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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. 

 

August 31, 2017   animal testing

 

Helping Scientists Worldwide Replace Animal Tests

Physicians Committee scientists traveled the globe this summer to attend scientific meetings where they shared their research on replacing animal use in research.

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

Alzheimer’s Association International Conference

Feng-Yen Li, Ph.D., attended the Alzheimer’s Association International Conference in London, England, in July, where she presented research on how a plant-based diet can help reverse late onset Alzheimer’s disease risk factors.

Feng-Yen Li, Ph.D., attended the Alzheimer’s Association International Conference in London, England, in July, where she presented research on how a plant-based diet can help reverse late onset Alzheimer’s disease risk factors.

International Society for Stem Cell Research Annual Meeting

Ann Lam, Ph.D., presented research on replacing animal-derived components in stem cell research at the International Society for Stem Cell Research annual meeting in Boston in June.

Ann Lam, Ph.D., presented research on replacing animal-derived components in stem cell research at the International Society for Stem Cell Research annual meeting in Boston in June.

10th World Congress on Alternatives and Animal Use in the Life Science

Physicians Committee scientists were a major presence at the 10th World Congress on Alternatives and Animal Use in the Life Science this August in Seattle. They gave five oral presentations and five poster presentations (links below).

Ryan Merkley highlighted problems with institutional animal care and use committees (IACUCs) at facilities covered under Animal Welfare Act.

Ryan Merkley highlighted problems with institutional animal care and use committees (IACUCs) at facilities covered under Animal Welfare Act.

Esther Haugabrooks, Ph.D., discussed her worldwide survey of LD50 tests, which measure the dose of a chemical that kills 50 percent of the animals who are exposed to it.

Esther Haugabrooks, Ph.D., discussed her worldwide survey of LD50 tests, which measure the dose of a chemical that kills 50 percent of the animals who are exposed to it.

Elizabeth Baker, Esq., shared progress and plans for replacing animal use in preclinical drug testing.

Elizabeth Baker, Esq., shared progress and plans for replacing animal use in preclinical drug testing.

Kristie Sullivan, M.P.H., (right) discusses adverse outcome pathways (AOPs), a method to replace animal use in identifying toxic chemicals.

Kristie Sullivan, M.P.H., (right) discusses adverse outcome pathways (AOPs), a method to replace animal use in identifying toxic chemicals.

World Congress

The Physicians Committee also held an event the day before the Congress to discuss roadblocks and solutions to replacing animals in medical research. The event attracted more than 60 students, researchers, and advocates and highlighted the need for more funding and training in nonanimal research methods and the availability of human tissues and cells.

Oral Presentations

Promise and Pitfalls of Induced Pluripotent Stem Cells: Learning from Past Mistakes (Ann Lam, Ph.D.): http://www.altex.ch/resources/185198_WC10_Theme_7_Orals3.pdf (page 191)

Computational Modeling: Moving from Data Mining to Understanding Systems (Ann Lam, Ph.D.): http://www.altex.ch/resources/151156_WC10_Theme_5_Orals3.pdf  (page 156)

The 3Rs in Action: A Canadian Roadmap (Charu Chandrasekera, Ph.D.): http://www.altex.ch/resources/231248_WC10_Theme_9_Orals3.pdf  (page 248)

Advocating for the Replacement and Reduction of Animals at a Global Level Requires Cooperation Among Diverse Stakeholders (Kristie Sullivan, M.P.H.): http://www.altex.ch/resources/231248_WC10_Theme_9_Orals3.pdf (page 242)

How Do Laws and Policies Regulating Chemicals Drive Alternative Methods Development? (Kristie Sullivan, M.P.H.): http://www.altex.ch/resources/020035_WC10_Theme_2_Orals3.pdf (page 22)

Poster Presentations

A Review of IACUC Practices at Major Public U.S. Research Universities (Ryan Merkley): http://www.altex.ch/resources/015019_WC10_Theme_1_Posters3.pdf  (page 17)

U.S. Public Opinion on the Use of Animals for Medical Training: Analysis of a Randomized 2016 Telephone Survey (Ryan Merkley): http://www.altex.ch/resources/174184_WC10_Theme_6_Posters5.pdf (page 184)

A Survey of Global Acute Systemic Toxicity Test Requirements to Support a Push Towards Harmonized Acceptance of Alternative Strategies (Esther Haugabrooks, Ph.D.): http://www.altex.ch/resources/249254_WC10_Theme_9_Posters3.pdf (page 252)

Preclinical Innovation and Patient Safety: A Collaborative Approach to Supporting Innovative Science and Replacing Preclinical Animal Tests (Elizabeth Baker, Esq.): http://www.altex.ch/resources/174184_WC10_Theme_6_Posters5.pdf (page 175)

Recombinant Antibodies: Replacement in Action (Charu Chandrasekera, Ph.D.): http://www.altex.ch/resources/174184_WC10_Theme_6_Posters5.pdf (page 184)

August 14, 2017   government and food policy

 

Ask the FDA to modernize preclinical testing

Health IT Now—a broad-based coalition of patient groups, provider organizations, employers, and payers that develop and advocate for policy supporting health information technology to improve patient outcomes—requested the Food and Drug Administration include preclinical innovation in implementation of the legislation 21st Century Cures.

In January 2017, Health IT Now attended a roundtable—hosted by the Physicians Committee—to discuss the need for modernizing preclinical tests. Participants included federal agencies, pharmaceutical companies, academics, technology companies, and patient, health, and research organizations. Discussions included scientific, legal, policy, educational, and training opportunities that should be addressed in order to advance the field.

The FDA requires pharmaceutical companies to test all potential new medicines in animals during preclinical tests. Preclinical tests are meant to help scientists understand how a drug will fare when given to humans. Will it be safe or toxic? Will it be effective?

While “preclinical” was once interchangeable with animal tests, the prevalence and promise of innovative, new technologies, such as organ chips, computer simulations, and 3-D bioprinting are on the rise. As Health IT states in a recent letter to the FDA commissioner, “New technologies that would allow scientists to ‘fail faster’ would reduce waste, speed up innovation, and most importantly deliver safe and effective treatments to more patients who need them.”

The legislation 21st Century Cures requires the FDA to host a public meeting and issue guidance on novel clinical trial designs. Health IT Now’s letter to the FDA commissioner requests that the FDA include preclinical innovation, as “it would be a missed opportunity for the FDA and stakeholders to not include the transformative potential of technology in the entire drug development process, including preclinical testing.”

 

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