Category Archives: Science News

Last surviving member of Pittsburgh polio vaccine team dies at 96

Dr. Julius S. Youngner, the last surviving member of the team that developed the Salk polio vaccine in the 1950s, died in his home on April 27 at the age of 96.

Yougner - Image by University of Pittsburgh

Dr. Julius Youngner. Photo courtesy of University of Pittsburgh

Dr. Youngner, like many scientists, pursued a passion to help people via his love of the scientific method.  His own experiences as a child recovering from numerous infectious diseases, including severe pneumonia that almost killed him at age 7, inspired him to pursue a career in science — specifically, virology.

His interest in infectious disease led him to join Dr. Jonas Salk’s vaccine team at the University of Pittsburgh in the quest to fight polio. Polio crippled an average of 1,000 children every day in more than 125 countries during its peak.  The polio vaccine ended this serious illness that plagued the United States from the late 1800s to the mid-20th century.

Dr. Youngner made three critical advances in the polio vaccine research, much of which relied on research with animals. He first devised a way to break down monkey cells so the team could grow large quantities of poliovirus in the lab. He then developed a way to inactivate the virus so it could be safely injected as a vaccine, and finally, he developed tests to determine the vaccine’s effectiveness in the first human patients. The number of polio cases went from an average of 35,000 a year before the vaccine to fewer than 2,500 two years later. Today, polio is virtually eradicated in the United States and much of the world.

Since his polio work, Dr. Youngner made other major advances in virology and immunology, continuing to rely on animal models. Youngner was the first to demonstrate that non-viral agents could trigger interferon infection in animals, and his research team devised a novel approach to antiviral therapy. By demonstrating that the live, attenuated virus vaccine for influenza A interacts with wild-type influenza to confer protection, rather than inducing a protective immune response, Youngner and his team demonstrated that this type of vaccine, tested in animal models, has the potential for significantly reducing morbidity and mortality associated with influenza.

A comprehensive obituary of Dr. Youngner, including his work on the Manhattan Project and his feud with Dr. Jonas Salk, was published on April 28 by the Pittsburgh Post-Gazette.

Research Roundup: An artificial womb for preemie lambs, umbilical cord protein enhances cognition, smartphones to control diabetes, and more!

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • An artificial womb has successfully kept premature lambs alive. Extreme prematurity — infants born at 22 to 23 weeks gestation — is a leading cause of infant mortality, and infants who do survive often have serious disabilities like cerebral palsy or major cognitive deficits. Researchers at the Children’s Hospital of Pennsylvania have developed a first-of-its kind artificial womb that mimics the uterine environment, and have found in studies of lambs that this womb allows the premature lambs to grow normally inside the womb for 3-4 weeks. The thought is that treating the preemies more like fetuses than newborns by extending normal gestation may give them a better chance of survival. The artificial womb, pictured below, is a fluid-filled transparent container that simulates how fetuses float in amniotic fluid inside the mother’s uterus. The womb is attached to a mechanical placenta that keeps blood oxygenated for the fetus. Over the four weeks of study, the lamb fetuses grew to open their eyes, grow wool, breathe, and swim. Human trials are still several years away, though the research team is already in discussions with the Food and Drug Administration. The study was published in Nature Communications and is freely available for download.

  • New research finds that at least one third of all gut nerve cells are replaced weekly. The gut contains the second largest nervous system in the body, the enteric nervous system. Similarly to the number of viable eggs that a woman is born with, it was a once held scientific belief that the gut nerve cells we’re born with are the same ones that we die with. Using healthy adult you mice, and a variety of modern techniques, this study confirmed previous research findings of ongoing neuronal cell loss because of apoptosis (cell death) — although total neuronal numbers remain constant. This observed neuronal homeostasis was found to be maintained from dividing precursor cells that are located within myenteric ganglia. Mutation of these adult precursors led to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Since gut nerve cells were thought to remain unchanged across time, it has limited our understanding and treatment of diseases which affect the gut. These results “enable a new understanding of the pathogenesis of enteric neuromuscular diseases as well as the development of novel regenerative therapies.” This study was published in the Proceedings of the National Academy of Sciences.

  • A new study finds that protein found in human blood makes mice smarter. Previous research investigating the effects of young blood on aging animals has generally focused on within (same) species comparisons. In this study, researchers investigated the role of a human umbilical cord plasma and its effects on aged mice — in particular with respect to hippocampus and behavioral measures of cognition. These particular measures were investigated as impairment is observed in older individuals. They found that human plasma, injected in mice, was associated with revitalization of the hippocampus with increased levels of gene expression there. Additionally, they found that behavioral measures of cognition were also improved. The protein tissue inhibitor of metalloproteinases 2 (TIMP2), was found to be implicated with these positive changes. This study has been published in Nature.

    hippocampus

    Schematic of the hippocampus. Source.

  • The European Ombudsman rejected a complaint by the “Stop Vivisection” European Citizens Initiative that they had not received adequate reasoning behind the decision by the European Commission to reject the initiative in July 2015. “Stop Vivisection” wanted to repeal the European animal research regulation, Directive 2010/63/EU and replace it with a proposal to speed a ban on such practices. The ombudsman noted that the Commission has complied with its duty to explain, in a clear, comprehensible and detailed manner, its position and political choices regarding the objectives of the ECI “Stop Vivisection””.
  • A new study uses your smartphone to control symptoms of diabetes. In a good example of multi-disciplinary translational medicine, and using “a multidisciplinary design principle coupling electrical engineering, software development, and synthetic biology” researchers based at the Shanghai Key Laboratory of Regulatory Biology “engineered a technological infrastructure enabling smartphone-assisted semiautomatic treatment of diabetes in mice.” Hydrogel capsules, containing cells that could produce “mouse insulin” in vivo and which contained wirelessly powered infrared LEDs were implanted in mice. Smartphones were then used to control this implant causing it to secrete “mouse insulin” as needed. Researchers were able to maintain glucose homeostasis over several weeks in the diabetic mice. This study provides a step toward translating cell-based therapies into the clinic. It also highlights that even though this technique was developed in vitro, safety and efficacy trials in animals are needed before they can be used in humans. This study was published in the journal Science.
Apr27_2017_ShanghaiKeyLabOfRegulatoryBiology_DiabeticMouseSmartPhone2447847722.jpg

Photo courtesy of Shanghai Key Laboratory of Regulatory Biology

Open letter: Private workshop on the “necessity” of monkey research does not represent broad public interests or the scientific community

This weekend there will be science marches around the globe. Scientists and science proponents will gather to provide a visible sign of support for work that benefits the public, the environment, and the world in innumerable ways. The march has been highly publicized  – rightfully so, because it serves as a reminder that scientific research and scientists can be threatened in a variety of ways that can have consequences with breadth and depth that should be of concern for society as a whole.

This week there will also be another event that has potential for consequences for science and public health. But it is neither a public event, nor one that has been publicized.

The private event is a workshop titled, “The necessity of the use of non-human primate models in research.” The workshop is supported by Johns Hopkins University and is organized by Prof. Jeff Kahn in the Berman Institute for Bioethics, with participants that include philosophers, bioethicists, a leader of the Humane Society of the US, veterinarians, and scientists– all by invitation only (see roster in workshop agenda below). Its stated goals and approach are: “To help address the issues of the use of NHPs in research, we are convening this working group to examine the science, ethics, and policy aspects of the use of NHPs in biomedical and behavioral research and testing, with the goal of identifying consensus findings, conclusions, and recommendations. The focus of the working group will be to evaluate the current and potential future uses of NHP models, drawing on the approach used in the 2011 IOM Report “Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity” (IOM, 2011).

The group lists as their objective: “The product(s) of the working group process will be a report or series of reports based on the working group’s expert analysis, which will include principles and criteria for assessing the necessity of the use of NHPs in research.” (emphasis added)

Detail is here: Animal Working Group Meeting 1 Briefing Book

In other words, the working group, privately convened, is intent on replicating the 2011 IOM process applied to chimpanzees in order to produce their own principles and criteria for assessing nonhuman primate research broadly. This process should cause grave concern for scientists and for the public who rely on research conducted with nonhuman primates.

The scientific community has publicly weighed in on the necessity of primate research. Most recently, the National Institutes of Health convened a working group to consider nonhuman primate research and concluded “that the oversight framework for the use of non-human primates in research is robust and has provided sufficient protections to date.” Similarly, a letter from over 400 scientists, including Nobel Laureates, rejected a claim from notable public figures that neuroscience research with non-human primates is no longer useful. The hundreds of scientists argued that, “primate research was still critical for developing treatments for dementia and other debilitating illnesses.” (https://www.theguardian.com/science/2016/sep/13/brain-experiments-on-primates-are-crucial-say-eminent-scientists)

Consideration of the ethical justification for research and of the care for animals in research occurs at many levels and in public space. Public health, including the interests of patients and of society as a whole, is integral to those decisions. The scientific community provides expert knowledge about what types of studies are needed for progress in the basic understanding of biology, brain, behavior, and disease and also about how to move forward with new prevention, intervention, and treatment to address health challenges. Funding agencies, such as the National Institutes of Health, are charged by the public to make decisions about science and do so through a process that involves multiple layers of expert review. Federal agencies also oversee research and standards of care for humans and animals involved in studies and provide opportunities for the public to comment on standards and to benefit from decisions.

The private workshop has the appearance of being secretive while also directly opposing the processes in place for responsible public decision-making. As such, it appears to be yet another attempt to influence decisions about science without adequately representing either public interests or the breadth and depth of expertise in the scientific community. Without adequate scientific representation the workshop conclusions cannot be taken as adequately representative of the current state of scientific knowledge. Without adequate representation of the public agencies that safeguard societal interests in scientific and medical progress the workshop conclusions cannot be taken as representative of fact-informed, balanced consideration of research.

Finally, without consideration informed by understanding the fundamental characteristics of the scientific process, the workshop conclusions will only reflect an agenda biased to reach a particular conclusion. As it is framed, it appears that the question of “necessity” is one that cannot account well for the role of basic research, of uncertainty, and of the difference between decisions based in a particular set of values and decisions about the best scientific course of action to answer questions and advance understanding of human and animal health.

For all of these reasons, the reports emanating from this private workshop must be critically examined with healthy skepticism, rather than taken as an authoritative account. We remain concerned that the products of a workshop will serve to advance an agenda that is harmful to public interests in scientific research.

[Note:  If you would like to sign on to this letter please add your name to the comments].

Signatories,

Christian Abee, DVM, DACLAM, Professor and Director, Michale E. Keeling Center for Comparative Medicine and Research, Univ. of TX MD Anderson Cancer Center

Jeremy D. Bailoo, PhD, University of Bern

Allyson J. Bennett, PhD, University of Wisconsin-Madison (Member and former chair, American Psychological Association Committee on Animal Research Ethics)

Michael J. Beran, PhD, Psychology Department and Language Research Center, Georgia State University

James Champion, Morehouse School of Medicine

Julia A. Chester, Ph.D., Associate Professor, Department of Psychological Sciences, Purdue University

Linda C. Cork, D.V.M, Ph.D, Emeritus Professor of Comparative Medicine, School of Medicine, Stanford University  (Senior member of the National Academy of Medicine;  Diplomate of the American College of Veterinary Pathologists)

Robert Desimone, Ph.D., Director, McGovern Institute for Brain Research at MIT, Doris and Don Berkey Professor of Neuroscience

Doris Doudet, PhD, University of British Columbia

Marina Emborg, MD, PhD, Associate Professor, Department of Medical Physics; Director, Preclinical Parkinson’s Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison

Lynn Fairbanks, PhD, Emeritus professor, Department of Psychiatry & Biobehavioral Sciences, Semel Institute, UCLA

Charles P. France, Ph.D., Professor, University of Texas Health Science Center-San Antonio

Patrice A. Frost, D.V.M, President of, and signing on behalf of, the Association of Primate Veterinarians

Michael  E. Goldberg, MD,  David Mahoney Professor of  Brain and Behavior in the Departments of Neuroscience, Neurology, Psychiatry, and Ophthalmology
Columbia University College of Physicians and Surgeons,  and Senior Attending Neurologist, New York Presbyterian Hospital. (Past chair, Society for Neuroscience Committee on Animal Research)

Katalin M. Gothard, MD, PhD, Professor of Physiology, The University of Arizona

Kathleen A. Grant, PhD, Professor, Oregon National Primate Research Center

Sherril Green, DVM, PhD, Professor and Chair, Department of Comparative Medicine, Stanford Medicine

Nancy L. Haigwood, PhD, Director and Professor, Oregon National Primate Research Center, Oregon Health & Science University

Keren Haroush, PhD, Assistant Professor, Department of Neurobiology, Stanford University

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

J.David Jentsch, PhD, Professor of Psychology, Binghamton University

R. Paul Johnson, MD, Director, Yerkes National Primate Research Center

Joseph W. Kemnitz, Ph.D., Professor, University of Wisconsin-Madison

Robert E. Lanford, PhD, Director, Southwest National Primate Research Center, Texas Biomedical Research Institute

Kirk Leech, Executive Director, European Animal Research Association

Jon Levine, PhD, Director, Wisconsin National Primate Research Center; Professor of Neuroscience, University of Wisconsin-Madison

Alexander Maier, Ph.D., Assistant Professor, Department of Psychology, Vanderbilt University

Juan Carlos Marvizon, PhD, Adjunct Professor, David Geffen School of Medicine at UCLA

Earl K. Miller, Ph.D., Picower Professor of Neuroscience, The Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology

John H. Morrison, PhD, Director, California National Primate Research Center, Professor, Department of Neurology, School of Medicine, University of California Davis

Michael Mustari, PhD, Director, Washington National Primate Research Center and Research Professor, Department of Biological Structure, University of Washington

J. Anthony Movshon, University Professor and Silver Professor, Center for Neural Science, New York University

William T. Newsome, Harman Family Provostial Professor, Stanford University, Vincent V.C. Woo Director, Stanford Neurosciences Institute
Investigator, Howard Hughes Medical Institute

Melinda Novak, PhD, Professor of Psychological and Brain Sciences, University of Massachusetts Amherst

Kimberley A. Phillips, PhD, Professor of Psychology and Co-Director of Neuroscience, Trinity University; Affiliate Scientist, Southwest National Primate Research Center, Texas Biomedical Research Institute

Peter J. Pierre, PhD, Behavioral Services Unit Head, Wisconsin National Primate Research Center, University of Wisconsin-Madison

Dario Ringach, PhD, Professor of Neurobiology and Psychology, University of California Los Angeles

Marcello Rosa, PhD, Professor of Physiology, Monash University, Melbourne, Australia

James Rowlett, PhD, University of Mississippi Medical Center (Chair, American Psychological Association Committee on Animal Research Ethics)

Mar Sanchez, PhD, Associate Professor of Psychiatry and Behavioral Sciences, School of Medicine; Yerkes National Primate Research Center, Emory University (Chair, Society for Neuroscience Committee on Animal Research)

Jeffrey D. Schall, Ph.D., Bronson Ingram Professor of Neuroscience, Department of Psychology, Department of Ophthalmology & Visual Sciences, Director, Center for Integrative & Cognitive Neuroscience, Department of Psychology, Vanderbilt University

Igor I. Slukvin, MD, PhD, Wisconsin National Primate Research Center, University of Wisconsin-Madison

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

Robert Wurtz, PhD, Scientist Emeritus, National Institutes of Health

 

Thomas Starzl (1926-2017) – The man who saved countless humans using animal research

Dr. Starzl, a pioneer in the field of surgery and the “father” of organ transplantation in humans, was the first surgeon to perform a human liver transplant.

The liver is a remarkable organ, although more specifically it is a gland. It is essential to the functioning of the human body and is involved in metabolism, the production of hormones, detoxification — to name a few of its many functions. Unlike some of the other organs in the human body — of which we have two, such as the kidneys — there is no redundancy for the liver. For example, if one kidney fails the other kidney can compensate for the loss of function, and in many cases people with one kidney can live a normal life. In contrast, in cases of liver failure the only way to continue living would be liver transplantation; although in the short term — usually while waiting for a liver transplant — liver dialysis may be used. However, the liver is quite remarkable, and unlike many other organs possesses the capacity to regenerate, even if as much as 50 to 75% of the organ is damaged. Chronic liver disease, lasting more than six months, is debilitating and if not assessed early and treated (where possible) leads to death. It is estimated that over 50 million people are impacted from chronic liver disease.

Dr. Starzl’s work on human organ transplants was based on his earlier fundamental (basic) research in dogs. Unaware then of the potential application to humans, Dr. Starzl was investigating the role of nutrient rich blood and its contribution to liver health. Dr. Starzl formulated this question based on a lecture by Dr. Stuart Welch in 1957, who described an experiment where he had grafted an extra liver into a dog. In this experiment, blood left the grafted liver via the same system as the original liver, while the system bringing blood to the liver was different. Dr. Starzl hypothesized that the reason Dr. Welch’s transplant failed was a consequence of the different blood supply which brought blood to the liver.

Image courtesy of the University of Pittsburgh

In his subsequent investigations, Dr. Starzl developed and refined several liver transplant procedures in dogs — with his first success (survival after the operation) occurring in 1958. Between then and 1963, when the first human liver transplantation occurred, much research was being performed into immunosuppression by Dr. Roy Calne — also in dogs. This research was integral to the organ transplant field. Without understanding immunosuppression, the body would reject the donor organ; rendering the transplant useless. This pioneering work, in conjunction with Dr. Starzl’s own work, led to the first attempt at a human liver transplant in 1963. This first transplant was not successful, with the patient dying during the operation. Subsequent operations also resulted in patient death within a few weeks. However, those deaths provided evidence that the donor liver was able to function in the recipient’s body.

Dr. Starzl continued to refine and update his method, later moving his investigations to pigs — grafts from pigs were better tolerated by the human recipient. Then in 1967, he reopened his program and performed the first successful human liver transplant. Mortality after the procedure decreased over time, and “more than half of the liver-transplant patients who underwent surgery in 1998 were alive ten years later, and in 2009, almost 50,000 Americans carried a transplanted liver” (Lasker Foundation).

In 2012, Dr. Starzl and Roy Calne were honoured with the Lasker Award for their pioneering work in liver transplantation – “an intervention that has restored normal life to thousands of patients with end-stage liver disease”.

Complete liver replacement in the dog. The fact that the recipient was a dog rather than a human is identifiable only by the multi-lobar appearance of the liver. Image from University of Pittsburgh

Dr. Starzl was a brilliant scientist with a prolific career; over 2200 articles, 26 honorary degrees, and thousands of lives helped/saved by his work. We have previously written about this here; discussing him receiving the Lasker award. Similar to that post, we recommend reading about Dr. Starzl and his remarkable life here. We also encourage our readers to reflect upon his work, and the remarkable progress that was made using non-human animals for research. In particular, much of his pioneering work was derived from fundamental research investigating surgical procedures in dogs and his later work, refining the method, involved other non-human animals: pigs and baboons. It is often difficult to estimate the prospective benefit of research performed in non-human animals — but Dr. Starzl’s work is a great example of the potential reach of such research.

Jeremy Bailoo

Winners of 2017 Brain Prize announced – Peter Dayan, Ray Dolan and Wolfram Schultz

The one million Euro Brain Prize, awarded by the Lundbeck Foundation in Denmark, has gone to three neuroscientists for their work understanding the mechanisms of reward in the brain. The winners are:

  • Peter Dayan – Director of the Gatsby Computational Neuroscience Unit, University College of London
  • Ray Dolan – Director of the Max Planck Centre for Computational Psychiatry and Ageing
  • Wolfram Schultz – Professor of Neuroscience and Wellcome Trust Principal Research Fellow at the University of Cambridge

Collectively, their work examines the ability of humans and animals to link rewards to events and actions. This capacity has been a foundation of our survival, but can also be the root of many neurological and psychiatric disorders, such as addiction, compulsive behaviour and schizophrenia. In order for the successful survival and reproduction of a species, an animal must be able to make decisions that avoid danger and bring benefits (such as food, shelter, etc.). T decision-making requires predicting outcomes from environmental clues and previously learned responses. For instance, certain smells may indicate that an animal should prepare to chase prey, or to avoid a fruit item. The brain plays a key role in this decision making and learning, and at the centre of this is the neurotransmitter dopamine.

wolfram-schultz

Wolfram Schultz

In the 1980s, Professor Wolfram Schultz developed a way of recording the activity of neurons in the brain that use dopamine to transmit information. He found that the dopamine neurons would respond whenever a monkey was given fruit juice reward. Schultz then showed the animals different visual patterns; whenever a certain pattern was shown, the monkey would receive a reward. After a time the dopamine neurons began to respond to the visual pattern, rather than the juice reward (response to the juice reward itself declined over time). Conversely, when no reward was given (after the correct pattern was shown), the dopamine neuron activity decreased below normal levels. If the reward was given at another time or was bigger than expected, the dopamine neuron activity would spike (1).  This was the first clear demonstration of the neurological basis of one cornerstone of learning theory in Comparative and Behavioural Psychology; Pavlovian conditioning (2).

Building on Schultz’s work, Peter Dayan found the pattern of activity from dopamine neurons described by Schultz resembled the ‘reward prediction error’.  This signal is the difference between predicted and actual reward resulting from an action or event. It continuously updates according to the result of new events and outcomes. Dayan would go on to work with Schultz to create computational models investigating how the brain uses information to make predictions and how this information is updated when new or contrasting information is presented.

Peter Dayan

Peter Dayan

Schultz explains the reward prediction error and resulting learning in the following analogy:

I am standing in front of a drink-dispensing machine in Japan that seems to allow me to buy six different types of drinks, but I cannot read the words. I have a low expectation that pressing a particular button will deliver my preferred blackcurrant juice (a chance of one in six). So I just press the second button from the right, and then a blue can appears with a familiar logo that happens to be exactly the drink I want. That is a pleasant surprise, better than expected. What would I do the next time I want the same blackcurrant juice from the machine? Of course, press the second button from the right. Thus, my surprise directs my behavior to a specific button. I have learned something, and I will keep pressing the same button as long as the same can comes out. However, a couple of weeks later, I press that same button again, but another, less preferred can appears. Unpleasant surprise, somebody must have filled the dispenser differently. Where is my preferred can? I press another couple of buttons until my blue can comes out. And of course I will press that button again the next time I want that blackcurrant juice, and hopefully all will go well.

Which button to push?

Which button to push?

What happened? The first button press delivered my preferred can. This pleasant surprise is what we call a positive reward prediction error. “Error” refers to the difference between the can that came out and the low expectation of getting exactly that one, irrespective of whether I made an error or something else went wrong. “Reward” is any object or stimulus that I like and of which I want more. “Reward prediction error” then means the difference between the reward I get and the reward that was predicted. Numerically, the prediction error on my first press was 1 minus 1/6, the difference between what I got and what I reasonably expected. Once I get the same can again and again for the same button press, I get no more surprises; there is no prediction error, I don’t change my behavior, and thus I learn nothing more about these buttons. But what about the wrong can coming out 2 weeks later? I had the firm expectation of my preferred blackcurrant juice but, unpleasant surprise, the can that came out was not the one I preferred. I experienced a negative prediction error, the difference between the nonpreferred, lower valued can and the expected preferred can. At the end of the exercise, I have learned where to get my preferred blackcurrant juice, and the prediction errors helped me to learn where to find it.

Professor Ray Dolan’s work has involved imaging the human brain in order to understand the mechanisms for learning and decision-making. Advancing the work of Schultz and Dayan, he showed that the reward prediction error can account for how humans learn, and the role that dopamine plays within it. He has collaborated with Dayan for the past decade to investigate human motivation, variations in happiness, and human gambling behaviour.

Ray Dolan

Ray Dolan

Schultz continues to study both animals and humans, using neuroimaging to study changes in neuron signals in Parkinson’s patients, smokers and drug addicts. The more we understand the process which leads people to take certain actions, the better positioned we are to intervene.

Professor Sir Colin Blakemore (University of London), chairman of the Brain Prize selection committee said,

“The judges concluded that the discoveries made by Wolfram Schultz, Peter Dayan and Ray Dolan were crucial for understanding how the brain detects reward and uses this information to guide behaviour. This work is a wonderful example of the creative power of interdisciplinary research, bringing together computational explanations of the role of activity in the monkey brain with advanced brain imaging in human beings to illuminate the way in which we use reward to regulate our choices and actions. The implications of these discoveries are extremely wide-ranging, in fields as diverse as economics, social science, drug addiction and psychiatry”.

Primate research remains today an invaluable tool for comparative research into human health and disease. While other animals remain useful as models for such investigations, non-human primates are arguably the best species to be used for such investigations due to their remarkable similarity to humans. The research performed by Schultz, and built upon by Dayan and Dolan, highlight this simple fact and perhaps also exemplifies why critical consideration against the use of non-human primates for research is needed. The Brain Prize also shows how animal and non-animal methods are often used together to build our understanding of how the brain works.

Speaking of Research

  1. Schultz, W., 2015, Neuronal Reward and Decision Signals: From Theories to Data, Physiol Rev 95(3)
  2. Schultz, W. et al, 1993, Responses of Monkey Dopamine Neurons to Reward and Conditioned Stimuli during Successive Steps of Learning a Delayed Response Task, Journal of Neuroscience 13(3)

Understanding the animal, not just its parts

A recent article in the Atlantic, “How Brain Scientists Forgot That Brains Have Owners” is making headlines. The journalist claims that in an article published in early February, titled “Neuroscience Needs Behavior: Correcting Reductionist Bias”, fancy new technologies have led the field of neuroscience astray. The original scientific publication does draw attention to an area of neuroscience that neglects behavior, and outlines the importance of measuring behavior and the brain. However, behavior is not necessary in all areas of neuroscience, and adding behavior to some neuroscience studies could be problematic. Furthermore, the overall goal of the scientific publication was only to suggest that the field of neuroscience is lacking in scientists interested in studying the whole brain rather than the just studying the sum of its parts.

The field of neuroscience is diverse. Take for example the 9 themes at the Society for Neuroscience Conference in 2016:

  1. Development
  2. Neural Excitability, Synapses, and Glia [Neurophysiology]
  3. Neurodegenerative Disorders and Injury
  4. Sensory Systems
  5. Motor Systems
  6. Integrative Physiology and Behavior
  7. Motivation and Emotion
  8. Cognition
  9. Techniques [Technologies]

Glancing over these themes it is apparent that many scientists specialize in different types of neuroscience. Thus, some neuroscientists may study behavior and some may not need to study behavior. For example, neuroscientists investigating questions about technologies or neurophysiology may not need to study behavior at all — it depends on the question. Those only interested in the integration of physiology and behavior would study both the brain and behavior. And those studying cognition or motor systems might conduct experiments on behavior without directly measuring the brain. Whether neuroscientists study brain and/or behavior depends on the research questions they are asking.

Although both publications neglected to discuss the diversity of neuroscience, the main theme of the scientific publication was to change the way scientists interested in the integration of physiology and behavior approach their research questions. Too many neuroscientists focus on using as many new technologies as possible, and then use behavior as an afterthought. The issue here is that some of these new technologies are not yet well understood. Thus, scientists’ research questions using these technologies could be misguided.

Furthermore, behavior is a separate area of research on its own and should never be treated as an afterthought. Thus, the authors suggest that neuroscience needs more interdisciplinary scientists who understand and study the relationships between brain and behavior. It needs scientists that can merge all areas of the field.

All neuroscientists however, no matter their specific question, will help advance the field in different ways. And all neuroscientists do not need to study behavior. However, Interdisciplinary scientists in particular may set the stage for understanding the whole animal and how the brain operates within it. Furthermore, these scientists may help increase the translation of research from animal to human.

The problem of neuroscience without interdisciplinary scientists

A possible issue with scientists only studying one part of the animal (i.e. the brain) is that they neglect the rest of the animal. The authors suggest many neuroscientists only interested in the brain use a top-down approach (brain-behavior) to infer how behavior operates — and this is problematic. A recent experiment on understanding a simple computer demonstrates the potential flaws in a top-down approach. Briefly, computer scientists tested whether the processes of three classic videogames could be inferred by only studying the microprocessor that operated the videogames. In contrast to the brain, the scientists already understood how this computer system operates. After much investigation of the hardware of the microprocessor and how it functions, it remained unclear how the processes in the videogames operated. Thus, by using a top-down approach to understand behavior we will not be able to understand the brain

The bigger problem with measuring the brain and inferring behavior without studying behavior is that you are only studying one part of the animal. Consider the blind men and the elephant:

blind-men-and-the-elephant

Quite simply, if I am blind-folded and given an elephant’s ear then I may think it is a fan. For me to understand and determine that I am holding an elephant’s ear, I would need to investigate the whole elephant — beyond a small part and beyond all parts individually. Interdisciplinary scientists study the “whole elephant.”

However, only studying the ear of an elephant isn’t completely problematic. I can measure what it is composed of, stick electrodes in it to see how it responds, pour different chemicals on it to see how it reacts, measure how it grows over time, test it in different scenarios etc. Thus, I can learn many different aspects about this so called fan. However, what I cannot do is infer its function or purpose without considering the whole elephant. Also, I may be unable to determine which findings are related to the potential functions, and which findings are not related to the potential functions.

The elephant and the blind men, also apply to all experiments using animal models for understanding human biology. If I do not investigate or consider the whole “elephant” I may never determine that the “ear” I am looking at has a similar function to “ears” in many other animals. More generally, if I only study neural circuitry in a mouse without considering the mouse as a whole (anatomy, organs, cells, behavior, environment, development, evolution, etc.) then it won’t help me determine how — or if – the neural circuitry may function similarly in the human.

Development is particularly important — and often forgotten — ­when studying the whole animal. You cannot just study the “ear” of the “elephant” at a specific time point in a specific environment because the structure or function may change over time. Consider the development of a frog:

development-of-a-frog

In the tadpole stage the frog has a long tail for swimming and gills for breathing underwater. As it develops into an adult frog, however, the tail is reabsorbed and the frog exchanges its gills for lungs. Developmental context is necessary for understanding the whole animal.

The necessity of neuroscience with interdisciplinary scientists

Interdisciplinary scientists study both neural circuitry and behavior to understand the processes of the brain. However, this does not mean that they study parts of the brain, then study some behaviors, and understand the system. It also does not mean that they take a top-down approach (brain to behavior) or bottom-up approach (behavior to brain) — the choice here should depend on the specific research question. Interdisciplinary scientists study both brain and behavior at the same time. By studying both at the same time they can see how behavior emerges from neural circuitry and how neural circuitry emerges from behavior. The two are dependent on one another, they are not separate.

Consider this optical illusion:

optical-illusion-face-and-candlestick

If I just look at the picture on the left, I might only see a chalice and begin describing all of its visual properties and then infer its function. However, if I look at the picture on the right then it might become apparent that the picture is both a chalice and two people looking at each other. If I have too narrow of a focus — only studying the chalice — then I completely miss understanding that this is an optical illusion. Understanding the whole is important, and one part is not the greater than the other.

However, as mentioned earlier when trying to identify the function of an elephant’s ear, if I do not have a starting point for inferring function or mechanism then I could be asking the wrong questions. This is the point that the authors in the original scientific publication also make. If you do not study the behavior of the animal or process that you are interested in, then you will be asking all the wrong questions concerning neural circuitry. One cannot understand the game of chess by just analyzing all the pieces and the board. You must first observe how the game is played, and then you can determine what makes the pieces and the board important.

This is example of watching chess being played first and then analyzing the pieces and the board, represents a top-down approach. However, as already mentioned, the approach you take is particular to the question you are interested in. Different approaches give you different answers. And in the unknown world of brain and behavior, we may really not know enough to properly infer how something functions.

Regardless, this example of chess also applies to all experiments using animal models. For example, I might have learned how to play chess on a large and heavy wooden board with specially molded iron pieces. And as long as I understand the rules and processes of chess, then I can play chess on any board — be it big or small, plastic or wood, physical or virtual. But if I spend all my time studying the chess pieces and never watching how the game is played, then it might be difficult for me to identify which chess piece does what on a different chess set. Just like it would be difficult for me to determine which brain areas of a mouse might be analogous to which brain areas in a human without measuring behavior.

The authors also explain that multiple neural circuits may be responsible for a single behavior, and a single neural circuit may be responsible for multiple behaviors. This further complicates the issue of studying one part of the animal over the other. Thus, one specific neural circuit does not map to one specific behavior.

neural-activity-in-animals-and-the-behaviours-associated

In conclusion, the neuroscientists who published the original scientific article are correct: behavior is necessary and you must study it if you want to understand the brain. However, all the fancy techniques neuroscientists have developed, independent of behavior, help us ask specific questions about neural circuitry and about behavior. Also, all scientists experimenting on animals —not just neuroscientists — should understand the arguments used in this paper and apply it to their own experiments. This will help us better understand how findings in one species might relate to findings in another, and thus help the translation of all science using animal models.

Justin Varholick

Germany’s animal research in numbers for 2015

The statistics for animal research conducted in Germany in 2015 were submitted to the European Commission last week. We have summarised the data below. We compare that to the 2014 statistics also available on their website.

Tierversuche

Animal research in Germany for 2015 by species [Click to Enlarge]

Germany used 2,799,961 animals in 2015, with an overall decrease (15.5%) in animal use when compared to 2014. Similar to other countries, mice remain the most popular species used in animal research, with an increase in use of 5% compared to 2014. Fish, birds, other rodents and other non-mammals saw sizable percentage decreases in their overall use compared to 2014, albeit compared to the total number of animals used, these relative differences are still small. Fish in particular saw a decrease because of differences in reporting between 2014 and 2015. According to the Bundesministerium für Ernährung und Landwirtschaf (BMEL), in 2014, “708,462 “other fish” (including about 563,600 fish larvae) were reported (21.38 percent). By 2015, however, the share of animals in the “other fish” category was only 2.88% (80,777 animals).”

Tierversuche

Mice, rats and fish account for 91% of all animal procedures, rising to 95% if you include rabbits. Similarly to 2014, Germany remains one of the few European countries where rabbits are the fourth most commonly used species in 2015. Dogs, cats and primates accounted for 0.31% of all animals, despite a doubling in the number of animals used for these species.

Tierversuche

Click to Enlarge

This year was the second year where there was retrospective assessment and reporting of severity (i.e. reporting how much an animal actually suffered rather than how much it was predicted to suffer prior to the study). The report showed that 43% of procedures were classed as mild, 17% as moderate, 4% as severe, and 36% as non-recovery, where an animal is anaesthetised for surgery, and then not woken up afterwards. Compared to 2014, there were some noticeable shifts in relation to severity. While the number of procedures which caused animals moderate and severe levels of stress and distress decreased, the numbers of procedures that were terminal increased.

Severity of animal experiments in Germany

Click to Enlarge

Looking at the historical data, we see that like several other countries, the number of animal experiments increased steadily between 2000-2012. The sharp increase in 2014 followed by a decrease in 2015, reflect in part differences in the accounting procedures used between 2014 and 2015. Thus, it is too early to say whether the fall in 2015 is a one-off or a sign of a future drop-off in animal experiments. It is likely that this drop also partly reflects a decrease in funding to science during the recession and economic turmoil of the past few years. Next year’s data may provide some insight into whether and how this trend will continue.

Trends in German animal experiments 2000-15. Click to Enlarge.

Trends in German animal experiments 2000-15. Click to Enlarge.

Other interesting information provided by the annual statistical release includes:

  • 8% of animals used were bred within the EU [Table 3]
  • The main purpose of research was “Basic Research” (58.7%), followed by “Regulatory use and Routine production” (22.5%), “Maintenance of colonies of established genetically altered animals, not used in other procedures”, “Translational and applied Research” (13.6%), and all other uses (5.2 %) [Table 9]
  • Two-thirds of the total dogs, cats and primates were used for Regulatory testing [Table 9]
  • 40% of animals were genetically altered, compared with 60% which were not. Over 98% of the genetically altered animals were mice or zebrafish [Table 20]

For further information about animal research (Tierversuche) in Germany see our background briefing, available in English and German.

Speaking of Research

2015 Statistics: http://www.bmel.de/SharedDocs/Downloads/Tier/Tierschutz/Versuchstierdaten2015.pdf?__blob=publicationFile

2014 Statistics: http://www.bmel.de/SharedDocs/Downloads/Tier/Tierschutz/Versuchstierdaten2014.pdf?__blob=publicationFile

N.B. Some our more eagle-eyed readers may have noted the 2014 statistics referenced in this article do not correspond to those we published a year ago. This is because the German authorities changed the counting methodologies for 2015 and re-released an altered 2014 statistics so that they could be fairly compared to the 2015 data.