Category Archives: Science News

Device to help stroke patients to recover moves from primates to people

Every year, 15 million people worldwide suffer a stroke, resulting in almost six million deaths and five million people left permanently disabled. It occurs when blood supply to the brain is blocked, or a blood vessel bursts. This prevents oxygen reaching the brain and can cause brain cells to die.

Many people who suffer strokes will subsequently experience spasticity, where the arm and leg muscles cramp or spasm as a result of message between the brain and muscle being blocked. This can cause long periods of contraction in major muscles resulting in bent elbows, pointed feet, arms pressed against the chest, or the distinctive curled hand common to many stroke survivors.

Neuroscientists at Newcastle University have developed a new device which aims to help stroke patients by strengthening a spinal connection known as the reticulospinal tract that can take over some of the function of more major neural pathways connecting the brain to spinal cord when they are damaged following a stroke. This strengthening can alleviate the symptoms of spasticity in the hand and arm of patients, allowing them additional control that can help them regain an important degree of independence in their life.

An article published yesterday in the Journal of Neuroscience (1) reports on the early success of this device, which is about the size of a mobile phone and can deliver an audible click followed by a small electric shock to the arm of patients. Electrical stimulation has previously been used to improve nerve function in other types of injury, but the combination with an auditory signal is new. The study shows that the device is able to strengthen the connections in the reticulospinal tract – the nerve tract in the spine which passes messages from the brain to the limb muscles. After a stroke, the body tends to recover the strength of connections to flexor muscles  (which allow you to close your hand)  more than extensor muscles (which allow you to open your hand). This is why many stroke patients suffer from a curled (semi-closed) hand.


Stuart Baker attaches the device to a patient

Healthy patients were wired up to receive weak electric shocks to their arm muscle alongside a click sound. The individuals were then sent about their day. By altering the timing of the clicks and shocks they could strengthen or weaken the patients’ reflexes. By wearing the portable electronic device for seven hours, during which time the patients could carry out their daily work, the scientists were able to show that the signal pathways were strengthened in more than half of the patients (15 of 25).

So how did they discover that following a small electric shock with a click could strengthen the nerve pathways between the brain and the arm? Well, it’s a classic case of “Fortune favours the prepared mind”!

Stuart Baker, Professor of Movement Neuroscience at Newcastle University who has led the work said: “We were astonished to find that a small electric shock and the sound of a click had the potential to change the brain’s connections. However, our previous research in primates changed our thinking about how we could activate these pathways, leading to our study in humans.

In 2012 Baker and his colleagues published a paper reporting on their evaluation of a non-invasive transcranial magnetic stimulation (TMS) in stimulating nerve cells in a part of the brainstem called the reticular formation –  where the reticulospinal tract begins – in anaesthetised macaque monkeys, which they undertook as preparation for using TMS in studies in monkeys and human volunteers.   They observed that while the TMS stimulus produced a the expected quick response in the nerve cells, they also produced a puzzling delayed response, which they thought might be triggered not by the changes in the magnetic field but rather to the audible click that the TMS making made when its coil discharged. To test this idea they used a miniature bone vibrator to generate the same kind of click, and found that it stimulated a very similar pattern of nerve activation to that evoked by the sound of the  TMS coil discharge.

At first they viewed this nerve response to the click sound made by the TMS machine as a complication that needed to be accounted for in future studies of the reticular formation, but very quickly realised that the click response could itself be useful as a non-invasive experimental tool, and might even be useful in the clinic.

Baker wanted to know exactly how much the arm-brain connections were controlled by the reticulospinal pathway they were studying, and determine if the timing of a click following the small electric shock made any difference. To assess this, they got primates to do a similar task to that later evaluated in human volunteers. What they found was that by changing the timing between clicks and small electrical shocks, they could change the strength of reflex of the monkeys by as much as 50%. This has given the researchers the confidence to move this into a clinical trial of stroke patients.


The macaques monkeys were given food rewards for performing a simple movement based task.

Baker recently published an article on The Conversation entitled “Using monkeys for research is justified – it’s giving us treatments that would be otherwise impossible“. An extract is provided below:

In my own work, we use a small number of macaques to gain this fine-grain understanding. Many pathways for movement control are different between primates such as humans and other animals such as rats. Only a primate model can give us information which is relevant to human diseases.

To learn how these pathways are actually used to control movements, in some studies we first teach the macaque to perform complex tasks with their hands or arm. Getting it right is rewarded with a treat (typically fruit or nuts, but chocolate or strawberry yoghurt also sometimes feature). Once they know what to do, we carry out a surgical implant to allow us to record from the brain using fine electrodes, with tips around the same size as single cells.

All surgery is done in a fully equipped operating theatre, with sophisticated anaesthetics and painkilling medication borrowed from state-of-the-art human care. Once the macaque has recovered, we can record from the brain cells while they do the trained task. An animal that is stressed or in pain would not willingly cooperate with the experiments. The animals seem to enjoy the daily interaction with the lab staff and show no distress.

Our studies are right at the crossroads of basic and clinical sciences. We are trying to understand fundamental brain circuits, and how they change in disease and recovery. Over the past ten years, we’ve shown that a primitive pathway linking brain to spinal cord can carry signals related to hand use. That was a surprise, as until now it was assumed that the primate hand was controlled only by more sophisticated pathways that developed later in evolution.

A clinical trial will now start in Kolkata, India, involving 150 stroke patients. It aims to see whether this new device can improve hand and arm control. The work at Newcastle University has been funded by the Medical Research Council and the Wellcome Trust.

chris-blowerChris Blower, 30, suffered a stroke at the age of seven, which paralysed him down onside, slurred his speech and caused him to lose bowel control and move unaided. Though he recovered from these immediate effects, he still suffers slow, limited and difficult movement in his right arm and leg. Here is an extract from his story:

My situation is not unique and many stroke survivors have similar long-term effects to mine. Professor Baker’s work may be able to help people in my position regain some, if not all, motor control of their arm and hand. His research shows that, in stroke, the brains motor pathway to the spinal cord is damaged and that an evolutionarily older signal pathway could be ‘piggybacked’ and used instead. With electrical stimulation, exercise and an audible cue the brain can be taught to use this older pathway instead.

This gives me a lot of hope for stroke survivors. My wrist and fingers pull in, closing my hand into a fist, but with the device Professor Baker is proposing my brain could be re-taught to use my muscles and pull back, opening my hand out. The options presented to me so far, by doctors, have been Botox injections and surgery; Botox in my arm would weaken the muscles closing my hand and allow my fingers to spread, surgery would do the same thing by moving the tendons in my arm. Professor Baker’s electrical stimulations is certainly a more appealing option, to me, as it seems to be a permanent solution that would not require an operation on my arm.

Keith toured the animal house at Newcastle University. He noted after:

The macaque monkey that I observed was calmly carrying out finger manipulation tests while electrodes monitored the cells of her spinal cord.

Although this procedure requires electrodes to be placed into the brain and spine of the animal, Professor Baker explained how the monkey had been practising and learning this test for two years before the monitoring equipment was attached. In this way the testing has become routine before it had even started and the animal was in no pain or distress, even at the sight of a stranger (me).

The animals’ calm, placid temperaments carry over to their living spaces; with lots of windows, natural light and high up spaces the macaques are able to see all around them and along the corridors.

It is great to see Newcastle University being clear about the contribution of animal studies to clincal work. In their press release they noted that “the research published today is a proof of concept in human subjects and comes directly out of the team’s work on primates”.

Baker notes in his recent article,” In my opinion, we should not condemn large numbers of people to disability and dependence, but need to use all of the tools of modern science to discover and innovate the solutions. I am confident that the next 50 years will see wonderful progress in treatments for these terrible disorders and primate research will be central to this effort.

You can read more about animal research at Newcastle University from their website.

Speaking of Research


  1. K.M. Riashad Foysal, Felipe de Carvalho, Stuart N. Baker. Spike-timing Dependent Plasticity in the Long Latency Stretch Reflex Following Paired Stimulation from a Wearable Electronic Device.  Journal of Neuroscience, 

Research with sheep demonstrates utility of new synthetic blood vessels

Children born with heart defects often undergo multiple surgeries throughout their lives because the synthetic materials used to replace blood vessels and heart valves do not grow with the patient (1). The implant needed for an infant will be far too small once that child grows up.  In addition, if the replacement is grafted from another person or from an animal, the child may need to take immunosuppressant drugs for the rest of their lives to prevent their body from rejecting the graft.

Scientists from the University of Minnesota, led by Dr. Robert Tranquillo, tested a new technique in lambs allowing for an implanted graft to grow with the patient (2). The scientists coaxed cells, called fibroblasts, into growing a tube of collagen—a stretchy matrix of protein that gives structure to skin and blood vessels. Once the tube was made, the researchers used a special solution to remove the fibroblast cells. What remained—a flexible collagen vessel—was implanted it into the pulmonary artery of an 8-week-old lamb. Since collagen is the natural structural component of blood vessels, the scientists expected that the lamb’s body would accept the graft and that the new vessel would grow with the animal. And that’s exactly what the researchers saw. Forty-two weeks after implantation, scientists discovered that the replacement artery enlarged in diameter and volume as the lamb grew. The implanted artery had also been fully colonized by the lamb’s own cells and had all the mechanical and biological features of a native artery.

"Researchers are working to create an “off-the-shelf” material that doctors can implant in a patient, and it can grow in the body. This research has the potential to prevent the need for repeated surgeries in some children with congenital heart defects." - Image courtesy of University of Minnesota

“Researchers are working to create an “off-the-shelf” material that doctors can implant in a patient, and it can grow in the body. This research has the potential to prevent the need for repeated surgeries in some children with congenital heart defects.” – Image courtesy of University of Minnesota

This finding builds off of Dr. Tranquillo’s extensive research into cardiovascular tissue engineering (1, 3, 4, 5). Previously, his laboratory has developed “tissue-equivalents” to replace diseased or damaged arteries.  He and his team are also working to develop new heart valves that can be introduced into the patient via a catheter instead of open heart surgery.

Earlier attempts to create implants that grew with the patient required extracting cells from the patient, waiting for them to grow in culture, seeding them within a bio-degradable scaffold, and then implanting the structure back into the patient. These attempts were successful, but since each artery was custom-made, this technique was costly, and would require developing reliable ways to extract and culture cells from patients before it could be widely used. In this new method, the artery does not need to be grown from the patient’s cells—any fibroblasts will work—so replacement arteries can be mass-produced and used ‘off-the-shelf’. In addition, all cells are washed from the collagen tube before implantation, so there’s no risk of rejection by the patient’s immune system. Most importantly, if these experiments from lambs carry over to humans, these grafts should be fully accepted by the patient and grow along with them, meaning that an infant who receives one of these grafts will have a permanent, fully functional blood vessel that won’t need replacement as she or he grows. Tranquillo and his team are working to develop replacement vessels that include valves (3).

"Robert Tranquillo, department head and professor of biomedical engineering, is leading tissue engineering research. He and his team are growing tissue that could one day replace a defective pediatric heart valve." - Image Courtesy of the University of Minnesota

“Robert Tranquillo, department head and professor of biomedical engineering, is leading tissue engineering research. He and his team are growing tissue that could one day replace a defective pediatric heart valve.” – Image courtesy of the University of Minnesota

Many anatomical and physiological similarities exist between the cardiovascular systems of sheep and humans, and large animal models, such as the sheep, are integral in moving research from the laboratory into the clinic. Dr. Tranquillo’s work with sheep and lambs is advancing our understanding of tissue bio-mechanics and could one day allow natural heart valve and blood vessel replacement.

Samuel Henager
Science Policy Fellow, FASEB
Graduate Student, Johns Hopkins University


(1) Implantation of a tissue-engineered tubular heart valve in growing lambs
Reimer, J.M., Syedain, Z.H., Haynei, B., Lahti, M., Berry, J. and R.T. Tranquillo
Ann Biomed Eng (2016). doi:10.1007/s10439-016-1605-7

(2) Tissue engineering of a cellular vascular grafts capable of somatic growth in young lambs
Syedain, Z.H., Reimer, J. M., Lahti, M., Berry, J., Johnson, S., and R.T. Tranquillo
Nat Comm (2016). doi:10.1038/ncomms12951

(3) 6-month aortic valve implantation of an off-the-shelf tissue-engineered valve in sheep
Syedain, Z.H., Reimer, J.M., Schmidt, J.B., Lahti, M., Berry, J., Bianco, R. and R.T. Tranquillo
Biomaterials 73:175-84 (2015).

(4) Implantation of completely biological engineered grafts following decellularization into the sheep femoral artery
Syedain, Z.H., Meier, L.A., Lahti, M.T., Johnson, S.L., Hebbel, R.P and R. T. Tranquillo
Tissue Eng Part A 20: 1726-34 (2014).

(5) Aligned human microvessels formed in 3D fibrin gel by constraint of gel contraction
Morin, K.T., Smith, A.O., Davis, G.E., and R.T. Tranquillo
Microvasc Res 90:12-22 (2013).

Nobel Prize 2016 – how yeast and mouse studies uncovered autophagy

Congratulations to Professor Yoshinori Ohsumi Tokyo Institute of Technology on being awarded the 2016 Nobel Prize in Physiology or Medicine for “for his discoveries of mechanisms for autophagy“!


Yoshinori Ohsumi. Image: Tokyo Institute of Technology

The process of autophagy is hardly one familiar to most people, but is is absolutely crucial to all complex life on out planet, including ourselves. The name autophagy comes from the Greek words for “self” and “eating” and describes the ordered process through which cells break down and recycle unnecessary or damaged structures or proteins, and allows the cell to reach an equilibrium between the synthesis and degradation of proteins.

The discovery of autophagy

The process itself was identified through studies in tissues of mice and rats back in the 1950’s and 1960’s, by scientists including Christian de Duve, who was subsequently awarded the Nobel Prize in Physiology or Medicine in 1974 for this and other work. They first discovered that mammalian cells contain a compartment which they termed the lysosome where proteins are broken down, and then that proteins and other molecules that were to be degraded were first isolated from the rest of the cell by the formation of a membrane sac around the protein in question  (later called the autophagosome). The process through which the autophagosome fused with the lysosome to deliver its protein cargo for degradation was given the name autophagy by Christian de Duve.



Progress in understanding how autophagy worked was slow, as at the time the genes or proteins involved in regulating the process had been identified. With the research methods available at the time it was difficult to measure autophagy as it happened in mammalian cells, and hence difficult to determine how altering different components affected the overall process, a key step towards understanding their role. It may have seemed an unpromising field to join, but Yoshinori Ohsumi had a different career philosophy to most researchers, which he described in an interview given in 2012:

I am not very competitive, so I always look for a new subject to study, even if it is not so popular. If you start from some sort of basic, new observation, you will have plenty to work on.

From cells to genes

What was needed was a simple experimental system in which to study the process, and the bakers yeast Saccharomyces cerevisiae  – a simple single celled organism separated from us by hundreds of millions of years of evolution, but sharing many of our key biological processes – was one candidate. Yoshinori Ohsumi had worked with yeast, and in particular had identified many proteins in a subcellular component of the yeast cell known as the vacuole, which was important as there was evidence that the vacuole performed the same role in yeast cells as the lysosome in mammalian cells. Still, as the Nobel Prize website highlights there were still hurdles to overcome as he began his study of autophagy in yeast at the end of the 1980’s:

But Ohsumi faced a major challenge; yeast cells are small and their inner structures are not easily distinguished under the microscope and thus he was uncertain whether autophagy even existed in this organism. Ohsumi reasoned that if he could disrupt the degradation process in the vacuole while the process of autophagy was active, then autophagosomes should accumulate within the vacuole and become visible under the microscope. He therefore cultured mutated yeast lacking vacuolar degradation enzymes and simultaneously stimulated autophagy by starving the cells. The results were striking! Within hours, the vacuoles were filled with small vesicles that had not been degraded (Figure 2). The vesicles were autophagosomes and Ohsumi’s experiment proved that authophagy exists in yeast cells. But even more importantly, he now had a method to identify and characterize key genes involved this process.

With an experimental system available Yoshinori Ohsumi and his team studied the process of autophagy in thousands of mutant strains of yeast, and identified 15 individual genes (most of them of previously unknown function) that are essential for the process in yeast, tho order in which the key events in autophagy take place, and the roles of the individual genes in them. This was the work for which he was awarded the Nobel Prize.

From yeast genes to us!

But it is not the end of the story! Identifying the genes essential for autophagy in yeast, and their roles in the process, was a major breakthrough, but what about humans and other mammals?

It turns out that that in humans and other mammals there are counterparts to almost all the yeast autophagy genes, though the situation is made a lot more complicated by the face that mammals have more than one copy for each of the genes…starting with yeast was a wise move! Professor Noboru Mizushima of the University of Tokyo made an important advance when, working with Yoshinori Ohsumi,  he developed a transgenic mouse in which a protein called LC3 that is found in the autophagosome membrane is fused to Green Fluorescent Protein (GFP – see Nobel Prize for Chemistry 2008) which allowed him and his colleagues to observe and monitor the process of autophage in vivo in mice for the first time.

Laboratory Mice are the most common species used in research

This LC3-GFP transgenic mouse proved to be a very powerful research tool for studying mammalian autophagy, allowing not only the role of indicudual genes in the process to be determined, but also the role of autophagy itself in processes as diverse as early embryonic development, tumor suppression, nerve cell survival and function, and protection against infection.

This research is still at a relatively early stage, but techniques such as the LC3-GFP system in mice – and others used in organisms such as fruit flies, are showing us how defects in autophagy contribute to many diseases, including neurodegenerative disorders such as Parkinson’s Disease, and metabolic disorders such as type 2 Diabetes. While the development of specific therapies to correct these defects in autophagy is still some way off, it is already clear that understanding autophagy has the potential to improve the treatment of a wide range of illnesses.

What the work of Yoshinori Ohsumi demonstrates once again is the crucial contribution of basic biological research in model organisms that may at first glance appear to share little with us to the advancement of medicine.

Speaking of Research



University of Stirling improving animal welfare for dogs

A study, conducted by the University of Stirling, in collaboration with AstraZeneca and Charles River Laboratories, aimed to look at the impact of modern, purpose-built dog facilities, on the animals’ welfare. Dr Laura Scullion Hall and Professor Hannah Buchanan-Smith, from the Behaviour and Evolution Group (BERG) at the University of Stirling, published a paper (1) that aimed to validate the welfare benefits of the modern home design pens for dogs. The research was funded by the Biotechnology and Biological Sciences Research Council in the UK, and the National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs).

There is a clear body of evidence showing the positive impacts of housing refinement on numerous species (2)(3)(4), however, according to Hall, the design of the home pens for dogs “has received little scientific attention since the 1990s, since when legislative minimum standards have improved”. Dogs spend most of their time in home pens, usually interspersed with occasional use of playrooms. The study compared animal welfare using the modern and traditional home pens.


From left to right: modern home pen; traditional home pen; indoor play area. Image Credit: Behaviour and Evolution Research Group, University of Stirling.

These newer home pens are larger (around 4.8m2/animal compared with the EU minimum of 2.25m2/animal), provide good visibility for the dogs and staff, choice of resting places, noise reducing materials, horizontal rather than vertical bars and enrichment toys inside. The researchers concluded that “the Refinements described here are implemented consistently across industry and suggest that factors such as home pen design should be included in the design of experimental studies.”

Laboratory housed dogs in home pens, AstraZeneca facility. Credit: Laura Hall / Refining Dog Care

Laboratory housed dogs in modern home pens, AstraZeneca facility. Credit: Laura Hall / Refining Dog Care

Dr Hall had previously won an award from NC3Rs for her paper on improving techniques for oral dosing in dogs.  She also developed the “Refining Dog Care” website, to:

[I]mprove the welfare of dogs used in scientific research and testing worldwide, and to improve the quality of data which is obtained from their use. We do this by collaborating with our partners in industry, drawing on expertise and empirical data, to provide guidance on best practice for housing and husbandry, and provide online resources and hands-on training to staff to implement positive reinforcement training protocols for regulated procedures.

Around 4,000 procedures on dogs are carried out in the UK each year (around 0.1% of the total), these are mainly for safety testing, conducted at pharmaceutical or contract research organisations. The fact this research was conducted in collaboration with such organisations will hopefully speed its implementation.

Speaking of Research


  1. Hall et al, 2016, “The influence of facility and home pen design on the welfare of the laboratory-housed dog” in Journal of Pharmacological and Toxicological Methods,
  2. Everds et al, 2013, “Interpreting stress responses during routine toxicity studies a review of the biology, impact, and assessment” in Toxicologic Pathology, 41 (2013)
  3. Hall, 2014, A practical framework for harmonising welfare and quality of data output in the laboratory-housed dog,D. thesis
  4. Tasker, 2012, Linking welfare and quality of scientific output in cynomolgus macaques (Macaca fascicularis) used for regulatory toxicology,D. thesis

2016 Lasker Awards shows importance of animal research

The 2016 Lasker Awards have highlighted some great discoveries and the scientists behind them. This guest post by Samuel Henager, a graduate student at Johns Hopkins University, investigates how animal studies contributed to the discoveries celebrated by this years’ Lasker Awards.

Basic Medical Research Award

The 2016 Albert Lasker Basic Medical Research Award was awarded to William G. Kaelin, Jr. of Dana-Farber Cancer Institute, Harvard Medical School, Peter J. Ratcliffe of University of Oxford, Francis Crick Institute, and Gregg L. Semenza of Johns Hopkins University School of Medicine for their work in discovering how cells sense and respond to changes in oxygen levels.

Image Credit:  Lasker Foundation

Image Credit: Lasker Foundation

Oxygen is crucial for survival, but at the same time, too much can be toxic for cells and damage DNA and proteins. Thus, it is crucial for cells to be able to sense and respond to the concentration of oxygen in its environment. Semenza and Ratcliffe discovered that under low-oxygen conditions the protein hypoxia-inducible factor-1a (HIF-1α) turns on many genes. Subsequently Kaelin and Ratcliffe discovered that under high-oxygen conditions, an enzyme called prolyl hydroxylase caused HIF-1a to be destroyed by the protein von Hippel-Lindau (VHL). VHL is mutated in von Hippel-Lindau disease, which is characterized by large tumors made of blood vessels. In the disease, HIF-1α levels are artificially high due to a defective VHL protein, thus tricking the body into thinking it needs more oxygen, and mistakenly growing unneeded blood vessels to carry oxygen to seemingly low-oxygen tissues.

The discovery of the full pathway for how cells respond to differing levels of oxygen has fueled ongoing research. Stopping the destruction of HIF-1α can help with anemia, a condition where low iron makes red blood cells less effective at carrying oxygen, by increasing the production of red blood cells. There are also cancer treatment applications, as some tumors’ survival depends on HIF-1α to spur the development of new blood vessels.

Anemia. Image Credit: NIH

Anemia. Image Credit: NIH

HIF-1α is conserved across a wide variety of species, and many animal models played a crucial role in the discovery of HIF-1α and its function. The first study by Ratcliffe that indicated a wide-spread response to low oxygen used multiple cell culture systems from monkey, pig, Chinese hamster, rat, and mouse cells. In later studies by Kaelin, Ratcliffe, and Semenza, reticulocytes—precursors to red blood cells—from rabbits were used to generate HIF-1α protein to study in vitro.  Xenopus laevis (frog) cells were used to study how prolyl hydroxylase was involved in the destruction of HIF-1α. C. elegans (roundworm) were used to investigate how mutations in VHL affected a whole organism’s ability to respond to low oxygen levels. Mice were used to study how HIF-1a might be involved in anemia. The discoveries celebrated by this award have fueled new avenues of research and the development of novel therapies, and animal models will surely continue to be a key part of this story.

Clinical Medical Research Award

The 2016 Lasker-DeBakey Clinical Medical Research Award was given to Ralf Bartenschlager of Heidelberg University, Charles M. Rice of Rockefeller University, and Michael J. Sofia of Arbutus Biopharma for their work in developing a system to replicate Hepatitis C virus (HCV) in the lab and for using this system to develop new drugs to cure Hepatitis C infections.

Image Credit: Lasker Foundation

Image Credit: Lasker Foundation

Hepatitis C can be a devastating illness, leading to cirrhosis of the liver, liver failure, and liver cancer.  Previous treatments to fight the infection were highly toxic and did not effectively cure the person from disease. Drs. Bartenschlager, Rice, and Sofia all contributed to discovering a much safer, effective treatment for Hepatitis C.

Hepatitis C prevalence

Hepatitis C prevalence. Image Credit: CDC

The virus responsible for Hepatitis C was identified in 1989. For many years after its discovery, scientists struggled to create a strain of HCV that could replicate under laboratory conditions so that they could study the components and life-cycle of the virus in order to develop treatments or a vaccine. In the late 1990s, Dr. Rice recreated the full genetic sequence of the virus, and used this sequence to infect chimpanzees with the virus. At the time, chimpanzees were the only animal model for hepatitis, and he needed to make sure that the sequence he had identified was capable of replicating and causing disease. At the same time, Dr. Bartenschlager was attempting to infect liver cells using the newly identified sequence, but never detected replication. He was unsuccessful until he inserted a drug-resistance gene into the virus which allowed infected cells to survive when the culture was treated with a lethal drug. He also identified several mutations in the virus that allowed for better replication. With this improved sequence he was able to successfully infect a liver cell line with hepatitis C, which allowed scientists to study the virus in depth and begin to develop therapies for the disease. Dr. Sofia led a team of pharmaceutical researchers that developed a novel therapy for hepatitis. This new therapy is able to cure chronic hepatitis for many patients, who otherwise would be at risk for liver failure and liver cancer.

This is not only a great story of finding a cure for what can be a devastating disease, but also a great example of the value of non-human primate (NHP) research. The cellular replication system developed by Dr. Bartenschlager was important for developing drugs and studying the life-cycle of the hepatitis viruses, but for many years, the only way to study HCV was in a chimpanzee model. Chronic hepatitis C infection can lead to liver cancer, but how the virus or disease contributes to cancer development is not known. Humanized mouse models of hepatitis have been introduced in recent years, and scientists continue to work to improve their accuracy. These mouse models will be crucial as scientists work to unravel the remaining questions surrounding this disease, and work to develop effective treatments and vaccines.

Samuel Henager

Graduate student, Johns Hopkins University

Of White Papers And Commentators: The Use Of Nonhuman Primates In Research

Two weeks ago, nine scientific societies, including the American Physiological Society, the Society for Neuroscience, and the American Academy for Neurology, published a white paper entitled “The critical role of nonhuman primates in medical research“. The paper, which notes how nonhuman primates are critical to all stages of research, provides a huge number of examples of medical breakthroughs made possible thanks to studies in nonhuman primates. Among the paper’s appendices is a list of over fifty medical advances from the last fifty years alone; these include: treatments for leprosy, HIV and Parkinson’s; vaccines for measles, mumps, rubella and hepatitis B; and surgeries such as heart and lung transplants. This is no small feat considering the group of species accounts for around only 0.1% of animal research in most countries (that provide data).


On September 2nd, 2016, John P. Gluck wrote an op-ed for The New York Times called “Second Thoughts of an Animal Researcher“. Gluck is a Professor Emeritus in the Department of Psychology at the University of New Mexico. However, this Op-Ed has not come out of the blue. Gluck has long worked alongside PETA and other animal rights groups to condemn nonhuman primate studies. This op-ed is timed for just before today’s NIH workshop on “Ensuring continued responsible research with non-human primates” – a workshop that PETA is petitioning congress about. The article explains why Gluck stopped conducting animal research, his ethical stance against it, and concludes by saying:

“The federal government should establish a national commission to develop the principles to guide decisions about the ethics of animal research. We already accept that ethical limits on experiments involving humans are important enough that we are willing to forgo possible breakthroughs. There is no ethical argument that justifies not doing the same for animals.”

This is disingenuous of Gluck. The strict regulatory system that exists in the US, and most other developed nations, is the very embodiment of principles aimed to guide decisions on when and how we should conduct studies on nonhuman primates (as well as other species). Some countries have specific regulations surrounding primate research (e.g. the UK considers them a specially protected species and researchers must explain why no other species can be used instead). In the US, all primate research is governed by the Animal Welfare Act (enforced by the USDA), and any research receiving federal funds will also be subject to the Public Health Service Policy on Humane Care and Use of Animals (PHS policy; enforced by OLAW). The PHS Policy also endorses the US Government Principles for the Utilization and Care of Vertebrate Animals Use in Testing, Research and Training, which forms the foundation for ethical and humane care and use of laboratory animals in the US. Every research protocol must be approved by an Institutional Animal Care and Use Committee – a group made up of including scientists, veterinarians and lay-persons – who review and evaluate the study, recommending ways in which it could be improved (both scientifically and from an animal welfare perspective).

Other commentators have noticed this as well. As Wesley J Smith writes in the National Review:

Gluck would have readers believe there are no strict ethical regulations that govern primate research. Nothing could be further from the truth. The Animal Welfare Act already has many stringent requirements governing research on monkeys-as the law should-including cost-benefit analyses, the requirement that any pain experiments cause be palliated, and the requirement that oversight boards approve the purpose and approach of proposed experiments.

Ultimately, Gluck’s article reads as an ethical objection to animal research with some scientific gloss. The heart of his objections is Singer-esque in nature (he mentions Peter Singer earlier in the article). He almost directly condemns our different treatment of humans and nonhuman primates as speciesist:

The ethical principle that many of us used to justify primate experiments seemed so obvious: If you are ethically prevented from conducting a particular experiment with humans because of the pain and risks involved, the use of animals is warranted. Yet research spanning the spectrum from cognitive ethology to neuroscience has made it clear that we have consistently underestimated animals’ mental complexity and pain sensitivity, and therefore the potential for harm. The obvious question is why the harms experienced by these animals, which will be at least similar to humans, fail to matter? How did being a different member of the primate grouping that includes humans automatically alter the moral universe?

No doubt our understanding of the cognitive abilities of animals has improved, and with it has come a greater appreciation for their capacity to suffer. We are a long way from the 17th century philosophers, like Malebranche, who thought animals could not suffer. Our greater understanding of the capacity of animals to suffer pain or distress informs the way we treat animals in laboratories. For example, it was not until the early 1990s that the USDA adopted regulations requiring group housing of nonhuman primates (DiVincenti and Wyatt, 2011), this was thanks to many years of studies showing that nonhuman primate welfare was best met by keeping primates in social groups. As such, it is wrong for Gluck to claim that harm to animals “fail to matter”. While we may give animals a different consideration compared to humans (it is legal to eat animals and keep them as pets), it would be wrong to say they exist outside our moral sphere. The UK’s House of Lords set up a select committee in 2002 to look at animal studies; when assessing the ethics they concluded (s 2.5):

The unanimous view of the Select Committee is that it is morally acceptable for human beings to use other animals, but that it is morally wrong to cause them unnecessary or avoidable suffering.

This is the heart of sensible moral consideration – that we should minimise the suffering of animals wherever possible while realising that we also have a moral imperative to conduct animal studies to reduce greater suffering among humans and animals.

Image from Californian National Primate Research Center

Photo by Kathy West.

Primates at the Californian National Primate Research Center. Reproduced with permission.

And there is no doubt we have a moral imperative. To return to the recent white paper:

Research with monkeys is critical to increasing our knowledge of how the human brain works and its role in cognitive, motor and mental illnesses such as Alzheimer’s, Parkinson’s and depression. This research is also fundamental to understanding how to prevent and treat emerging infectious diseases like Zika and Ebola. NHP research is uncovering critical information about the most common and costly metabolic disorder in the U.S. – type 2 diabetes – as well as the obesity that leads to most cases.

Without NHP research, we lose our ability to learn better ways to prevent negative pregnancy outcomes, including miscarriage, stillbirth and premature birth. This research is also helping scientists to uncover information that makes human organ transplants easier and more accessible, literally giving new life to those whose kidneys, hearts and lungs are failing.

The eradication of these diseases is not worth giving up on. For some animals such research could be the difference between survival and eradication. Ebola has a 95% mortality rate for gorillas. An outbreak in 1995 reportedly killed more than 90% of the gorillas at a national park in Gabon. Overall it is estimated that one third of all the world’s gorillas have been wiped out by Ebola in the last 20 years. If nonhuman primate research (primarily in monkeys rather than great apes), can come up with a vaccine then it will be both animals and humans who can benefit. Humans are unique in that they are the only species with the cognitive capability of making a decision of this magnitude. In the words of Wesley J Smith:

This is the difficult fact that can’t be avoided: We need primate research if we are going to advance science, relieve human suffering, and bring new treatments into medicine’s armamentarium. At some point, we have to decide whether to help humans or not experiment on monkeys.

Looking forward to today’s NIH workshop (which will be streamed live online), it would seem they have struck the right tone. Reviewing the evidence, reviewing the policies, and looking to see what can be improved – that is the essence of science – while still appreciating that the duty of the NIH is to improve the health of a nation.

[T]he Office of Science Policy is taking the lead in planning a workshop on September 7th, 2016 that will convene experts in science, policy, ethics, and animal welfare. Workshop participants will discuss the oversight framework governing the use of non-human primates in NIH-funded biomedical and behavioral research endeavors. At this workshop, participants will also explore the state of the science involving non-human primates as research models and discuss the ethical principles underlying existing animal welfare regulations and policies. NIH is committed to ensuring that research with non-human primates can continue responsibly as we move forward in advancing our mission to seek fundamental knowledge and enhance health outcomes.

Tom Holder

The ethics and value of responsible animal research

This post, signed by over 90 scientists, is in response to an article published 09/04/16 in the New York Times titled: “Second thoughts of an animal researcher.” 

The ethics and value of responsible animal research

Last week we learned that in the first decade since its introduction the HPV (human papilloma virus) vaccine has cut the rate of cervical cancer by half. Experts estimate that the vaccine could eradicate cancer caused by the virus within the next 40 years. This is indeed good news, as today cervical cancer kills about 250,000 women every year.

Such breakthroughs are the result of decades of research that typically begin with the study of basic mechanisms of cancer in-vitro, the development of disease models and therapies in animals, and their translation to humans. In the particular case of the HPV vaccine rabbits, mice, cattle and human volunteers were used in the research dating back to the 1930s, when Richard Shope first isolated viral particles from wart-like tumors in the Eastern cottontail rabbit.

Medical history is replete with such stories and their contribution to human health is undeniable. A couple of generations ago a visit to a physician might have resulted in a recommendation to induce vomiting, diarrhea or, more commonly, bleeding. Diphtheria, mumps, measles and polio were common and untreatable. Treatment for mental health disorders included malarial shock therapy, lobotomy, lifelong institutionalization, and worse. Life expectancy in the U.S. was less than 50 years; it is now close to 80 years.

Animal research was instrumental in most of these past achievements, and the overwhelming majority of scientists agree that the use of animals in research is critical to make progress in many areas of biomedical and behavioral research. However, some members of the public and a few scientists express doubt about the moral justification for the work.

Such is the case with Professor John Gluck, a former primate researcher who conducted lab research decades ago, in the 1960s-1980s, during a time with different standards and regulations compared to contemporary practice. Gluck writes about his own ethical unease which eventually led him to abandon his work with animals and to argue that the existing system for reviewing and conducting animal research should be revised. Gluck appears to think that if others have not arrived at his same conclusion it must be because of their failure to engage in moral reasoning.

Studies in rhesus macaques first indicated that Tenofovir could block HIV infection. Photo: Understanding Animal Research

Studies in rhesus macaques first indicated that Tenofovir could block HIV infection. Photo: Understanding Animal Research

The fact is that most scientists and the public have wrestled with moral questions about the use of animals in research for over 100 years. The results of this ongoing, thoughtful reflection are personal and professional codes of ethics, laws and regulations in the US and other countries, and widespread societal changes in our views and treatment of other animals. Society as a whole considers as morally permissible the regulated and justified use of animals to advance medical knowledge, to improve the well-being of human and nonhuman animals alike, and to understand the health of the environment.

Had animal research leading to the HPV vaccine been banned, cervical cancer today would continue to kill women at a constant rate. Many of us believe that there is a moral imperative to use scientific knowledge and research skills to improve the lives of these women by means of well-regulated, responsible animal research. Opponents may argue that such research should be banned because all nonhuman animals deserve equal moral concern to what we offer human beings.

Image of mice courtesy of Understanding Animal Research

Image of mice courtesy of Understanding Animal Research

As a society we must grapple with and debate these questions and arrive at a democratic decision to such moral disputes. It is unfortunate that meaningful debate is impeded when critics attack the work by falsely claiming that animal research has no value for human health. They incorrectly assert that scientists can do as they please in their laboratories or, worse, that scientists, veterinarians and technicians do not truly care about the well-being of their animal subjects. And they mislead the public by claiming that alternatives exist (such as computer simulations, cell culture, human testing) that can fully substitute the goals of animal research. Indeed, Professor Gluck attempted to reinforce such falsehoods about animal research and animal researchers in his op-ed piece.

The truth is that the care and treatment of animal subjects is protected not only by carefully specified standards, but also by a well-developed federal oversight system that is transparent to the public. Alternatives are used when they exist and when it is possible. Scientists themselves have worked effectively to produce many of the alternative methods and to continue to refine practices to improve animal welfare. The weighing of scientific objectives with consideration of animal welfare is required by law before the approval of any experimental protocol.

Gluck argues that the US government should convene a national commission to consider the ethical treatment of nonhuman animals in medical research. However, he must recognize that animals in research studies are just a small fraction of all animals used by humans for a wide range of purposes that include food, entertainment, labor, clothing, and companionship.

The comparison is particularly true with respect to the number of chickens, turkeys, cows, pigs, and fish that are eaten. But even restricting the discussion to nonhuman primates (the topic of Gluck’s essay) it is also the case that nonhuman primates are a small, but important, fraction- generally less than 1%- of captive animals involved in research. Furthermore, in the US, there are just over 1,000 facilities that house nonhuman primates and that are licensed or registered with the USDA. Of those, fewer than 20% are research-registered facilities. The gross majority are licensed zoos, or various entertainment venues for the public.

Rhesus monkeys at the California National Primate Research Center. Photo credit: Kathy West

Rhesus monkeys at the California National Primate Research Center. Photo credit: Kathy West

Dr. Gluck and others have called on NIH to review its ethical practices when, in fact, following their logic, they should be asking the FDA for a moral justification for the production and consumption of filet mignon. Eating a steak has never saved a life; vaccines and therapies developed with the use of animals in research do so every single day. When such inversion of priorities is made evident, one must conclude that it is not those seeking to advance knowledge and human health via carefully regulated work who are at fault in their moral reasoning.

Moral decisions about the use of animals in research require consideration of the fact that science does not provide a recipe that will lead us directly to a cure for an illness. Instead, it provides a recipe to understand incrementally the physical and biological processes in nature, which we can then apply to make this a better world by reducing suffering for humans and for other animals.

Scientists, students, veterinarians, and staff who engage in biomedical and behavioral research with animals do it not because they have failed to consider the moral issues. They do it precisely because they have thought about them carefully and arrived at the conclusion that failing to do the research would prevent us from developing new cures, such as the HPV vaccine that now stands to eradicate cervical cancer, or being prepared to face new threats, such as confronting the Zika virus.

As the National Institutes of Health convenes this week to examine the science and ethics of research with nonhuman primates, one must remember the important contributions the work has made to the study of child health and development, diabetes and obesity, mental health, transplant tolerance, vaccines, HIV/AIDS, deep brain stimulation (DBS) and the development of brain-machine interfaces, among many other areas. Evidence for the contributions of animal research to such advances is widely available, including most recently, in a white paper. It is this evidence that provides the foundation for why animal research — occurring within an ethical and regulatory framework that requires consideration of both scientific objectives and animal welfare — is endorsed by a wide range of scientific and medical organizations.

Dario L. Ringach, PhD, Departments of Neurobiology & Psychology, University of California Los Angeles

Allyson J. Bennett, PhD, Department of Psychology, University of Wisconsin-Madison

Megan R. Gunnar, PhD, Institute of Child Development, University of Minnesota

Mark A. Krause, PhD, Department of Psychology, Southern Oregon University

Mary Dozier, PhD, Department of Psychology, University of Delaware

Aaron Batista, PhD, Department of Bioengineering, University of Pittsburgh

Bijan Pesaran, PhD, Center for Neural Science, New York University

Brittany R. Howell, PhD, Institute of Child Development, University of Minnesota

Greg Horwitz, PhD, Department of Physiology and Biophysics, University of Washington

John P. Capitanio, PhD, Department of Psychology, University of California-Davis

Jose Carmena, PhD, Helen Wills Neuroscience Institute, University of California, Berkeley

Robert A. Shapiro PhD, Department of Neuroscience, University of Wisconsin-Madison

Koen Van Rompay, DVM, PhD, California National Primate Research Center

David Jentsch, PhD, Department of Psychology, Binghamton University

George F. Michel, PhD, Department of Psychology, University of North Carolina-Greensboro

Chana Akins, PhD, Department of Psychology, University of Kentucky

Ian Nauhaus, PhD, Center for Perceptual Systems, University of Texas at Austin

Kimberley A. Phillips, PhD, Department of Psychology and Neuroscience Program, Trinity University

Drake Morgan, PhD, Department of Psychiatry, University of Florida

Michael Shadlen, MD/PhD, The Kavli Institute for Neuroscience, Columbia University

Ed Callaway, PhD,  The Salk Institute for Biological Sciences

Eliza Bliss-Moreau, PhD, Department of Psychology, University of California-Davis

Mehrdad Jazayeri, PhD, McGovern Institute for Brain Research, MIT

Wayne E. Pratt, PhD, Department of Psychology, Wake Forest University

Ken Miller, PhD, Center for Theoretical Neuroscience, Columbia University

Kristina Nielsen, PhD, The Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University

Mary E. Cain, PhD, Department of Psychological Sciences, Kansas State University

Mar Sanchez, PhD, Department of Psychiatry & Behavioral Sciences, Emory University

Anthony Movshon, PhD, Center for Neural Science, New York University

Michael E. Goldberg, MD, Departments of Neuroscience and Psychiatry, Columbia University

Michele Basso, PhD, Brain Research Institute, University of California Los Angeles

Andreas Tolias, PhD, Baylor College of Medicine

Margaret Livingstone, PhD, Harvard Medical School

Doris Tsao, PhD, Department of Biology and Biological Engineering, California Institute of Technology

Dora Angelaki, PhD, Baylor College of Medicine

Jeff Weiner, PhD, Department of Physiology and Pharmacology, Wake Forest School of Medicine

Elizabeth Simpson, PhD, Department of Psychology, University of Miami

Robert Wurtz. PhD, Scientist Emeritus, NIH

Christian R. Abee, DVM, DACLAM, University of Texas MD Anderson Cancer Center

Jon Levine, PhD, Wisconsin National Primate Research Center, University of Wisconsin-Madison

John H. Morrison, PhD, California National Primate Research Center, University of California Davis

Paul Johnson, MD,  Yerkes National Primate Research Center, Emory University

Nancy L Haigwood, PhD, Oregon National Primate Research Center, Oregon Health & Science University

Michael Mustari, PhD, Washington National Primate Research Center, University of Washington

Andrew A. Lackner, DVM, PhD, Dipl. ACVP, Tulane National Primate Research Center, Tulane University Health Sciences Center

Alessandra Angelucci, PhD, Department of Ophthalmology and Visual Sciences, University of Utah

Brenda McCowan, PhD, Population Health & Reproduction School of Veterinary Medicine, UC-Davis

Alan Brady DVM, ACLAM, Michale E. Keeling Center for Comparative Medicine and Research, University of Texas MD Anderson Cancer Center

Lisa Savage, PhD, Department of Psychology, Binghamton University

Steven J. Schapiro, PhD, Department of Veterinary Sciences, University of Texas MD Anderson Cancer Center

Nicolle Matthews-Carr, PhD, BCBA-D

Stephen I Helms Tillery, PhD, School of Biological & Health Systems Engineering, Arizona State University

Regina Gazes, PhD, Department of Psychology, Bucknell University

Nim Tottenham, PhD, Department of Psychology, Columbia University

Michael J. Beran, PhD, Department of Psychology, Georgia State University

Doug Wallace, PhD, Psychology Department, Northern Illinois University

Gary Greenberg PhD, Professor Emeritus, Psychology, Wichita State University

Richard Born, MD, Harvard Medical School

Lee E. Miller, PhD, Departments of Physiology & Biomedical Engineering, Northwestern University

Paul M Plotsky, PhD, Professor Emeritus, Department of Psychiatry & Behavioral Sciences, Emory University

John J. Sakon, PhD, Center for Neural Science, New York University

Rick A. Finch, PhD, Department of Veterinary Sciences, University of Texas MD Anderson Cancer Center

Charles R. Menzel, PhD, Language Research Center, Georgia State University

Farran Briggs, PhD, Department of Physiology and Neurobiology, Dartmouth University

Alan M. Daniel, PhD, Department of Social Science, Glenville State College

Corrina Ross, PhD, Department of Biology, Texas A&M University

Cynthia Anne Crawford, PhD, Department of Psychology, California State University

William D. Hopkins, PhD, Neuroscience Institute, Georgia State University

Klaus A. Miczek, PhD, Department of Psychology, Sackler School of Biomedical Sciences, Tufts University

Jeffrey Schall, PhD, Psychological Sciences, Vanderbilt University

David A. Washburn, PhD, Department of Psychology, Georgia State University

Gene P. Sackett, PhD, Professor Emeritus, Department of Psychology and National Primate Research Center, University of Washington

Jerrold S. Meyer, PhD, Department of Psychology, University of Massachusetts

Lynn Fairbanks, PhD, Professor Emeritus, Department of Psychiatry and Biobehavioral Sciences, UCLA

Moshe Syzf, PhD, Department of Pharmacology and Therapeutics, McGill University

Mark Seagraves, PhD, Department of Neurobiology, Northwestern University

Thomas Albright, PhD, Salk Institute for Biological Studies

Peter J. Pierre, PhD, Wisconsin National Primate Research Center, UW-Madison

Jack Bergman, PhD, Department of Behavioral Biology, McLean Hospital, Harvard Medical School

Michael A. Taffe, PhD, The Scripps Research Institute

Kim Wallen, PhD, Department of Psychology and Yerkes National Primate Research Center, Emory University

John A. Vanchiere, MD, PhD, Department of Pediatrics, LSU Health Sciences Center – Shreveport

Anita A Disney, PhD, Department of Psychology, Vanderbilt University

Limin Chen, MD, PhD, Department of Radiology & Radiological Sciences, Vanderbilt University

Stanton B. Gray, DVM, PhD, DACLAM, Department of Veterinary Sciences, University of Texas MD Anderson Cancer Center

David Abbott, PhD, Department of Obstetrics and Gynecology, University of Wisconsin-Madison

Ramnarayan Ramachandran, PhD, Department of Hearing and Speech Sciences, Vanderbilt University Medical Center

Dorothy M. Fragaszy, PhD, Behavioral and Brain Sciences Program, Psychology Department, University of Georgia

Joe H. Simmons, DVM, PhD, DACLAM, University of Texas MD Anderson Cancer Center

Kathleen A. Grant, PhD, Department of Behavioral Neuroscience, Oregon Health Sciences University

Gary Dunbar, PhD, Department of Psychology, Central Michigan University

Paul Glimcher, PhD, Professor of Neural Science, Psychology and Economics, New York University

Larry Williams, PhD, Department of Veterinary Sciences, UT MD Anderson Cancer Center

Julie M. Worlein, PhD, Department of Psychology, University of Washington

Nathan Fox, PhD, Department of Human Development and Quantitative Methodology, University of Maryland

Mary Dallman, PhD, Emerita, Department of
Physiology, University of California, San Francisco

W. Thomas Boyce, MD, Departments of Pediatrics and Psychiatry, University of California, San Francisco

Philip H. Knight Chair, PhD, PSI Center for Translational Neuroscience,  University of Oregon

The signatories here are expressing their personal views which do not necessarily reflect those of their institutions.