Category Archives: Science News

Speaking of Addiction Research

J. David Jentsch is a Professor of Psychology and Psychiatry & Biobehavioral Sciences at the University of California, Los Angeles. He is the recipient of the 2010 Joseph Cochin Young Investigator Award from the College on the Problems of Drug Dependence and the 2011 Jacob P Waletzky Award for Innovative Research in Drug and Alcohol Abuse from the Society for Neuroscience. He is a member of the Speaking of Research Committee and writes his own blog: the Unlikelyactivist.

This post is the full version of a piece originally written for Substance.com under the title “A Scientist Comes Out Swinging at PETA’s Addiction Research Stance”.

Biomedical research seeks to expose biological principles and mechanisms that cause disease in order to advance from a time where medications and treatments were discovered by chance to one where we reason our way to solutions for human and animal health through scientific discovery. Since the founding of the National Institute on Drug Abuse (NIDA) in 1974 (only 40 years ago), immense progress has been made into understanding, at the level of brain cells and molecules, why some drugs are addictive, why some people are particularly prone to addictive behaviors and how to treat drug use disorders. One of the reasons that so much progress has been made so quickly is that animal models for drug abuse are remarkably accurate and informative.

In the clearest example of all, if you place a laboratory rat into a chamber and allow it to trigger delivery of cocaine, methamphetamine, nicotine, alcohol, heroin, etc., into their bloodstream by voluntarily pressing a button, they will do so. Rats will seek out and voluntarily “self-administer” drugs of abuse, just like people do, precisely because of the remarkable similarity in the reward pathways in the human and rat brain, as well as due to the fact that these drugs act upon brain chemicals in nearly identical ways in rodents and humans. Moreover, if you allow rats to consume the drug daily over a long period of time, a subset of them will progressively become “dependent” upon the drug, just the same way a subset of people that abuse drugs do. Dependence is indicated by the fact that the subject loses control over their drug use and continues to use the drug, despite efforts to abstain. Because of these incredible parallels between humans and animals, we now understand the mechanisms by which drugs of abuse produce reward at a deep level, as well as how these agents encourage drug-seeking and –taking behaviors. For example, we now know how parts of the brain like the nucleus accumbens, amygdala and prefrontal cortex participate in the development of drug-taking behaviors, and we know how crucial brain chemicals like dopamine and glutamate are to these phenomena. This information would not have been possible without responsible and humane research involving a variety of animal models – ranging from invertebrates (fruit flies, roundworms) to rodents (rats and mice) to non-human primates (mostly monkeys).

Rat Rodent Addiction Animal Testing Research

It is reasonable to ask why, given these advances and the value of animal models, we have not yet cured addictions. The answer is simple. When NIDA was founded 40 years ago, we actually knew very little about the basic biology of the brain and its relationship to drug abuse. Decades of basic research were required before we knew enough about the brain pathways involved in reward to further understand how drugs acted on these pathways and changed them in response to long-term drug intake. Decades of basic research, still on-going, was and remains required to identify all the genes, molecules and cell processes that drugs act on but which were unknown to us as recently as 10 years ago. Basic research continues in an attempt to fully describe how the hundreds of billions of nerve cells in the brain work together to create behavior and how the tens of thousands of genes in our genome affect the function of our bodies. Coupled with amazing advances in the technology needed to study the brain, this knowledge from basic research will yield unprecedented progress towards treating addictions, as well as other disorders of the brain (from Alzheimer’s Disease to schizophrenia) will be possible.

So, what has research into the biology of addictions done for us so far? In a recent blog post, Katherine Roe from PeTA claims that only one new medication has been approved for the treatment of alcoholism/alcohol use disorders based upon animal research in recent years, that it has only “limited” effect and that animal research has “green-lighted” decades of failed medication trials. Not only are each of these statements factually wrong, the truth that is subverted by her points actually demands more animal research, not less.

Firstly, there are actually three medications approved for the treatment of alcohol use disorders (one is old and two are new). One new drug naltrexone (that blocks opioid systems in brain) was approved in 1994; in 2004, the FDA approved another medication (acamprosate). Both specifically target brain chemical systems discovered to be important to alcohol’s effects though animal research. In addition, the development of both medicines required animal research since they act on molecules in brain that might be unknown at all without basic research studies in rodents and non-human primates.

Secondly, referring to the efficacy of these medicines as limited seems to misunderstand the nature of pharmacology. These medications do not effectively treat everyone that is medicated with them – but then, no drug used for any disease does. That’s not the way pharmacology works. That said, for tens of thousands of people with alcohol use disorders around the world, they achieve and maintain abstinence thanks to one or both of these medications: something that wouldn’t be possible for them without the medicines. For those people, animal research on alcohol addiction has literally saved their lives.

Thirdly, the fact of the matter is that the desperate need for medications for drug and alcohol abuse has led both NIDA and the National Institute on Alcoholism and Alcohol Abuse (NIAAA) to undertake many clinical trials for medications before there was adequate evidence for efficacy in animal models. Many of the failed clinical trials involved these kinds of medicines. Therefore, if one is concerned about the failure of clinical trials (and we certainly should be), we should be calling for more investment in research, including in research involving animal models. Saying that animal research had “green-lighted” every single medication is simply and unequivocally wrong.

It is for all these reasons that the drug abuse research community is incredibly supportive of animal-based research. The pre-eminent professional society in this area – the College on the Problems of Drug Dependence – which includes epidemiologists, neuroscientists, clinical psychologists and psychiatrists and policy experts has published a statement clarifying their position on animal research:

There is an urgent need to know more about psychoactive drugs, particularly those features that lead some individuals to escalate initial use into regular use or dependence.  Research with laboratory animals will play a key role in these and related efforts… The College on Problems of Drug Dependence recognizes the value and importance of drug abuse research involving laboratory animals and supports the humane use of animals in research that has the potential to benefit human health and society. Such research plays a vital role in acquisition of the new knowledge needed to understand and reduce drug abuse and its associated problems.

Because drug and alcohol abuse are diseases with far-ranging health effects, contributing to death from overdose, cancer, stroke and metabolic disease, all of the National Institutes of Health (NIH) have a clear interest in seeing research end addictions. Animal activists’ claims that former NIH director Elias Zerhouni has spoken against the value of animal research are misleading given that he has recently made his opinion clear:

I understand that some have interpreted these comments to mean that I think that animals are no longer necessary in medical research. This is certainly not what I meant. In fact, animal models and other surrogates of human disease are necessary — but not sufficient — for the successful development of new treatments. In short, animal models remain essential to the basic research that seeks to understand the complexities of disease mechanism.

Overall, opposition to animal research on addictions seems to require a deep misunderstanding of basic science research, of the state of current scientific understanding of addictions and their treatment and of basic principles of biology, like pharmacology. It also defies the overwhelming consensus of the scientific and drug abuse treatment community that emphasizes the critical need for more research, including animal-based research, in that effort.

J. David Jentsch

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

Better Mice, Better Research, Better Results

This guest post was written by Mark Wanner from The Jackson Laboratory. He has previously written a guest post for us in 2013 responding to an article in the New York Times. This article is adapted from his earlier post on the The Jackson Laboratory blog, Genetics and your health, here. This focuses on a recent Nature commentary by Steve Perrin, which has been misunderstood by many in the animal rights community. Mark also discusses ways of improving the accuracy of the mouse model.

In February 2013, I wrote a post about the use of mice in preclinical research. It was largely in response to a New York Times article about a scientific paper that impugned data obtained from mice used in trauma and sepsis research. The NYT article in turn implied that research using mouse models for human disease was pretty much useless, or misleading at best.

Laboratory Mice animal testing

My counterpoint at the time was that research using inbred mouse strains (or in this case a single inbred mouse strain), while valuable for understanding basic biology, can be very difficult to translate to human medicine for a variety of reasons. It also does nothing to address human genetic variation and the accompanying variability of responses to any one therapy or drug.

So can mice be good experimental models for human disease? Yes, they certainly can, but it’s imperative that changes be made on a broad scale to preclinical (both biomedical and pharmaceutical) research. That’s something that scientists at The Jackson Laboratory have long advocated, and now it’s the point of a comment piece in Nature published in late March titled “Preclinical research: Make mouse studies work” that has generated significant coverage and discussion.

Noise in the data

In the commentary, Steve Perrin, chief scientific officer at the ALS Therapy Development Institute, describes how findings in mice have failed to translate to more effective ALS therapies. Unlike the NYT article, however, Perrin doesn’t imply that mice are necessarily a poor disease model system. He instead asserts that much preclinical research uses mice quite poorly, with specific examples from the ALS field.

Perrin has ample reason to broadcast his concerns. He’s working with a patient population that is inexorably dying. As he says, “patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment.” Sadly, trials of about a dozen treatments that showed survival benefits in a mouse model yielded only one that “succeeded” in human patients in recent years. And even that one, a drug called Riluzole, had minimal benefits.

With the stakes so high, you would think that any experimental therapy that reaches the clinical trial stage would have robust animal data backing it up. That is often not the case, however. As Erika Check Hayden points out in a follow-up piece in Nature News, a particular ALS mouse model that carries a mutation in a protein called TDP43, has a disease phenotype that is quite different from that of humans: “TDP43 mice usually died of bowel obstructions, whereas humans with the disease tend to succumb to muscle wasting, which often results in the inability to breathe.”

TDP43 is but one example of what Perrin calls “noise,” preclinical data that may look good but provides no insights into clinical realities because the research was not sufficiently careful or rigorous. Care and rigor don’t come easily, however, especially for the behind-the-scenes work of developing and characterizing the mouse models needed before good research can even begin. Perrin acknowledges in conclusion: “This is unglamorous work that will never directly lead to a breakthrough or therapy, and is hard to mesh with the aims of a typical grant proposal or graduate student training programme. However, without these investments, more patients and funds will be squandered on clinical trials that are uninformative and disappointing.” Or, as Derek Lowe states more bluntly in a commentary on his “In the Pipeline” blog, which covers the pharma industry: “Crappy animal data is far worse than no animal data at all. . . . If you don’t pay very close attention, and have people who know what to pay attention to, you could be wasting time, money, and animals to generate data that will go on to waste still more of all three.”

Driving change

For decades, The Jackson Laboratory (JAX) has worked to improve the efficacy of its mouse models for preclinical research. It has long recognized the limitations inherent in working with only one or two strains of inbred mice—imagine testing a drug in only one or two people!—and has spearheaded the development of mouse populations (Collaborative Cross and Diversity Outbred) that provide effective models of human genetic variation. It works to fully characterize both the genotypes and phenotypes of the mouse strains it distributes and to share the data with the research community. It has been at the forefront of developing mice that express human disease genes and/or recreate the human immune response.

“JAX has provided leadership from the beginning, even before disease foundations and funding agencies realized this was a problem,” says Associate Professor Greg Cox, Ph.D., who studies neuromuscular degeneration, including forms of ALS, at JAX. “It is nice to finally hear the message coming from someone other than the ‘fanatical’ mouse biologists. It is up to us to make sure that poorly designed mouse genetics experiments stop, both for the sake of good biology and for future decisions regarding clinical applications of the research.”

So how do you design experiments well? Perrin lists four ways to fight “noise.” The first three are basic ways to correctly manage research animal populations—exclude irrelevant animals (i.e. unrelated mortality), balance for gender and split littermates—but the fourth, track genes, may be the most vital. If you don’t know the animals’ precise genotypes and as much as you can about normal and disease phenotypes, it’s just about impossible to generate relevant data. Differences between background strain genetics can yield highly misleading results, making correct strain characterization essential. Also, inheritance between generations needs to be carefully tracked.

Another way to significantly improve the power of preclinical research is to use mouse panels that reflect human genetic diversity rather than one or two inbred strains. As long ago as 2009, JAX Professor Ken Paigen and collaborators at the University of North Carolina at Chapel Hill effectively implemented a new approach to testing drugs for potential toxicity. Paigen and colleagues tested acetaminophen, the commonly used NSAID, on 40 different mouse models chosen specifically for their strain genetics. The research revealed several gene variations associated with toxic reactions, which the researchers then matched with those in human patients experiencing adverse reactions to the drug. Such screening, which could also provide essential information regarding the effects of genetic variation on efficacy and general side effects, is not part of the current standard drug testing process.

Perrin calls for a community effort to generate the mouse models needed to undertake effective preclinical research. JAX has already served as a vital hub to several such efforts, collecting, curating and distributing mouse strains useful for research into many diseases. These mouse repositories provide researchers access to quality control, standardization and mouse genetics expertise unattainable without a central resource of this nature.

Last July I wrote about the pervasiveness of positive bias in preclinical research findings and the associated problems. Now Perrin’s commentary indicates that such positive bias is based on generally poor data. More thought and care are not only important for preclinical research, they’re absolutely necessary. Using mice in a way that provides valuable, translatable preclinical data takes far more up-front time and money, investments that can be difficult to justify in competitive pharma and academic settings. But the costs of not doing good research—and generating “crappy” animal data—are immeasurable on both financial and human scales.

Mark Wanner

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

Santa Cruz Biotechnology: Dealing with Bad Behavior

We believe that the vast majority of scientists who study animals and the professionals charged with providing them care have a deep regard for animal welfare. However, as in any field, some people lack commitment to the standards of their profession, and this casts a shadow over everyone else. After all, how can people know whether this behavior is the exception or the rule?

Santa Cruz Biotechnology (SCBT) is a major producer of antibody products that stands accused of major animal welfare violations. Antibodies are substances produced by certain white blood cells as part of the body’s immune defenses. Their job is to tag foreign proteins, marking them for destruction by other cells in the immune system. Due to their widespread usefulness, antibodies sales is a multi-billion dollar a year business. Because each antibody targets a specific protein, they are important for both medicine and research. Since antibodies latch onto proteins that are markers for specific diseases, doctors can use them to diagnose these conditions in patients. Doctors also use antibodies to treat certain diseases, including some cancers. Researchers use antibodies to detect the presence of particular proteins and also to isolate proteins within a sample of blood or tissue.

nerve cells, neurotransmitter, antibodies

Brain sample where nerve cells containing a particular neurotransmitter were detected using antibodies.

Commercial antibody production usually involves injecting animals with a foreign protein and then collecting blood to harvest the antibodies generated in response to that protein. When done correctly, this process should not cause any pain or distress to the animal. Antibody production is most commonly done in rabbits, although sometimes large animals such as goats and donkeys are used since they are able to provide larger blood samples without ill effects to them.

Research institutions that conduct animal research must register their facilities with the USDA and comply with the requirements of Animal Welfare Act (AWA). Companies that use large animals to produce antibodies also fall under the AWA. However, as has been widely reported, SCBT stands accused of repeated, severe violations of many of the USDA’s AWA regulations (Nature, The Scientist, The New Yorker, the Mercury News, Santa Cruz Sentinel, and Monterey Herald).

The USDA uses a risk-based inspection system to focus more of its resources on facilities where there is a history of problems. SCBT was subject to a whopping nine unannounced inspections by the USDA in 2012 because of problems noted in previous years. Each of those inspections documented inadequate veterinary care at the SCBT facility. Its record of Animal Welfare Act violations was deemed to be so serious that on July 19, 2012, the USDA issued a formal complaint against the company. The complaint cited such serious problems as a lack of adequate veterinary care, improper handling of the animals, and poorly-trained animal care personnel.

A USDA complaint is a legal document requiring the recipient to address the concerns raised. Most institutions that are subject to such a complaint respond by working with the agency to rectify the situation by bringing their program into compliance with the Animal Welfare Act. However, SCBT has not attempted to do so. Rather, it plans to respond to the charges at a hearing scheduled for July 14-18, 2014.

Even after the USDA issued its July 2012 complaint against SCBT, the company did not mend its ways. On October 31, 2012, USDA inspectors reported finding SCBT animal facilities that had never been registered with the agency or inspected as required by law. The inspectors also said that some of the animals at this secret facility were in poor health.

The New Yorker reportedly contacted SCBT’s attorney, who said that the company “has strong defenses that will be addressed in the litigation.” Our U.S. legal system upholds the principle of innocent until proven guilty so we do not want to jump to conclusions. Nevertheless, if these serious allegations are true, then SCBT deserves condemnation for its callous treatment of animals.

Alice Ra’anan and Bill Yates

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

How to help girls with Rett syndrome, and strike a blow against extremism!

Today we have a guest post by Dr Nicoletta Landsberger, Associate Professor at the University of Insubria and Principle Investigator at the San Raffaele Rett Research Center. The San Raffaele Rett Research Center is supported by the Pro Rett Ricerce (proRett), a small but energetic Italian patient organization that funds research in Italy and abroad to find a cure for the neurodevelopmental disorder Rett syndrome, which affects about 1 in 10,000 girls. 

A fortnight ago Dr Landsberger was forced to cancel a fundraising event – which included a raffle – for proRett due to the threat of disruption from animal rights extremists. Our friends in Pro-Test Italia wrote an open letter to Italian prime minister Matteo Renzi about this attack on medical progress, and bought 200 tickets for the raffle (worth 400 Euros).

Regular readers of this blog will be well aware of the recent increase in animal rights extremism in Italy, but the campaign against a charity that seeks to find effective therapies for a disease that devastates many thousands young lives around the world marks a new low. We need to support our friends in Italy, to support the children who suffer from Rett syndrome, and to send a strong message to animal rights extremists that their intimidation and bullying will not be tolerated. We are not asking you to march in the streets, or to sign a petition, or even to write a letter, we are asking you to do something a lot simpler; we are asking you to make a donation to proRett.

Please take a few minutes to give proRett what you can via their PayPal account, even a small donation will help (The PayPal account is in Italian, but essentially identical to the English language version. United States is Stati Unita in Italian, and United Kingdom is Regno Unito. If you are unsure of anything just use Google Translate).

Imagine Anna, a wonderful eight months girl sitting in her high chair and turning the pages of a book while watching it. Imagine Anna’s mother showing you other pictures of her daughter, smiling to her siblings or grasping objects. Everything seems normal, but then, few months later, the pictures are different. Anna is not smiling anymore, the expression of her face is different, the brightness has disappeared and in many pictures Anna has protruding jaws. Anna’s mother tells me “this is when I realized that something was changing…. At that time Anna’s progress stopped, the ability to hold the book and turn its pages was lost, overcome by continuous stereotyped hand-wringing movements. Rett syndrome and its regression phase were taking Anna away, locking her in her body for good”.

Anna is now 16, she is wheel chair bound, unable to talk and to play; like most girls affected by Rett syndrome she suffers from seizures, hypotonia, constipation, scoliosis, osteopenia, and breathing irregularities. Like most girls affected (over 90%) by typical Rett syndrome she carries a mutation in the X-linked MECP2 gene.

Today, almost 30 years after Rett syndrome was internationally recognized as a unique disorder mainly affecting girls, we know that it is a rare genetic disease, and that because of its prevalence (roughly 1:10.000 born girls) can be considered one of the most frequent causes of intellectual disability in females worldwide.

Rett syndrome is a pediatric neurological disorder with a delayed onset of symptoms and has to be clinically diagnosed relying on specific criteria. Girls affected by typical Rett Syndrome are born apparently healthy after a normal pregnancy and uneventful delivery and appear to develop normally usually throughout the first 6-18 months of life. Then their neurological development appears to arrest and, as the syndrome progresses, a regression phase occurs that leads to a documented loss of early acquired developmental skills, such as purposeful hand use, learned single words/babble and motor skills. During the regression phase, patients develop gait abnormalities and almost continuous stereotypic hand wringing, washing, clapping, and mouthing movements that constitute the hallmark of the disease. Many other severe clinical features are associated with typical Rett syndrome, including breathing abnormalities, seizures, hypotonia and weak posture, scoliosis, weight loss, bruxism, underdeveloped feet, severe constipation and cardiac abnormalities. Rett syndrome patients often live into adulthood, even though a slight increase in the mortality rate is observed, which is often caused by sudden deaths, probably triggered by breathing dysfunctions and cardiac alterations. There are no effective therapies available to slow or stop the disease, only treatments to help manage symptoms.

Genetic analyses show that most cases are caused by a mutation in the X-linked MECP2 gene, and many different missense mutations and deletions have been identified within the MECP2 gene of girls with Rett syndrome that prevent the protein from functioning correctly. The formal genetic proof of the involvement of the MECP2 gene in Rett syndrome is further provided by a number of diverse mouse models carrying different MECP2 alterations, which display the same symptoms observed in human patients (for more information see this recent open-access review by David Katz and colleagues) . These animals that fully recapitulate the disease have permitted us to demonstrate that the neurons have a constellation of minor defects, but that no degeneration is occurring, and that our brain need MECP2 at all times. Whenever the gene gets inactivated the disease appears.

Genetically modified mice have made crucial contributions to our understanding of Rett syndrome. Image courtesy of Understanding Animal Research.

Genetically modified mice have made crucial contributions to our understanding of Rett syndrome. Image courtesy of Understanding Animal Research.

Rett syndrome is mainly a neuronal disease, and obviously the amount of research we can do with the girls’ brains is limited. Because of this a range of mouse models of the disease have been instrumental for the study of the pathology. Furthermore, the same mice have permitted scientists to find the first molecular pathways that appear altered in the disease leading to test some therapeutic molecules in mice. Translational research leads to a clinical trial; and this is the case here, for example a clinical trial of IGF1 therapy is currently under way. Importantly, in 2007, Professor Adrian Bird and colleagues at the University of Edinburgh demonstrated in a mouse model that it is in principle possible to reverse Rett syndrome, and that MECP2-related disorders can be treated even at late stages of disease progression. However, the functional role(s) of MECP2 and their relevance to different aspects of development and neurological function are not fully understood, and different mutations in the MECP2 have varying effects on these roles, which any treatments will have to account for. Research indicates that too much MECP2 expression can be damaging, so scientists will need to find a way to express just the right amount of MECP2, in just the areas it is required. The clinical community has decided that no drug can be given to Rett syndrome girls without having first been tested in two different laboratories and on at least two diverse mice models of the disease. Nevertheless, this research is very promising, and not just for those with Rett syndrome and their families, as the insights gained through developing therapies for Rett syndrome are likely to be applicable to therapeutic strategies for a wide range of neurodevelopmental disorders. Studies in mouse models of Rett syndrome have a crucial role to play in this ongoing work.

proRETT is an association founded in 2004 by parents of children born with Rett syndrome, who began their activity by raising funds for the US based Rett Syndrome Research Foundation (now the International Rett Syndrome Foundation). proRett now supports the work of top Rett researchers in Italy, the UK and USA. I am a professor of molecular biology who has worked on MECP2 since I was a post-doctoral fellow in the team of the late Dr Alan P Wolffe at the National Institute of Child Health and Human Development.

In 2005 I met with proRETT to launch a collaboration in order to accelerate the scientific interest in the disease in Italy and abroad, and over the next few years   we worked together to organize two international scientific meetings (e.g. the European Working Group on Rett Syndrome) and attracted the interest of several Italian researcher to the disease. In 2010 proRETT felt the necessity to support more research in Italy and decided to open a laboratory – the San Raffaele Rett Research Center  – at the prestigious San Raffaele Scientific Institute in Milan. The laboratory, which I lead, employs 2 post-doctoral scientists, 3 PhD students and an undergraduate student. Further a second laboratory employing 8 scientists, supervised by myself and Danish researcher Dr. Charlotte Kilstrup-Nielsen, and fully dedicated to Rett syndrome is located at the University of Insubria in Busto Arsizio. As I outlined earlier, our research, as well as that of many other laboratories in the world, is interested in defining the molecular pathways that get deregulated because of a dysfunctional MECP2.  We are also examining the role of the gene during early development and outside of the brain itself. Eventually we hope to develop some novel protocols of gene therapy that can reverse Rett syndrome.

The Rett syndrome research team at the University of Insubria in Busto Arsizio

The Rett syndrome research team at the University of Insubria in Busto Arsizio

Because one of the two labs supported by proRETT is in Busto Arsizio and in Busto Arsizio there is a strong female volleyball team – Unendo Yamamay – almost one year ago we decided to organize a match of the Yamamay team dedicated to proRETT. The idea was for a female team to support research on a disease that affects girls, with both volleyball and research in the same town. The team were keen to help and the event was scheduled to be held on Saturday 15th March 2014. That evening we would have been the guests of Yamamay, and we were going to hold a raffle to raise money for research.

Unfortunately, once the event was announced last month, the trouble started. It began when the Busto Arsizio branch of the large Italian animal rights group the Lega Anti Vivisesione published decontextualised images of dead mice (seems familiar – SR)not belonging to my lab on their facebook page and claimed that our activities were unscientific  in order to stir up anger amongst their supporters against our lab (you can read more details about this in Italian here). They then tried to start a boycott of Unendo Yamamay and started a mass  e-mailing campaign, writing on social networks and to the proRETT and Unendo Yamamay. At the end of this nightmare, and because the local police headquarters was not confident about keeping the event safe from disruption by violent animal rights extremists, we had to give up. The match went ahead but proRETT were no longer guests, with Unendo Yamamay issuing a statement expressing their extreme regret at the events leading to the cancellation that had “caused serious harm to persons engaged daily in medical research against this terrible disease”.

Organizers had hoped to sell 6 thousand tickets for the lottery in aid of Rett syndrome research

Organizers had hoped to sell 6 thousand tickets for the lottery in aid of Rett syndrome research

The cancellation was felt as a tragedy by the parents, who, obviously, felt themselves even more alone than before. Because of that we decided to hold the raffle in our university in Busto Arsizio on Friday evening the in order to raise some money for proRETT, where we were joined by some parents and girls with Rett syndrome, as well as several journalists, and the president of Pro-Test Italia, who chose to show solidarity by attending. In the end we raised almost 6,000 euros from the raffle, less than we had initially hoped, but enough to show us and the parents of girls with Rett syndrome that there are still good people who are prepared to stand up for vital research.

We need to make sure this never happens in Italy again. This fight goes beyond Rett girls but is in the name of the progress of biomedical science in Italy and in the world; it is in the name of a future with less suffering. We would like the parents of Rett girls  and researchers dedicated to curing this disease to not feel alone, so we ask you to join good people in Italy and across the world to show your support for our girls, and your contempt for animal rights extremism, by making a small donation to proRETT.

Thank you.

Nicoletta Landsberger

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

Understanding addiction: NIDA article highlights contribution of animal research

Professor David Jentsch is a highly respected UCLA neuroscientist who specialises in the study of addiction, one of the most widespread and serious medical problems in our society today. Sadly, by devoting his career to finding out how to better treat a condition that ruins – and all too often ends – many millions of lives in the USA and around the world every year, David has found himself, his colleagues, and his friends and neighbors under attack from animal rights extremists whose tactics have ranged from harassment, stalking and intimidation, to arson and violence.

Did this extremist campaign persuade David to abandon his research?

No chance!

In 2009 David responded to the extremist campaign against him and his colleagues by helping to found Pro-Test for Science to campaign for science and against animal rights extremism at UCLA, and has been a key contributor to Speaking of Research, writing articles on the role of animal studies in the development of new therapies for addiction, what his studies on rodents and vervet monkeys involve, and how addiction research can help us to understand obesity.

Vervet monkeys involved in David Jentsch's research program live in outdoor social groups to ensure optimal welfare

Vervet monkeys involved in David Jentsch’s research program live in outdoor social groups to ensure optimal welfare

This week the NIH’s National institute on Drug Abuse (NIDA) has published an excellent article on David’s ongoing research entitled  “Methamphetamine Alters Brain Structures, Impairs Mental Flexibility”, which highlights the importance of non-human primate research in identifying how addiction alters the brain and why some individuals are more prone to develop damaging methamphetamine dependency than others. You can read the article in full here.

Human chronic methamphetamine users have been shown to differ from nonusers in the same ways that the post-exposure monkeys differed from their pre-exposure selves. The researchers’ use of monkeys as study subjects enabled them to address a question that human studies cannot: Did the drug cause those differences, or were they present before the individuals initiated use of the drug? The study results strongly suggest that the drug is significantly, if not wholly, responsible”

This knowledge of how drug use disrupts brain function will be crucial to development effective clinical interventions for methamphetamine addiction, and the huge scale and devastating impact of methamphetamine use makes it clear that such interventions are desperately needed, as David highlights in the article’s conclusion.

Methamphetamine dependence is currently a problem with no good medical treatments, when you say a disease like methamphetamine dependence is costly, it’s not just costing money, but lives, productivity, happiness, and joy. Its impact bleeds through families and society.”

At a time when animal rights activists in many countries are pushing to ban addiction research involving animals, the NIDA article on the work of David and his colleagues shows why this work is so valuable, and just what would be lost if animal rights extremists are allowed to have their way.

Speaking of Research

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From clinic to mouse to clinic: New HIV gene therapy shows promise!

Yesterday a team of University of Pennsylvania researchers – led by Dr Pablo Tebas, Professor Carl June, and Dr Bruce Levine – announced the successful conclusion of a clinical trial to evaluate the safety of a new gene therapy technique for treating HIV. It is a result that may eventually allow millions of HIV positive people to control the infection without having to take daily medication.

Two technicians in Penn Medicine's Clinical Cell and Vaccine Production Facility hold up a bag of modified T cells. Image: Penn Medicine

Two technicians in Penn Medicine’s Clinical Cell and Vaccine Production Facility hold up a bag of modified T cells. Image: Penn Medicine

Their study, published in the New England Journal of Medicine, involved taking a sample of T-cells from 12 patients and then using an adenoviral vector to introduce into these cells an enzyme known as a zinc-finger nuclease (ZFN) that has been targeted to the CCR5 receptor gene so that it introduces a mutation called CCR5-delta-32.  They then expanded the number of T-cells in vitro until they had billions of the transformed T-cells ready for transplant back into the patients.

Most HIV strains need to bind to CCR5 to infect T-cells, and the CCR5-delta-32 mutation prevents this binding and subsequent infection, as was dramatically demonstrated in the case of the “Berlin patient”, so the Pennsylvania team are hoping that their method will enable long-term control of HIV infection in patients, so that they may no longer need to take anti-retroviral medication.

An important part of the development of this therapy was its evaluation in vivo in an animal model of HIV infection. To do this they turned to mice rather than the more usual SIV/macaque model, as the sequence of the CCR5 gene at the site targeted by ZFN in macaques is not conserved with humans and would require the design and assembly of a distinct ZFN binding set for testing in SIV infection. Mice don’t normally become infected with HIV, but by using NOG mice that have been genetically modified so that their own immune system do not develop and then transplanting human immune cells into the mice they were able to produce mice with “humanized” immune systems that could be used to evaluate the ability of their ZFN modified T-cells to block HIV infection. In a paper published in the journal Nature Biotechnology in 2008, the team led by Carl June reported that the transformed human T-cells could successfully engraft and proliferate when transplanted into the NOG mice, and protect against subsequent HIV infection.

To our knowledge, genome editing that is sufficiently robust to support therapy in an animal model has not been shown previously. The ZFN-guided genomic editing was highly specific and well tolerated, as revealed by examination of the stability, growth and engraftment characteristics of the genome-modified sub-population even in the absence of selection…We also observed a threefold enrichment of the ZFN-modified primary human CD4+ T cells and protection from viremia in a NOG mouse model of active HIV-1 infection. As predicted for a genetically determined trait, the ZFN-modified cells demonstrated stable and heritable resistance in progeny cells to HIV-1 infection both in vitro and in vivo. These results demonstrate that ZFN-mediated genome editing can be used to reproduce a CCR5 null genotype in primary human cells.”

Following this they also undertook more extensive regulatory studies in mice to demonstrate that there were no toxicities associated with the ZFIN transformation of the T-cells.

While the clinical trial announced yesterday focused on the safety of the technique, the authors also reported that HIV RNA became undetectable in one of four patients who could be evaluated, and that the blood level of HIV DNA decreased in most patients, which bodes well for future trials when larger quantities of ZFN-modified cells will be transplanted.

This is not the first time that the pioneering work of Bruce Levine and Carl June has caught our attention, they are the same researchers who have hit the headlines with an innovative “Chimeric Antibody Receptor” gene therapy for leukemia that is part of the cancer immunotherapy revolution now underway. Their latest breakthrough is another indication of how gene therapy is becoming an important part of 21st century medicine.

Paul Browne

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Zerhouni Sets the Record Straight on Animal Research

On June 4th 2013, Elias Zerhouni, a former Director of the National Institutes of Health (NIH) made some comments at a Scientific Management and Review Board (SMRB) meeting that were reported in NIH Record as follows:

“We have moved away from studying human disease in humans,” he lamented. “We all drank the Kool-Aid on that one, me included.” With the ability to knock in or knock out any gene in a mouse—which “can’t sue us,” Zerhouni quipped—researchers have over-relied on animal data. “The problem is that it hasn’t worked, and it’s time we stopped dancing around the problem…We need to refocus and adapt new methodologies for use in humans to understand disease biology in humans.”

This comment has been used by many animal rights activists to claim that animal research does not work. Here is a selection (many more examples exist):

Zerhouni animal research doesn't workHow much of this comes down to Zerhouni playing fast and loose with words, and how much comes down to the interpretation of the NIH Record reporter is unclear, but now we can clear this myth up for good.

The National Association for Biomedical Research, a national organization which provides the unified voice for the scientific community on legislative and regulatory matters affecting laboratory animal research, wrote to Zerhouni to ask him to clarify his previous comments at the SMRB meeting. His response is very clear (full letter below):

I understand that some have interpreted these comments to mean that I think that animals are no longer necessary in medical research. This is certainly not what I meant. In fact, animal models and other surrogates of human disease are necessary — but not sufficient — for the successful development of new treatments. In short, animal models remain essential to the basic research that seeks to understand the complexities of disease mechanism. [my emphasis]

We, at Speaking of Research, could not agree more. Animal models are essential to developing new medicines. They are, obviously, not sufficient - cell cultures, human studies and computer models (among others) are also crucial methods used alongside animal models.

Zerhouni’s original point in his talk was that more human studies were needed earlier in the drug development process – to help pick “winners” among promising research in animals (not all of which will successfully translate into humans).

Zerhouni letter

Click image for PDF of letter

We would like to thank NABR for taking the time to write to Zerhouni. Hopefully, this clarifies his position, and the quote he’ll be remembered for will not be about “kool-aid”, but that he “can say unequivocally that animal research remains indispensable element in improving both human and animal health”.

Tom

Correction: The letter to Zerhouni was sent by the National Association for Biomedical Research, not their partners the Foundation for Biomedical Research.

USDA Statistics for Animals Used in Research in 2012

In 2011 the USDA stopped publishing its animal research statistics on the Animal and Plant Health Inspection Service (APHIS) website (with the last full stats being 2010). We have recently received the 2012 statistics for animals used in research under the Animal Welfare Act. Overall the number of animals used in research fell by 16% since 2010, falling over 180,000  from over 1.1 million (2010) to just over 950,000 (2012).

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These statistics do not include all animals as most mice, rats, and fish are not covered by the Animal Welfare Act – though they are still covered by other regulations that protect animal welfare.

We can see that rodents (guinea pigs, hamsters and other rodents) and rabbits together account for 67.3% of all research animals, with cats, dogs and primates accounting for 16% of research. In the UK, where mice, rats, fish and birds are counted in the annual statistics, over 98% of research is on rodents, birds and fish. Across the EU, which measures animal use slightly differently, 93% of research is on species not counted under the Animal Welfare Act. We would expect similar patterns to be true in the US – although there are no statistics to confirm this.

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Click to Enlarge

If we look at the changes between the 2010 and 2012 statistics we can see a drop in the number of animals of most species between 2010 and 2012, with only pigs and cats going against the trend. Most notably the number of non-human primates has fallen by 9.5%, with an even larger drop in the number of rabbits (11.1% drop).

Animals used in research 2010 vs 2012

It is unclear whether the 16% drop represents a clear downward trend for the numbers of animals used in research, or is simply annual variability, though it would fit in a general downward trend in the US statistics since the mid 1980s. It is also likely that, similar to the UK, a move towards using more genetically altered mice has reduce the numbers of other animals used (those counted by the USDA under the Animal Welfare Act).

Speaking of Research