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November 8, 2017   animal testing

 

Physicians Committee Scientists Provide Expert Advice on Replacing Animal Tests

“Proper planning prevents poor performance.” It’s a timeless quote used to inspire people to apply adequate thought prior to any action in which great results are expected. U.S. governmental agencies are making plans to move away from animal testing to what many are now calling “new approach methodologies”—a catch-all term referring to nonanimal toxicity test methods. Physicians Committee toxicologists Esther Haugabrooks, Ph.D., and Kristie Sullivan, M.P.H., capitalized on the opportunity to aid in the proper development of this plan by providing advice to regulators and other government scientists at the Scientific Advisory Committee for Alternative Toxicological Methods (SACATM)’s annual meeting.

SACATM is a federally chartered advisory committee for the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), and the Directors of the National Institute of Environmental Health Sciences (NIEHS) and NTP. This committee and its advisee agencies are the hub of government efforts to replace animals in toxicology.

The U.S. government has finally begun to put serious resources toward replacing animals in chemical, pharmaceutical, and other product testing. To properly plan these investments, NICEATM is creating a U.S. Strategic Roadmap: New Approaches to Evaluate the Safety of Chemicals and Medical Products, which ICCVAM has been developing since earlier this year. The roadmap is centered on three main goals:

  1. Encourage the adoption and use of new nonanimal methods and approaches by federal agencies and regulated industries;
  2. Foster the use of efficient, flexible, and robust practices to establish confidence in these new methods; and
  3. Connect end-users with the developers of nonanimal methodologies.

Other updates shared at the meeting and further indication of the resources available to reduce the use of animals in safety testing include EPA’s progress in using high-throughput nonanimal methods to quickly screen a large number of chemicals for safety and its very own strategic plan on replacing animal tests under the Lautenberg Chemical Safety Act.

Physicians Committee toxicologists gave several technical comments during the meeting. We commended the work of NICETAM in leading U.S. agencies towards the common goal of replacing animals, and for the ambitious, specific plans outlined to achieve this goal.

We encouraged ICCVAM member agencies, such as the Food and Drug Administration, to be more aggressive in implementing and requiring industry to use such technologies especially for the cases where nonanimal alternatives are already available.

And we suggested in order to make faster progress, the United States needs to share its technological developments with agencies in other countries, and that chemical and pharmaceutical companies should do its part to share data and fund validation of nonanimal methods. Furthermore, the Physicians Committee and other organizations are providing opportunities for training that regulators can leverage to continue to increase the use and acceptance of nonanimal methods.

Kristie Sullivan, M.P.H.
Kristie Sullivan, M.P.H., Physicians Committee toxicologist and vice president of research policy, providing comments at SACATM.

For more information on the SACATM meeting, click here.

Later that week, the American Society for Cellular and Computational Toxicology (ASCCT), a scientific society co-founded by the Physicians Committee, held its 6th annual meeting in the Washington, D.C., metro area. ASCCT is a rapidly growing society that supports toxicologists working to develop nonanimal toxicology approaches by 1) providing opportunities to communicate and collaborate with each other and with regulatory authorities, 2) facilitating mentorship and training opportunities for young toxicologists, and 3) highlighting new toxicology approaches that do not use animals.

ASCCT organizers took advantage of the themes presented at the SACATM meeting to delve deeper into the science and policy behind the progress reported by government agencies. During the two-day ASCCT meeting attendees could view posters and attend session with presentations from EPA regulators and leading scientists from industry and nonprofit organizations.

The first day, tandem presentations by Anna Lowit of the EPA and Dan Wilson of Dow Chemical Company focused on stakeholder efforts to replace the EPA six-pack—a battery of animal intensive tests to determine acute systemic toxicity for (1) oral, (2) dermal, (3) inhalation routes of exposure, (4) skin corrosion and irritation, (5) eye corrosion and irritation, and (6) skin sensitization—with alternative approaches. Several shorter presentations highlighted the exciting scientific work making it possible to replace these tests.

The second day focused on the EPA’s responsibility to reduce and replace animals under the Lautenberg Act, with presentations and a panel discussion, moderated by the Physicians Committee’s Kristie Sullivan, again focusing on the scientific and policy needs to achieve this objective.

The Physicians Committee gave two poster presentations and one oral presentation. Elizabeth Baker, Esq., senior policy specialist, presented her work on Preclinical Innovation and Patient Safety: A Collaborative Approach to Supporting Innovative Science and Replacing Preclinical Animal Tests  and Esther Haugabrooks, Ph.D., presented a survey of global testing requirements titled Understanding Global Acute System Toxicity Testing Requirements as a Framework for Rapid and Harmonized Acceptance of Alternative Approaches .  Dr. Haugabrooks also presented an oral presentation outlining recommendations for the EPA strategic plan.

Dr. Haugabrooks, Physicians Committee toxicologist Esther Haugabrooks, Ph.D., Physicians Committee toxicologist, giving a presentation entitled the ‘Vision for U.S. Strategic Plan to Implement Alternative Toxicology Testing’ at the ASCCT meeting.

Baker by her poster at ASCCT.

Elizabeth Baker, Esq., senior policy specialist, by her poster at ASCCT.

For a full list of the ASCCT presentations, click here.

It is evident from the scientific presentations and discussions at the ASCCT meeting that the science of new approach methodologies has surpassed the archaic use of animals to predict human safety, and that we are already seeing the legislative mandates in the Lautenberg Act inspiring more scientific progress.

Proper preparation through scientific advances will make it possible to shift from traditional toxicology testing to alternative, nonanimal methods. Some of these methods, as highlighted at SACATM and ASCCT, are already being used within U.S. regulatory agencies. However, with the development of ICCVAM’s strategic roadmap, the EPA’s strategic plan to promote and develop alternative methods, and the continual efforts nongovernmental organizations like the Physicians Committee, a broader acceptance of nonanimal approaches within regulatory agencies is on the rise.

The Physicians Committee is looking for two spring semester interns to work on our programs promoting the replacement of animals in testing, research, and medical education with human-relevant methods. Apply today!

October 5, 2017   organ on a chip

 

organs on chips

The National Institutes of Health (NIH) recently awarded 13 investigators around the country two-year grants totaling about $15 million per year to further develop tissue chips to model certain human diseases, including rheumatoid arthritis, kidney disease, flu infection, neurodegenerative diseases, heart conditions, and even rare genetic disorders. This Tissue Chip for Disease Modeling and Efficacy Testing initiative serves as the first phase of a five-year program to support new research tools for modeling human diseases in the laboratory and testing the effectiveness of new therapies. This exciting announcement is a sign of dramatic change in the way we study human diseases, and a promising sign of continued progress.

 

These tissue chips or organs-on-chips are miniature platforms support living cells or tissues in a 3-D architecture to mimic the complex biological interconnections and interactions within human organs or systems. They promise to yield more human-relevant results while reducing and replacing the use of animals in research and toxicological testing. They may also be utilized one day to personalize medicine by allowing an individual patient’s responses to drugs to be tested prior to administration. The goals of the Tissue Chip for Disease Modeling and Efficacy Testing initiative include:

  • Developing tissue chips as human-relevant disease models using cells derived from humans, including stem cells and primary human tissues
  • Determining the disease relevance of these models by verifying key experimental features in pilot tests.
  • Testing the ability of these models to measure the effectiveness of candidate drugs

Upon successful completion of the first phase, the awarded investigators will partner with pharmaceutical companies to develop a plan to use these models for testing the safety and efficacy of candidate drugs.

The Tissue Chip for Disease Modeling and Efficacy Testing initiative is part of a continuing effort by the National Center for Advancing Translational Sciences (NCATS) at the NIH to support this promising area of research. In 2012, NCATS partnered with the Defense Advanced Research Projects Agency (DARPA) and the Food and Drug Administration (FDA) to launch the Tissue Chip for Drug Screening program to develop tissue chips to mimic human organ systems and to integrate them to form a human body-on-a-chip. Over the last five years, NIH and DARPA awarded about $70 million of research funding to support this program.

Up to 95 percent of drug candidates fail in human clinical trials due to lack of efficacy or safety. Having better predictive models for testing candidate drugs is not only essential for avoiding major drug failures or disasters in humans but also to avoid missing out on potentially helpful treatment for humans that have been erroneously labeled as ineffective or toxic in animal tests. Given that animal experiments are unreliable predictors of drug responses in humans, developing tissue chips as human-relevant models for drug testing is essential to replacing the costly and unreliable animal tests.  "The goal is for these tissue chips to provide more accurate platforms to understand diseases, and to be more predictive of the human response to drugs than current research models, thereby improving the success rate of candidate drugs in human clinical trials," said NCATS director Christopher P. Austin, M.D.

Unfortunately, this timely announcement comes the same month that the National Institute for Environmental Health Sciences (NIEHS) announced available grants for developing “animals-on-chips.” They’re funding work to create miniature dog, rat, or monkey organs because drugs are currently tested in these animals, and they hope to compare the results of the animal-organs-on-chips to results from animal tests. This approach is a distraction from what we really need, and what our government should be funding—models that give us information on how humans react to drugs. The $2 million they are offering would be better spent on human cell and tissue models.

September 21, 2017   animal testing, animals in education

 

dog emotion studies

When Dr. Gregory Berns' favorite dog Newton, a 14-year-old pug, died, Berns found himself asking whether Newton had loved him the same way he loved Newton. That was the beginning of a unique research endeavor for the Emory University Distinguished Professor of Neuroeconomics, one in which Callie, another of his rescued dogs, has played a trailblazing role. A recent interview psychologist Marc Bekoff, Ph.D., conducted with Dr. Berns reveals the potentially game-changing results.

What Dr. Berns' research shows is that noninvasive, nonradioactive, and (importantly) noncoercive MRI brain scans can teach us much about how dogs or other nonhumans receive and process information and experiences. In many instances, canine responses involve the same brain regions that are activated by similar human experiences, such as pleasure from a familiar object, sound, or smell. But these responses and brain activation patterns differ among dogs, just as they differ among humans.

By performing functional MRI scans on community-living dogs who willingly participate, Dr. Berns has begun to localize brain responses to hand signals, smells, and other exposures. For example, the caudate nucleus in dogs and humans is activated by the anticipation and perception of pleasure, whether a favorite dog toy or a photo of a beloved family member. Dr. Berns has provided further confirmation that the emotional lives of dogs are rich in much the same ways that human lives are rich. Our canine friends and their nonhuman brethren are not senseless beasts, no matter what Claude Bernard and René Descartes believed in less enlightened eras.

One of Dr. Berns' preliminary findings is that the canine caudate nucleus—the pleasure center—is activated by the return of the dog's guardian from a brief absence. So do dogs love us, miss us when we are gone, and anticipate our return? Animal lovers know the answers intuitively, but science has not made all the connections. Dr. Berns' research is a step in that direction.

What is clear are the bonds and shared emotions that have made Sparky man's longest-tenured companion. The studies conducted by Gregory Berns are confirming what may seem obvious to people who share their lives with dogs, cats, and other companions, and it deconstructs the claim of animal researchers that it is ethical and moral to experiment on nonhumans because they don't experience life as we do. Dr. Berns' research and decades of unproductive animal research to study human diseases or develop drugs tell us just the opposite: Our nonhuman cohabitants of Earth differ from us in ways that invalidate translation of animal research to humans, but they share with us the characteristics of fear, pain, suffering, (and yes, love) and other emotional and physical attributes that make experimenting on them immensely cruel.

September 15, 2017   Alzheimer's disease

 

Advances in Alzheimers disease research

As one of the top ten causes of death in the United States, Alzheimer’s disease is the only major chronic disease growing at an epidemic rate with no disease-modifying treatments available. The disease is of such great concern that the U.S. government passed the National Alzheimer’s Project Act (NAPA) in 2011 with the goal of finding a way to prevent and effectively treat Alzheimer's disease by 2025 while also optimizing care support services and public awareness. This law led to the creation of an advisory council that meets regularly to evaluate and update recommendations for the National Plan to achieve the goals of NAPA. In 2014, the government also passed the Alzheimer's Accountability Act to require the National Institute of Health (NIH) to propose annually a Bypass Budget which determines the amount of additional funds needed to reach the research goals of the National Plan. Congress and the President decide on an annual basis whether to approve this Bypass Budget. Once approved, the NIH is the decision-maker for where these additional funds are allocated in Alzheimer’s research. 

As detailed in our previous blog, Alzheimer’s research has not made any significant breakthroughs in treatments likely due to its focus on flawed animal models and a pathological observation that may not be a key underlying factor driving the most common form of the disease. The Physicians Committee presented these and other flaws with Alzheimer’s research at the Advisory Council meeting in January 2017. We recommended that the Council direct research toward human-relevant models and modifying lifestyle factors driving the most common form of the disease. In the April meeting, the research subcommittee of the Advisory Council made two recommendations in line with our input: 

  • Identify and evaluate (non-drug) care strategies that reduce disease burden and delay disease progression and evaluate their costs and downstream effects.
  • Convene a conference of key stakeholders to identify a meaningful pathway or pipeline for developing and testing nonpharmacological treatments, and scaling up and implementing effective approaches.

 A National Research Summit on Care, Services and Supports for Persons with Dementia and their Caregivers is scheduled to occur in October 2017, and the National Institute of Aging (NIA) plans to integrate the recommendations following the summit into their future research funding planning. 

In March 2017, Physicians Committee sent a commentary to the NIA to request an increase in allocation of funds in the Bypass Budget for epidemiological and clinical studies as well as human-based research approaches. Compared to the fiscal year 2018 Bypass Budget, the recently released Bypass Budget for fiscal year 2019 reflected an increase funding allocation in the areas consistent with our recommendations: 4 percent in translational research and clinical interventions, 2 percent in epidemiology, and 1 percent in research resources. 

These shifts in research support are encouraging in the development of disease-modifying interventions through human-based approaches.   These changes follow on the heels of promising clinical studies including a recent lifestyle intervention clinical trial utilizing diet, exercise, and cognitive training in 1,260 people in Finland demonstrating significant improvements in cognitive functions relative to controls. Scientific American magazine featured the study on the front cover of their April 2017 issue and called it “A Rare Success Against Alzheimer’s.”  At the Alzheimer’s Association International Conference in July 2017, there were presentations announcing plans to repeat the study at many sites worldwide. During this meeting, the Alzheimer’s Association even announced its support of this trial in the United States by committing 20 million dollars to it. With more funding going into these types of clinical trials, perhaps Alzheimer’s research may finally move toward producing effective disease-modifying interventions.

August 31, 2017   Alzheimer's disease

 

Retiring the Amyloid Cascade Hypothesis as a Cause of Alzheimer’s

When you consider the decades-long track record of dead-end Alzheimer’s disease research, it's reasonable to ask: What drives this research? The amyloid cascade hypothesis has been foundational for Alzheimer’s disease research and drug development since its description based on mouse experiments by Hardy and Allsop in 1991 and a noteworthy Science update in 2002. Postmortem exams of Alzheimer’s disease patients in the 1970s and 1980s had characterized accumulations of amyloid plaques that soon became a hallmark of the disease. As often happens, researchers took this clinical finding back to the lab, and a long history of Alzheimer’s disease animal research (predominantly in mice and rats) ensued.

Amyloid is a protein found in the brain. The amyloid cascade hypothesis states that the cause for Alzheimer’s disease is one or more mutations which cause the protein to be cleaved, producing a sticky protein fragment called beta-amyloid. This protein fragment forms plaques in the brain that begin the "cascade" leading to the formation of neurofibrillary tangles. The beta-amyloid plaques and neurofibrillary tangles cause inflammation and destruction of neurons to produce the clinical signs and symptoms of Alzheimer’s disease.

Widespread acceptance of this hypothesis has dominated the directions of basic science and clinical research and influenced funding agencies such as the National Institutes of Health, journal editors, peer reviewers, and pharmaceutical companies. With so much time and money invested in the animal-derived model of Alzheimer’s disease's cause, it has been difficult for researchers with novel approaches to obtain support for their work. Alzheimer’s disease scientists, funding agencies, patient advocacy groups, and Big Pharma have bet the ranch on the amyloid cascade hypothesis as the key to tracking and treating Alzheimer’s disease.

However, abundant information has been discovered casting doubt on the amyloid cascade hypothesis. Among contrary information is the finding that a meaningful percentage of young adult and older persons without dementia have substantial beta-amyloid plaque deposition demonstrated on brain imaging and postmortem studies. Dr. Lon Schneider of the University of Southern California Keck School of Medicine has stated: "There are people who die with a head full of amyloid and have no cognitive impairment whatsoever." Conversely, beta-amyloid plaques may be absent or minimally present in clinically diagnosed Alzheimer’s disease patients. A recent report demonstrates that tau oligomers, produced after beta-amyloid deposition, also are present in the sera of unaffected people of the same age as well as Alzheimer’s disease patients, and it has been reported (here and here) that some degree of tau pathology is ubiquitous in postmortem human brains, including unaffected and young persons.

Hundreds of drugs developed on the basis of the amyloid cascade hypothesis have been tested in Alzheimer’s disease clinical trials, and the overall failure rate for 244 drugs in 413 trials just from 2002-2012 is reported to be 99.6 percent. Only a single drug was approved from these trials (memantine in 2003). An analysis of subsequent Alzheimer’s disease clinical drug trials reported from Jan. 1, 2004, (after memantine approval) through July 19, 2017, reveals 1,273 completed or closed trials and no approved drugs. Only four drugs are approved overall for treating various stages of Alzheimer’s disease, and they offer minimal if any temporary symptomatic benefit to a minority of patients, with no effect on long-term prognosis or survival. No disease-modifying drugs have been developed based on the science and pharmacology of the amyloid cascade hypothesis. 

Since some drugs have successfully removed brain beta-amyloid plaques without producing improvement in cognition and other symptoms, and without improving clinical course or mortality, it has been proposed that beta-amyloid plaques may not be causative for Alzheimer’s disease. Tau pathology not only is triggered by beta-amyloid plaques and disrupts brain intracellular functions, but also appears to progress even after removal of beta-amyloid plaques, suggesting that therapies targeting beta-amyloid cannot succeed in controlling Alzheimer’s disease. Some recent research has focused on a possible role for tau proteins rather than beta-amyloid plaques, but the only completed tau-targeting phase 3 drug trial (a tau protein aggregation inhibitor known as LMTX, LMTM, or TRx0237) failed to show benefits.

Some researchers believe that the timing of beta-amyloid-targeted therapies may be key: once substantial beta-amyloid plaque has formed and tau pathology has occurred, it may be too late to reverse the pathological consequences. Clinical trials are thus employing earlier detection and intervention for Alzheimer’s disease, even before symptoms occur, often by using biomarkers to identify at-risk persons.

Earlier intervention is derived logically from the failure of later clinical intervention, but its value is debatable for at least three reasons. First, the biomarkers indicating risk for Alzheimer’s disease are not yet sufficiently accurate to exclude from clinical trials those who would never develop Alzheimer’s disease or even mild cognitive impairment. Second, fewer than half of those with mild cognitive impairment will develop Alzheimer’s disease, making even this later indicator of limited utility and suggesting that earlier biomarkers may have low predictive value (here and here). Third, this approach does not directly address the failure of animal and other basic science research to identify disease-modifying therapies, though it is postulated that some failed therapies may be effective if applied earlier.

So the validity of the amyloid cascade hypothesis remains unknown but appears tenuous. Its demise would largely invalidate decades of basic science, clinical, and pharmaceutical work. Outcomes to date do not support the validity of the amyloid cascade hypothesis, and if current and pending early-stage and presymptomatic beta-amyloid-targeted studies fail to impact outcomes, it must be presumed to be incorrect.

That would be another heavy blow against the reliability of animal research, in this case for a fatal disease with increasing prevalence. It is self-evident that the first step in treating disease is to determine the cause(s). We have not demonstrably done this for Alzheimer’s disease, arguably because animal research has been unable to accomplish the task despite more than three decades of effort. 

 

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