research often portray two of the pioneers of experimental physiology, François Magendie (1783-1855) and his student Claude Bernard (1813-1878), as deranged, vicious, and sadistic individuals who derived pleasure in harming animals. Moral philosophers Peter Singer and Lori Gruen convey this sort of message in their book “Animal Liberation: A graphic guide”.

Portrayal of Claude Bernard in Singer and Gruen's book

Portrayal of Claude Bernard in Singer and Gruen’s book

A quick look at how Claude Bernard’s face is portrayed in their book is sufficient to get a sense of Singer and Gruen’s feelings towards scientists who engage in animal research. The peculiar use of quotes around ‘experiment’ in the caption suggests they believe the work did not qualify as legitimate scientific research, nor that it could contribute any benefits to mankind. Such view fails to consider the historical context of their experiments.  In particular, one could ask how were human patients treated by their physicians of the time.

Here is a brief summary of 19th century medicine —

The theory of counter-irritation was in vogue. To counter-irritate basically meant causing additional wounds to the patient as a form of treatment. One technique involved inserting inflamed limbs were into giant anthills. More convenient was produce large blisters by means of a fire iron or acid. In 1824, an article in the Lancet by Dr. Abernathy suggested that a 1 foot square blister was probably a bit too large — several small blisters were indicated instead.  A third method of counter-irritation involved making a saw-shaped wound and inserting dried peas or beans into it. The doctor would then ensure the wound remained open, keeping it from healing, from weeks to months, replacing the peas and/or beans as necessary.

Leeches were used in vast quantities and for many purposes.  Physicians would lower leeches down patient’s throats.  Hundreds of them would be used to bleed a man’s testicle over days. Leeches were also applied to the vagina to relieve “sexual excitement” and, not to discard other orifices, doctors would push them up the anus. It was noted that during these procedures there was always a possibility that some of the leeches would get lost inside the patient body which, according to the physicians of the time, resulted in  “very annoying accidents”.

What about mental disease? A common treatment involved psychiatrists spinning patients in centrifuge-like machines a hundred of times per minute. This is how unruly patients came to understand the authority of the doctor, with one of them asserting that the more lively his intimidation towards the apparatus the more charitable the effects of the therapy.”  

rush

Benjamin Rush’s tranquilizer chair

Benjamin Rush, one of the founding fathers and signatories of the Declaration of Independence, adopted some of these same methods and developed them further.  He would pour acid on his patients backs and cut them with knives to allow the discharge “form the neighborhood of the brain”.  Rush also developed the famous “tranquilizer chair” where patients were restrained for up to entire days — the chair had a convenient hole for defecation at the bottom.

Bloodletting was used to treat a number of ailments.  It also often led to death.  One famous incident involves George Washington, who in 1799 suffered from a bad sore throat and died shortly after a visit by three different doctors who, altogether, took about half of his blood volume. The famous medical journal The Lancet derives its name from the tool used in these procedures.

Given Singer and Gruen’s depiction of animal research one must also ask — How did human surgeries look back then?  By all accounts they were the most excruciating, traumatic and dangerous experience for patients.  As an example, the novelist Fanny Burney recounted part of her experience with a mastectomy as follows:

I mounted, therefore, unbidden, the Bed stead & M. Dubois placed me upon the Mattress, & spread a cambric handkerchief upon my face. It was transparent, however, & I saw, through it, that the Bed stead was instantly surrounded by the 7 men & my nurse. I refused to be held; but when, Bright through the cambric, I saw the glitter of polished Steel I closed my Eyes. I would not trust to convulsive fear the sight of the terrible incision. Yet — when the dreadful steel was plunged into the breast cutting through veins arteries flesh nerves I needed no injunctions not to restrain my cries. I began a scream that lasted unintermittingly during the whole time of the incision & I almost marvel that it rings not in my Ears still? so excruciating was the agony. When the wound was made, & the instrument was withdrawn, the pain seemed undiminished, for the air that suddenly rushed into those delicate parts felt like a mass of minute but sharp & forked poniards, that were tearing the edges of the wound. I concluded the operation was over Oh no! presently the terrible cutting was renewed & worse than ever, to separate the bottom, the foundation of this dreadful gland from the parts to which it adhered Again all description would be baffled yet again all was not over, Dr. Larry rested but his own hand, & — Oh heaven! I then felt the knife (rack)ling against the breast bone scraping it!

Ms Burney was lucky to have survived to describe her experiences.  Most surgeries taking place in surgical theaters simply ended up in death.

The above were some of the common practices of medicine a mere 200 years ago. Magendie was one among the main critics of the dominant medical theories (humorism and vitalism) and the use of unproven methods on human patients. On the use of animals in research he said at a meeting [] I beg my honorable colleague to observe that I experiment on animals precisely because I do not wish to experiment on men.  That is what he felt about medicine — it was nothing short of human experimentation.

In the introductory pages of his Journal de Physiologie Expérimentale Magandie, he added:

“What subject is indeed more fertile in gross errors and absurd beliefs than that of health and disease? Consider the painful disquietude you would produce in the minds of the majority of men if you said to them:There are no such things as rheumatismal humour, gouty humour, scabby virus, venereal virus, and so forth.  Those things which are so designated are imaginary things, which the human mind has created to hide from itself its own ignorance.’   The chances are that you would be taken for a lunatic just as it but recently befell those who maintained that the sun was immovable and the earth turned.”

Any honest reading of medical history has to give credit to the experimental physiologists who put medicine in the right track to become what it is today. The handful of physicians and psychiatrists that speak against animal research should remember that from Hippocrates to the early 19th century, their profession caused more harm than good to their patients.  They ought to be reminded that it was the work of the experimental physiologists that turn this around.  Charles Darwin acknowledged this fact when he wrote:

[] I know that physiology cannot possibly progress except by means of experiments on living animals, and I feel the deepest conviction that he who retards the progress of physiology commits a crime against mankind.

As experimental medicine advanced, so did our ability to treat the potential pain and suffering animals may experience in research.  Animal welfare laws were established. Today, the vast majority of animals participating in research benefit from the use of modern anesthetics and analgesics. The public and our representatives recognize that responsible, regulated animal research has continued to produce new therapies and cures through the years — benefiting humans and non-human animals alike. Stopping the work and depriving future generations of new advances would be immoral.

Responsible Antibody Production

Antibodies Part 2 (read Part 1 here)

As noted in our previous post, there are many promising uses for antibodies. Therefore, it is no wonder that antibody production is big business. The Scientist reported that revenues from antibody sales were over $1.6 billion in 2011. In the United States, antibody producers that use regulated species of animals must comply with the Animal Welfare Act, just as research institutions that use animals must do.

Earlier this year, we reported that one large antibody producer, Santa Cruz Biotechnology (SCB), was accused by the United States Department of Agriculture (USDA) of numerous animal welfare violations. The company originally planned to address these allegations at a USDA administrative law hearing scheduled for the week of July 14, 2014. That hearing has since been postponed while SCB and the USDA try to reach a negotiated settlement on the alleged violations. We would welcome such a settlement if the end result is better animal welfare practices at SCB.

Mice in a Cage

“We would welcome such a settlement if the end result is better animal welfare practices at SCB.”

Meanwhile, the USDA recently announced a settlement with another antibody producer: Rockland Immunochemicals, Inc.  Rockland paid a $32,071 fine for multiple Animal Welfare Act violations in 2012 and 2013. It is noteworthy that all inspections of Rockland Immunochemicals by the USDA thus far in 2014 have indicated that the company was compliant with the Animal Welfare Act. Hopefully, Rockland has learned an important lesson: animal welfare matters

Neither Rockland Immunochemicals nor Santa Cruz Biotechnology discusses corporate responsibility or their commitment to animal welfare on their websites, but other antibody producers do. For example, the Aves Labs website plainly states its commitment to animal welfare and heralds the fact that the company voluntarily sought accreditation of its animal use program by the Association for the Assessment and Accreditation of Laboratory Animal Welfare (AAALAC).   Protocols describing the company’s use of animals for antibody production are also provided on its website.

Other examples of antibody producers with strong commitments to animal welfare and transparency in animal use include ImmunoPrecise, Pocono Rabbit Farm and Laboratory, EMD-Millipore, and Bethyl Laboratories.

We urge all antibody producers to establish corporate responsibility practices and transparency regarding their animal use programs. We also urge scientists and pharmaceutical companies to weigh the producers’ commitment to these important values in selecting which antibodies to use.

Alice Ra’anan and Bill Yates