Good Science Digest

The Physicians Committee
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January 26, 2018   animal testing

 

Great Science: 2017’s Top 10

This past year was full of advances in science and policy that demonstrate exciting progress in making science more humane and human-relevant. Here are our favorites:

1. USDA database mostly restored

The removal of USDA inspection reports from their online database earlier this year left the public with no way of readily accessing these reports, preventing public knowledge of which facilities using animals had violations of the Animal Welfare Act. After great pressure from the Physicians Committee and other animal advocacy organizations, the database was partially restored. While inspection reports can now be readily accessed again, identifying information of certain violators, specifically breeders, has been blacked out. 

2. Bioprinting of human tissues 

Bioprinting of three-dimensional (3-D) human tissue allows researchers to create more accurate models of human tissues and organs to study and eliminate the use of animals. There are often differences between individuals in the effectiveness or toxicity of a given drug, mostly because we all absorb and metabolize—or break down—drugs at different rates. The differences between animals like rats or mice and people are even greater. With 3-D bioprinting, models can be made from the patient’s own cells, allowing researchers to tailor treatments to the specific person. We have reported on two different studies authored by scientists who created tissues to help assess how drugs are absorbed into or metabolized in the body. We also reported on a 3-D-printed brain model. In fact, there were 199 studies in the scientific literature this year reporting advances in creating human tissues models using bio-printing techniques, and we expect this to keep growing in the coming years. 

3. Surgical simulation advances

This year saw the rise of a new way to teach medical procedures without animals. Maximum Fidelity Surgical Simulations has pioneered a groundbreaking method for perfusing the blood vessels of human cadavers. Using artificial blood, the cadavers can be used in scenarios ranging from operating rooms to outdoor exercises for military medics.

4. Organs-on-chips

Miniature versions of human organs make up microphysiological systems, or organs-on-chips. These tiny devices, which are about the size of a USB flash drive, are designed to mimic human tissues and allow scientists to see how human cells and tissues behave. Organs-on-chips are capable of replacing animals for drug testing and the development of new treatments, as well as studying a variety of disease processes and responses. The National Institutes of Health doubled down on previous investments in 2017, providing $15 million a year for two years to scientists around the country to develop models for human diseases. They even debuted a “tissue chips in space” project. Major progress on developing these breakthrough systems was made in 2017, in studying lung cancer, cardiotoxicity, asthma and infection, vascular biology, and the blood brain barrier

5. FDA Releases Predictive Toxicology Roadmap

In December, the Food and Drug Administration released a groundbreaking Predictive Toxicology Roadmap aiming to transform the safety testing conducted for FDA-regulated products. The six-part Roadmap reflects a shift at FDA from animal-based testing toward cutting-edge human-based approaches, such as organs-on-chips, computational toxicology and read-across methodologies. Human-based approaches are expected to provide more predictive information than animal testing because they enable scientists to directly investigate how drugs interact with human cells, tissues and processes. 

6. Adverse Outcome Pathway for Respiratory Sensitization  

This fall, scientists led by the Physicians Committee’s Kristie Sullivan, M.P.H., published a paper outlining an Adverse Outcome Pathway for chemicals which cause sensitization of the respiratory tract. This dangerous condition develops often in health care, cleaning, and chemical industry workers, and causes them to experience severe coughing, wheezing, constriction of the airways, and other asthma-like symptoms that worsen upon repeated exposure to smaller and smaller amounts of specific chemicals, making work dangerous or impossible. Our team of toxicologists, immunologists, and chemists combed the scientific literature for all studies related to this endpoint, and constructed a pathway for how we think this condition develops, from exposure to chemicals at the molecular level to priming of immune cells to over-react and cause these symptoms.  

AOPs outline the state of the science for a particular toxicological endpoint (or effect, such as carcinogenicity) and make it easier for scientists to develop nonanimal approaches to test chemicals for effects of interest. Now that the AOP has been published in the scientific literature, the team is evaluating the human cell-and computer-based methods they identified to build evidence for regulatory agencies to use these methods instead of animals to identify chemicals that may cause this devastating disease. 

7. State and county officials speak out against UW’s use of animals

The University of Washington has the only paramedic training program in the nation known to use live animals. Pigs are used to teach surgical airway and then killed. But in January 2017, after outreach from Physicians Committee staff and members, eight members of the Washington House of representatives wrote to UW to raise their concern about the practice. A few months later, two elected officials in King County, home to UW, followed suit. The university is feeling the pressure and has agreed to pursue the development of a method to replace animals. While several human-based methods are already available for surgical airway training, UW’s decision is progress.  

8. Stem cell resource established

Human induced pluripotent stem (iPS) cells provide a human-based approach to model diseases. This year, significant advancements were made in modeling several diseases with stem cells, giving us better insight into the effects of those disease in humans. Some breakthroughs include the use of stem cells to model diabetes, prion disease, and anorexia nervosa. To continue to facilitate breakthroughs, researchers from the Human Induced Pluripotent Stem Cell Initiative created the most comprehensively characterized bank of human stem cell lines complied to date. These normal human-derived stem cells will benefit scientists by allowing them to better understand the natural variations of stem cell lines, and thus natural variations among the human population.

9. Funding for EPA research to develop alternatives supported by Congress

Research at the EPA’s National Center for Computational Toxicology is essential for spurring progress to replace animal testing with human-relevant methods, especially under a mandate from the Lautenberg Chemical Safety Act for the 21st Century that requires EPA to replace and reduce animal tests for assessing chemical safety. However, the Trump administration’s 2018 budget proposal would have slashed funding for the chemical research by 31 percent. After lobbying by the Physicians Committee and other organizations, these proposed cuts to EPA budget did not become a reality and computational toxicology funding levels were maintained, allowing the EPA to continue developing studies that protect public health and countless animal lives. 

10. Plants Found to Model Anesthetic Drug Efficacy

A very unique study published in December found that plants exhibiting touch-induced movements (such as the Venus fly-trap) respond to anesthetic drugs in similar ways to humans. The drugs apparently block the same molecular mechanisms and electrical signals at work in humans and other animals, and could represent an alternative to testing the safety and effectiveness of new drugs in animals.

January 17, 2018   dementia

 

Microsoft founder Bill Gates recently announced a personal investment of $50 million in the Dementia Discovery Fund (DDF), a public-private fund supported by charities, industry, and government to diversify the search for a drug to treat dementia. Gates wants the scientific community to look beyond amyloid and tau proteins in the brain, two key hallmarks of the disease, for the causes of dementia with the ultimate goal of creating an effective treatment. He is correct that so narrowly focusing research into the role of these proteins has diverted our attention from more productive research. But his laser focus on treating rather than preventing dementia is not the only strategy to overcome this disease. The search for a drug to treat Alzheimer’s disease and related dementias has met with little success. And given the rapid rise in the incidence of these diseases, the scientific community and those who fund their work would better serve the public by shifting their focus to prevention—or, at the very least, making prevention a high priority.

We have some suggestions:

First, as we have learned in other major research pursuits, the use of animal models of disease typically fails to provide us with meaningful insights into how a disease originates and progresses in humans. Therefore, all research should take full advantage of the many innovative methods that are human relevant. We applaud DDF for its support of in vitro human-based approaches in their search for therapeutics. These include using cell-biology based approaches to find targets in human brain tissues (Cerevance), human neurons derived from induced pluripotent stem cells (Gen2), in vitro platforms to restore immune cell function (TIAKI therapeutics), and an in silico program to screen a library of more than 500,000 compounds virtually for drug candidates (DDF ChemCo).

Second, investments should be made in these underfunded areas:

  • Human brain tissue banks and resources like the Allen Cell Types Database. To better understand the causes of dementia at the population level, we need more research into the lifestyle factors that play a critical role in driving the disease, which can help explain racial-ethnic disparities.
  • A better clinical test to diagnose the disease earlier and track its progression. This will help identify patients for earlier intervention studies. If we had a disease specific biomarker like cholesterol for heart disease or hemoglobin A1C for diabetes, the development of Alzheimer’s may become easier to control. The key to finding such a biomarker will require a better understanding of the external factor(s) driving the disease in humans and strictly focusing the search in human specimens. More clinical trials assessing the efficacy of nonpharmacological interventions such as changing dietary habits, so that we can give people evidence-based advice to take control of their health.
  • Design clinical trials to include patients with multiple chronic conditions so that interventions can be broadly applicable to patients with many chronic conditions. Many drug trials exclude these individuals in order to demonstrate the specificity of a treatment for the disease. However, Alzheimer’s often occurs with other chronic medical conditions. Testing lifestyle interventions would fill this research gap and encourage patients to participate in trials before they develop any signs of the disease.
  • Use the common database for which Gates advocates to catalog links between modifiable lifestyle patterns and dementia prevalence or incidence over time in different parts of the world. Moving away from focusing on data derived from animal models and failed drug trials will help us better understand what is really driving dementia that we can change in a short period of time.

Despite billions of dollars spent, pharmaceutical companies have not been able to find a drug to even delay the onset or progression of dementia. Pfizer’s recent announcement to end its research program on developing new drugs for Alzheimer’s is indicative of how fruitless and disappointing these efforts have been. With the high financial burden the disease implies and the devastating impact on the patient and families, we must invest more in human studies that will help us understand how to treat and prevent this disease. If Gates devoted a mere 10 percent of his $100 million planned investment in these areas, we might

December 12, 2017   organ on a chip

 

road map

Image Credit: FDA.

The Food and Drug Administration (FDA) has joined other drug development stakeholders in pushing for the development and implementation of more predictive preclinical testing approaches. Last week FDA unveiled its Predictive Toxicology Roadmap, which aims to transform the development, qualification, and integration of new toxicology methods across FDA centers.

Toxicology testing is crucial for the development of safe medical products that are regulated by FDA because it informs potential risk to humans. Traditionally, toxicity testing has used animals to make predictions about human outcomes. However, the quality of information gained from animal tests has been the subject of much debate.

For far too long animal-based toxicity tests have been accepted as the benchmark for testing despite a general failure to provide information that is sufficiently relevant to humans. For example, the FDA and drug development stakeholders have known for more than 13 years that approximately 92 percent of new medicines fail in humans after passing animal tests.

This Roadmap acknowledges the scientific advances made and establishes a plan for support and implementation.

In an article released on the subject, FDA’s acting chief scientist stated, “Today, novel methods such as organs on a chip or mathematical modeling are being developed for toxicity testing that are generating unique opportunities to improve our ability to quickly and more accurately predict potential toxicities and reduce associated risks.”

The six-part Roadmap seeks to improve toxicity testing and formalizes FDA’s position on replacing/reducing animal testing.

The Roadmap establishes a Toxicology Working Group to facilitate communication among FDA centers. FDA knowledge will no longer be siloed in separate centers, but will rather be shared to help determine which approaches may be used for which purposes.

The group will identify gaps in current test methods and determine where newer approaches—

such as organ chips and computer simulations—may be identified, further developed, scientifically evaluated, and implemented.

The group will also develop a Toxicology Seminar Series to facilitate agency-wide training on new testing approaches. We’ve pushed for this much-needed initiative through consistent input to FDA and ICCVAM, as agency scientists must build their knowledge-base, confidence and familiarity with modern approaches to toxicity testing.

The Roadmap encourages frequent and often communication with FDA regarding interest in using new methods. FDA should take this opportunity to update its regulations that mandate animal data, to ensure the Roadmap is properly implemented. Companies may not be willing to rely on the Roadmap in the face of inconsistent regulations.

The Roadmap solidifies FDA’s commitment to working with the stakeholder community, which has seemed to increase over the past year. In January 2017, FDA participated in a Preclinical Innovation and Patient Safety (PIPS) roundtable hosted by the Physicians Committee. The roundtable aimed to increase stakeholder collaboration to advance modern, predictive approaches. FDA has also collaborated with the National Center for Advancing Translational Sciences (NCATS) and the Microphysiological Systems Working Group of the IQ Consortium to provide input on tissue chip technology.

The Toxicology Working Group will track progress and provide annual reports to the chief scientist to increase oversight and accountability.

We applaud FDA for its transparency and vision set forth in the Roadmap, and look forward to continued collaboration to save human and animal lives.

Learn more from our The Hill op-ed and The Exam Room.

 

United States Department of Agriculture

In October, organizations that represent animal experimenters and their institutions released a troubling report. It proposes drastically cutting protections for animals in laboratories, including a significant change to the Animal Welfare Act.

The report, titled Reforming Animal Research Regulations, recommends weakening federal standards for animals in laboratories and also giving animal experimenters greater control over the creation of new rules. Essentially, it would help create an oversight system that allows laboratories to self-regulate.

A 2014 Pew Research Center survey of adults in the United States found that 50 percent of respondents "oppose" the "use of animals in scientific research” compared to 47 percent who "favor" the practice. Pair that level of concern with the federal government's poor enforcement of animal welfare in laboratories. In 2014, the U.S. Department of Agriculture’s (USDA) own Office of Inspector General (OIG) found:

  • USDA inspectors did not always review animal use protocols and annual reports (the documents that list how many of each species were used and in what pain category), as required.
  • USDA closed investigations involving grave Animal Welfare Act (AWA) violations, including animal deaths and serious repeat violations.
  • USDA failed to properly punish laboratories by reducing fines by an average of 86 percent – despite previous OIG recommendations to end this practice.
  • Some laboratories’ Institutional Animal Care and Use Committees (IACUCs) are not adequately monitoring their facilities.
  • USDA wasted resources by conducting more than 500 inspections at more than 100 facilities that hadn’t housed AWA-covered animals for more than two years.

All of this should be cause for greater protections for animals and improved openness about what happens inside laboratories. Yet the authors of the report suggest that the government actually pare back its requirements.

Some of the report’s recommendations include:

  • Drastically reducing how often most research facilities are inspected by the U.S. Department of Agriculture (USDA). This change would significantly impair the public’s ability to monitor those facilities’ compliance with the law.
  • Exempting many animal use requests (called protocols) from review by a laboratory’s full Institutional Animal Care and Use Committee when the protocols include "low-risk, noninvasive, or minimally invasive procedures." Instead, the report proposes allowing much animal use to be approved by only one or two members of the committee. But when Congress amended the Animal Welfare Act in 1985, it intended these committees to serve as groups of people, not simply individuals. In addition, even protocols that don’t involve invasive procedures are still harmful to animals, who will experience the stress of confinement, handling, and preparation for experiments. Also, there is no shortage of reported injuries and deaths to animals during routine laboratory practices, including animals who died of dehydration due to broken air conditioning or water feeders and animals who died when their cages were sent through industrial washers.
  • Giving animal experimenters greater control over the creation of regulations and stifling public input. The report’s authors suggest that "[n]ear-final documents should be reviewed by an external advisory committee of experts engaged in animal research from the regulated community before they are disseminated for public comment or final agency review." This suggests that the comments of animal experimenters and the facilities that employ them should be given more weight—or be the only comments considered—when making new rules.

At a time when there is more pressure than ever to reduce government regulation, it’s crucial that we stand up for the rules that give some modicum of protection to those who are most vulnerable. And that's what the Physicians Committee is doing. We’re working with other organizations to plan a strategic response to the recent report and the larger effort to weaken federal animal welfare regulations.

 

November 27, 2017   animal testing, cancer

 

Mice are telling cancer researchers to give it up

It is widely known that mouse research to study human cancers is fraught with unreliability. Scientists have for decades attempted to replicate human cancer growth and treatment responses in mice by disabling their immune systems and grafting human-cell-line-based cancers onto them, a model known as a xenograft. These studies have notoriously faulty outcomes. A new report has shown that recent “improvements” to this technique are just as faulty.

In general, cancer animal research (see here, here, and here) has a failure rate of at least 95 percent, as determined by the results of clinical trials based partly on mouse studies. The few "successes" are usually clinically irrelevant, providing minimal or no real-life value. A 2014 study from the National Cancer Institute revealed an average 2.1 month life prolongation (and often as little as a few days) for the 72 cancer drugs approved from 2002-2014, and even this minimal benefit is illusory in two-thirds of the drugs in clinical use.

Researchers characteristically address the very high attrition rate for drugs developed from animal research by postulating that “better” techniques with animals are needed. Various approaches to improve the predictability of these stand-ins for human cancers have been tried without success. In recent years, there has been much hope ascribed to an approach referred to as patient-derived xenografts (here, here, and here). The mice used in these studies are termed PDX mice and are often called human avatars. To produce these avatars, extracts from human cancers (obtained by biopsies or surgical excisions) are injected into mice, thereby creating mice purportedly expressing the injected cancer. These models can be created from a patient's own tumor, in which case the patient then has a “model” specific for his or her own cancer. It has been thought that such "precision oncology" models will remedy the problems with cell-line-derived cancer tissue, and will identify tumor markers, genetic targets, and effective treatments for a patient's specific cancer.

A recent report from Boston researchers reveals why the ballyhooed PDX approach fails to solve the age-old problem of translation from mice to humans—a problem researchers understandably call the Valley of Death. Using 1,110 tissue samples from 24 different cancer types, these researchers evaluated genetic changes occurring after transplantation of patient-derived cancer tissue into PDX mouse avatars.

Genetic changes in the transplanted tumors occurred rapidly, and these were markedly different from initial genetic characteristics and genetic changes observed during tumor evolution in patients. Genetic mutations noted in patient tumors sometimes disappeared after transplantation. The authors concluded: "Notably, the genomic stability of PDXs was associated with their response to chemotherapy and targeted drugs. These findings have major implications for PDX-based modeling of human cancer."

In other words, the human cancer in the PDX mouse's biological environment leads to mouse-specific changes that invalidate the mouse as a descriptor of the human tumor or as a method for identifying tumor targets and developing treatments. It is no wonder that this precision oncology approach displays no more precision than previous failed cancer research methods using mice. Similar genetic discrepancies would surely be expected for any species using PDX technology, and the conclusion remains that nonhuman research is immutably inadequate for the study and treatment of human cancers.

Where to from here? First, it's long past time that we take notice of the many ways that mice have shown us that they are not tiny humans. Despite decades of research model manipulation, mice are no better at recapitulating the course or treatment responses of human cancers. Second, the logical transition to human-relevant cancer research methods is overdue. Whether the barriers to this transition are researcher arrogance, career and funding considerations, or regulatory restrictions, these must be overcome if the abject failure of mouse research for cancer is to be reversed.

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