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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

Dr. Dettmer Goes to Washington, Part 4

Dr Dettmer

Dr Dettmer

In the first 3 parts of this series, I described my experiences at Capitol Hill Day, my interview with the National Association for Biomedical Research, and my interview with Rep. John Delaney (D-MD, 6). In this instalment of the series, I interview Lisa Kaeser, J.D., the Director of Legislation and Public Policy for the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Here, she answers questions regarding her role in the legislative process, focusing in particular on science policy, and the ways in which NIH as an institution – and individual scientists – can become involved.

According to Kaeser, one of the major ways scientists funded by the NICHD, and other institutes within NIH, can become involved is by regularly engaging with their institute’s Office of Legislation and Public Policy about recent scientific discoveries, advances in the field, and especially the rigorous methods involved. This interaction helps these offices to “get it right” when giving briefings to policymakers in Congress.

What role(s) do you take in the legislative process surrounding science policy?

Our office is named the Office of Legislative and Public Policy to address the nexus between science and public policy. Helping to explain scientific advances and the scientific process to policymakers means that we must have a broad understanding of the wide range of science conducted and supported by NICHD. This often takes the form of briefings on Capitol Hill and responding to letters and other inquiries. Of course, I work closely with our scientists to make sure I’m getting it right. Conversely, policymakers in Congress — who must answer to their constituents — offer legislative proposals that may have a helpful, harmful, or benign effect on the science we fund. It’s up to our office to interpret those proposals and, if asked, provide technical assistance on what their impact might be on NICHD’s work.

How does your office work to keep legislators informed of science topics and the latest scientific findings to inform policy?

NICHD has a terrific Office of Communications that provides a huge amount of information on our website, including press releases on new scientific findings and “spotlights” that highlight a researcher or scientific topic area. NICHD also is fortunate to work with a wide variety of constituency organizations that support some aspect of our research. These range from large professional medical societies, to organizations representing scientific disciplines, diseases or condition-specific groups, and are collectively known as the “Friends of NICHD.”  These organizations and their members are effective advocates for science, so it’s critical that we keep them informed about recent advances and get their input on research priorities. For example, NICHD has a monthly newsletter that pulls together the most recent scientific highlights, which we send to all of these groups to help them describe NICHD’s work on Capitol Hill. In addition, the groups are helpful in sponsoring and arranging for congressional briefings, where our scientific staff are asked to speak about research in their fields of expertise.

nichd

What particular steps in the legislative process does NIH become involved in (and, is there an example of science policy that NIH has been involved in that you could provide)?

  • Responding to congressional requests/inquiries: everything from science policy (e.g., stem cell research, research with animals), an update on the latest research developments (e.g., autism), to the status of a grant application in their state or district.
  • Requests for briefings: scientific presentations must be tailored to a lay audience.
  • Requests for technical assistance on proposed legislation: NICHD may not take a “position” on legislation unless the Administration has taken a position. So comments must be limited to what effects the proposed legislative language might have on the research enterprise. For example, legislation that would require NICHD to report back to Congress on progress being made in a specific area might not be especially onerous, whereas legislation that would require establishment of a large research resource (but without additional funding) might not only be redundant with current research efforts, but force difficult funding decisions for the Institute.
  • Preparing for hearings and briefings: The NIH Director is asked to appear before both the House and Senate Appropriations Committees each year. Staff of the 27 NIH Institutes and Centers contribute to a large database of scientific issue briefs that he uses to prepare for the multitude of questions that may be posed by the committees’ members. In addition, each Institute Director may submit a statement for the hearing record that highlights recent research advances and priorities.

In which steps of the process can scientists effectively engage and become involved?

The first step is to become informed about the process, which is what the SfN Early Career Policy Ambassador program, and others like it, do so effectively. While scientists who are Federal employees may not lobby using government time or resources, they are free to speak or write to policymakers on their own time without using their government titles. Non-government scientists are not restricted from working with policymakers, including writing, meetings, or even tours of their labs; they would probably want to work with their home institutions in arranging these visits. And most of the professional societies are deeply engaged in this process, so being an active member of these groups is an excellent way to make your voice heard.

Dr Amanda M. Dettmer

The views and opinions here are solely those of the author and do not reflect the NIH.

Scientific community unites in defence of primate research

The Backstory

It’s been a busy few weeks for those who wish to explain the role of primates in research. Last week the NIH held a workshop on “Ensuring the Continued Responsible Oversight of Research with Non-Human Primates” (watch it back here). The Congressionally mandated workshop resulted from report language that was associated with a PETA campaign. PETA hoped the workshop would question whether primates should be used in research at all. Instead PETA were disappointed when many experts came together to talk about how primates remained important to medical and scientific research. Days before the event, PETA activist, Professor John Gluck, wrote to the New York Times to criticise the use of primates in research. Speaking of Research posted a response – “The ethics and value of responsible animal research” – that was signed by over 100 scientists. Other organisations have subsequently written back to the newspaper with letters published this week.

Over in the UK, a group of 21 academics (primarily anthropologists) including Sir David Attenborough (notable broadcaster and naturalist) wrote to the online-only Independent newspaper to call for an end to certain neuroscience experiments involving primates. This provoked a backlash from the research community, who accused him of being “seduced by pseudoscience“. They may have had a point – Attenborough’s letter,  organised by Cruelty Free International, backed itself up with a recent paper “Non-human primates in neuroscience research: The case against its scientific necessity” (authored by two staff at Cruelty Free International). The UK Expert Group for Non-Human Primate Neuroscience Research told The Independent:

“We are disappointed to see that David Attenborough and a number of scientists have been misled by the pseudoscience in the paper by CFI, an organisation intent on ending research with all animals, not just primates. “

The paper (by Bailey & Taylor, 2016) itself suggests that several medical advances – such as Deep Brain Stimulation – did not rely on animal studies. This would not seem to match what can be seen in the academic literature, indeed Alim Benabid, who won a Lasker Award for his role in developing the technique noted the important role of animal models, including primates.

Researchers Unite!

There are many other events which have played into a frustration by primate researchers, but the response was huge. Understanding Animal Research coordinated a letter on the role of primates in research. Within a few days hundreds of primate researchers and neuroscientists had signed up. Notable signatories included: Sir John Gurdon, who won the 2012 Nobel Prize in Physiology or Medicine, and the 2009 Albert Lasker Basic Medical Research Award, for their work in reprogramming mature cells into early stem cells; Sir John E Walker, who won the 1997 Nobel Prize in Chemistry for elucidating the mechanisms behind the synthesis of ATP; Professor Mahlon DeLong and Alim Benabid, who jointly won the 2014 Lasker-DeBakey Clinical Medical Research Award for their research developing Deep Brain Stimulation as a surgical treatment for Parkinson’s (the same discovery that the Bailey & Taylor, 2016, paper suggested did not require  primates); and Professor Miguel Nicolelis, whose Walk Again project allowed a young paraplegic in an exo-skeleton to kick a football.

neuroscience-starsOver twenty organisations, including Speaking of Research, the Society for Neuroscience (SFN), and the American Psychological Association (APA) signed their support ( a full list of signatories can be found here). The letter was published by the UK newspaper, The Guardian, on 13th September (and the following day in print), along with an accompanying article.

Furthermore, around 400 researchers also signed on to the letter:

Nonhuman primates have long played a key role in life-changing medical advances. A recent white paper by nine scientific societies in the US produced a list of fifty medical advances from the last fifty years made possible through studies on nonhuman primates. These included: treatments for leprosy, HIV and Parkinson’s; the MMR and hepatitis B vaccines; and earlier diagnosis and better treatment for polycystic ovary syndrome and breast cancer.

The biological similarities between humans and other primates means that they are sometimes the only effective model for complex neurodegenerative diseases such as Parkinson’s. More than ten million people suffer from Parkinson’s worldwide, and a recent study estimated that one in three people born in 2015 will develop dementia in their lifetime. Primate research offers treatments, and hope for future treatments, to patients and their families. Already over two hundred thousand Parkinson’s patients have had their life dramatically improved thanks to Deep Brain Stimulation surgery, which reduces the tremors of sufferers. This treatment was developed from research carried out in a few hundred monkeys in the 1980-90s.

Given that primates are intelligent and sensitive animals, such research requires a higher level of ethical justification. The scientific community continues to work together to minimise the suffering of primates wherever possible. We welcome the worldwide effort to Replace, Refine and Reduce the use of primates in research.

We, the undersigned, believe that if we are to effectively combat the scourge of neurodegenerative and other crippling diseases, we will require the careful and considered use of nonhuman primates. Stringent regulations across the developed world exist to ensure that primates are only used where there is no other available model – be that the use of a mouse or a non-animal alternative and to protect the wellbeing of those animals still required. The use of primates is not undertaken lightly, however, while not all primate research results in a new treatment, it nonetheless plays a role in developing both the basic and applied knowledge that is crucial for medical advances.

A segment of the letter printed in the Guardian

A segment of the letter printed in the Guardian

Get involved – show your support!

While, the letter itself is published. Understanding Animal Research are continuing the accept signatories from neuroscientists and primate researchers (signatories must be from academia and must hold a PhD, MD or equivalent). These are being updated on a regular basis on their website.

So if you wish to sign – click here: https://www.surveymonkey.co.uk/r/PrimateLetter

Already they are up to over 550 signatories – just one week after they started collecting (considerably more than the 21 signatories that Cruelty Free International managed in their letter, and with a lot more expertise in the area of Neuroscience).

Speaking of Research

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).

critical-role-of-non-human-primates-in-medical-research

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

Hungary publishes 2015 animal research statistics

Hungary has published its annual statistics showing the number of procedures carried out on animals for scientific purposes in 2015. This post has translated much of the statistics into English and aims to interpret the data as a whole. In 2015, Hungary conducted 184,648 animal procedures on animals – all regulated under EU Directive 2010/63. This figure is 8% lower than in 2014.

Procedures on animals in Hungary for research in 2015. Click to Enlarge

Procedures on animals in Hungary for research in 2015. Click to Enlarge

Overall, 87.7% of procedures were done on mice, birds and rats. This figure rises to 93.8% when cold-blooded animal reptiles, amphibians and fish are included. Dogs, cats and primates together accounted for less than 0.15% of the total.

Trend over time in animal experiments in Hungary. Click to Enlarge.

Trend over time in animal experiments in Hungary. Click to Enlarge.

Using the trend graph we can see how – bar an anomalous year in 2013 – there has been a steady downward trend in animal procedures in Hungary from over 300,000 in 2007, to less than 200,000 in 2015. Perhaps coincidentally the 2013 high point coincides with the implementation of the EU Directive (and its rules around counting procedures), meaning it is possible that this figure is a statistical error caused by incorrect data from the first year under a new counting regime.

Animal Research by Species in  Hungary Pie Chart 2015

Other things to note in the Hungarian statistics:

  • Only 3.8% of animal procedures were on genetically altered animal – a much lower proportion than, say, the UK, where almost half of procedures were the breeding of a genetically altered animal.
  • 40% of procedures were for regulatory purposes, 34% were for translational or applied research, 21% was for basic research, and the remainder was for other purposes. It is common in smaller European countries for a larger proportion of animal studies to be for regulatory purposes.
  • Hungary also provided retrospective severity data for animal procedures. 71% of procedures were classified as mild, 15% as moderate, 6% as severe, and 8% as non-recovery (where the animal is not woken up after being anaesthetised for surgery).

Speaking of Research seek to be the best source of information on the internet on animal research and testing statistics. Unfortunately language barriers mean that we often find it hard to get statistics from non-English speaking countries. If you speak multiple languages and are able to help us out finding the statistics from other countries we would be very grateful. See more about how to help here.

Find more on the Hungarian stats here: https://www.nebih.gov.hu/data/cms/176/152/Allatkiserleti_jelentes_2015.pdf

Speaking of Research

Research using sheep leads to a new device to record and stimulate the brain

A group of Australian and American researchers have used sheep to develop and test a new device (original paper) – the stentrode – for recording electrical signals from inside the brain. The research was published in Nature Biotechnology. This new technology removes one of the main obstacles to developing efficient brain-computer interfaces: the need for invasive surgery.

The “stentrode” is a group of small (750 µm) recording electrodes attached to an intracranial endovascular stent, which allows implantation of the electrodes inside the brain without invasive surgery. This allows high quality recording or stimulation of specific areas of the brain, without many of the risks associated with invasive brain surgery.

Image courtesy of the University of Melbourne

Image courtesy of the University of Melbourne

A stent is a tube-shaped device whose walls are made from a metallic mesh, designed to navigate inside brain’s system of blood vessels, until a desired position is reached. Once in place the mesh is expanded, securing it against the blood vessel walls. Importantly, stents are designed to be implanted by inserting them through a large blood vessel, like the jugular vein, and gradually “pushing” them into the desired position, by twisting and turning at critical juncture points where veins branch. During this implantation procedure the surgeons observe the stent’s location using a non-invasive imaging technique named cerebral angiography.

Recording the electrical activity of brain cells with high fidelity is the basis of new technologies to restore quality of life to many people with neurological diseases. For example, through brain-computer interfaces that interpret neural signals, people paralysed by damage of the spinal cord have been made able to control external devices, such as wheelchairs, robotic arms, and exoskeletons. Much of this work was initially done in monkeys– getting them to also control wheelchairs and robotic arms. Moreover, brain recording devices can be used to detect the timing and location of seizures with great precision, which helps minimise damage to healthy parts of the brain when treatment involving surgery is necessary.

One obvious problem with the current technologies is that there is a clear trade-off between the quality of recordings obtained, and degree of invasiveness. To explain this, let’s look at two extremes of techniques for recording brain activity – electroencephalogram (EEG) and microelectrode arrays.

EEG, recording from the scalp, is by far the least invasive technology: electrical activity of the brain can be recorded through a cap dotted with electrodes, and no surgery is required. However, because the signals being measured are so weak (due to the distance between brain cells and the recording electrodes), this technique can only detect the combined activity of millions of brain cells, when they work at the same moment (signals from small groups of cells tend to average out, not producing an electrical “spike” large enough to be detected far away). Thus, devices controlled by brain-computer interfaces based on EEG tend to be difficult to control, and have few “degrees of freedom” (how many different actions can be specified by the user). Moreover, it is difficult to determine exactly where the signals of interest are coming from, and electrical activity from regions well inside the brain is much harder to detect.

EGG. Image courtesy of Saint Luke’s Health System

EGG. Image courtesy of Saint Luke’s Health System

At the other end of the continuum are recordings using microelectrode arrays- small devices that are implanted directly in the brain, which contain many small metallic probes each capable of “listening” to the electrical activity of a single neurone, or a small groups of neurones. This technique, developed over many years of studies in rats, cats and monkeys, has been used recently to demonstrate the ability of a tetraplegic patient to control its own muscles again, using a brain-computer interface which included a microelectrode array to record the signals that encoded the participant’s intention to move, coupled to stimulation devices attached to different arm muscles.  Much more refined control can be achieved with this method, as one can potentially record individual signals from thousands of neurones, across many brain areas. The disadvantage, however, is clear: these devices have to be implanted directly in the brain, requiring complex neurosurgical procedures. Moreover, the insertion of the electrode arrays in the brain causes local damage, which triggers inflammatory tissue responses that, over time, can reduce the quality of recordings. Although this damage can be minimised by using larger electrodes that lie on the surface of the brain, instead of penetrating it (electrocorticography, ECoG), the need for invasive surgery remains.

Microelectrode array. CC Image by Richard A Normann. Tbe actual size of this array is 4 x 4 mm

Microelectrode array. CC Image by Richard A Normann. Tbe actual size of this array is 4 x 4 mm

As we can see, the stentrode has the potential to be the best of both worlds – offering the accuracy of microelectrode arrays and the benefits of avoiding non-invasive surgery usually associated with technologies like EEG.

Part of the problem solved by the stentrode developers was to find an adequate animal model, which would yield information valid to the situation of the human brain. Sheep were chosen due to the similar topology of the brain’s venous system, and the similar diameter of the critical blood vessels. The stentrodes were implanted inside a large vein that lines the somatosensory cortex – the part of the brain that encodes sensory information about touch, as well as muscle contraction and position of the body’s joints. Importantly, once implanted, they stayed in place without damaging the brain or blood vessels, and allowed stable neural recordings for over 6 months – while the sheep were freely moving around.

Stock image of sheep in research (in the UK) by Understanding Animal Research.

Stock image of sheep in research (in the UK) by Understanding Animal Research.

Currently envisaged applications of this new technique include “reading” signals for control of artificial limbs and seizure prediction in epilepsy. With some modifications, the same technique can be used for localised electrical stimulation of the brain, which may allow new treatments for Parkinson’s disease, and obsessive-compulsive disorder. Deep Brain Stimulation, a currently used treatment to treat the tremors associated with Parkinson’s, requires invasive brain surgery to implant electrodes – this process could be made easier and safer using stentrodes. Besides being good news for people who may one day benefit from an easier way to have electrodes inserted in the brain for treatment of diseases, this story also illustrates two important points. First is the usefulness of animal models to develop treatments that directly benefit people. The sheep brain is not identical to the human brain, but can be judiciously used to model a critical feature of the latter, in a manner that is directly relevant for testing a device intended for human use. Second, that results take time to translate from basic research in animals to human use. The current generation of brain-computer interfaces would never have been developed were it not for decades of research on seemingly “basic” topics, such as how to best record different types of electrical signals from the brain, how and where the brains of various animals encode information for sensation and movement, and how blood vessels are organised and function. This is however just the beginning, and a lot more needs to be done on the way to useful and safe devices.

Marcello Rosa and Tom Holder

Original Paper: Oxley, Thomas J., 2016, Minimally invasive endovascular stent-electrode array for high-fidelity, chronic recording of cortical neural activity, Nature Biotechnology34, 320-327. Doi:10.1038/nbt.3428

Switzerland’s animal research in numbers for 2015

The statistics for animal research conducted in Switzerland in 2015 were released last week. We have translated these tables to English and these data are summarized below.

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Animal Research in 2015 in Switzerland. Click to Enlarge

Number of animals used in research in Switzerland in 2015. We have added a column titled "Total 2014" to aid comparison. Click to Enlarge

Number of animals used in research in Switzerland in 2015 in greater detailClick to Enlarge

Overall, there were 682,333 animals (not including invertebrates except Cephalopoda and lobsters) used in research and animal testing in Switzerland in 2015. Most of these animals were involved in basic research (66.1%), with “discovery, development and quality control” being the next most common (19.2%). The remainder were used for other reasons including disease diagnosis, education and training and protecting the environment. Mice were again the most prevalently used species (60.4%).

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92.2% of the animals used in research and testing were conducted on mice, rats, fish and birds, similar to other European countries. Monkeys (198), cats (621) and dogs (2,518) together accounted for 0.6% of all research animals, with an overall decrease of 547 animals from 2014 for these species.

Animal Research in Switzerland

Animals used in research in Switzerland in 2015. Click to Enlarge

Pain, suffering and harm, were also measured and classified under four grades of severity; 0, 1, 2 and 3. In 2015, 42.9% of experiments were Grade 0, 34% were Grade 1, 21% were Grade 2 and 2.1% were Grade 3. These are defined as follows:

The following four categories are used for constraints on animals resulting from procedures or measures in the context for animal experiments:

  • Severity grade 0 – no constraint: Procedures and actions performed on animals for experimental purposes that do not inflict pain, suffering or harm on the animals, engender fear or impair their general well-being;
  • Severity grade 1 – mild constraint: Procedures and actions performed on animals for experimental purposes that cause short-term mild pain or harm or a mild impairment of general well-being;
  • Severity grade 2 – moderate constraint: Procedures and actions performed on animals for experimental purposes that cause short-term moderate or medium to long-term mild pain, suffering or harm, short term moderate fear or short to medium-term severe impairment of general well-being;
  • Severity grade 3 – severe constraint: Procedures and actions performed on animals for experimental purposes that cause medium to long-term moderate pain or severe pain, medium to long-term moderate harm or severe harm, long-term severe fear or a severe impairment of general well-being.
Severity Data in Switzerland since 1997. Click to Enlarge

Severity Data in Switzerland since 1997. Click to Enlarge

These numbers are relatively consistent across time, with on average 78% of all animals being exposed to no or minor short-lasting pain and distress.

Trend over time in animal experiments in the Switzerland. Click to Enlarge.

Trend over time in animal experiments in the Switzerland. Click to Enlarge.

Overall there has been a steady downward trend in the number of animals used in research in Switzerland over the last 30 years, despite the observed increase in the number of animals used between 2014 and 2015. According to SwissInfo, Switzerland’s federal veterinary office said in a statement that “the increase in animal experiments was linked to studies involving large herds of animals and to species conservation projects”.

See details of Switzerland’s 2014 statistics

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