Good Science Digest

The Physicians Committee
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Good Science

October 15, 2018   animal testing

 

While vaccines have helped eradicate and control a wide range of infectious diseases, many diseases still lack a cure, and emerging diseases are always on the horizon. A new approach is needed to study and complete our knowledge of the human immune system—an approach that can transform human health by preventing and treating diseases and accelerating product development.

To accomplish this aim, the Michelson Medical Research Foundation and the Human Vaccines Project have partnered together to reward and support innovative scientists across the world by establishing The Michelson Prizes for Human Immunology and Vaccine Research. The Michelson Prizes are annual awards of $150,000 granted to young investigators who are applying disruptive research concepts and innovative methods to advance vaccine and immunotherapy research for major global diseases. Applicants under the age of 35 and knowledgeable in various disciplines, including clinical research, protein engineering, biomedicine, computer science, engineering, and nanotechnology are encouraged to apply.

The Michelson Prizes support research that has the potential to transform vaccine and immunotherapy discoveries. Prizes are awarded in three focus areas: Human Immunology, Computational Biology and Protein Engineering, and Neglected Parasitic Diseases.

  1. The Human Immunology focus area is aimed towards addressing challenges in human vaccine development and increasing knowledge of key immune processes that impact vaccine and immunotherapeutics expansion.
  2. The Computational Biology and Protein Engineering focus area utilizes advanced models and computational approaches to interpret protein structures involved in immune recognition, immunogenicity, protein-ligand interactions, or other biological functions related to the human immune response.
  3. The Neglected Parasitic Diseases focus area fosters research on antigen discovery, immune response mechanisms, and the development and testing of vaccines and immunotherapeutic agents for neglected parasitic diseases.

The 2018 Michelson Prizes were awarded to three outstanding researchers conducting revolutionary human-relevant research, and we anticipate the same revolutionary spirit in the 2019 winners.

The 2019 Michelson Prizes are currently accepting applications, but don’t wait to apply. The due date for applications is Oct. 29, 2018!

October 2, 2018   animal testing

 

Cannabis testing on rats

Recently, researchers from Washington State University reported “breaking” research that found that cannabis use alters eating behaviors, findings which they claim may lead to treatments for appetite loss in chronic illness. 

The study exposed rats to cannabis vapor to assess how the drug affects appetite and triggers hunger hormones. When the rats were forced to inhale cannabis, their brains released a flow of ghrelin, the hunger hormone, which stimulated their appetites and triggered them to eat. The researchers conducted this study in hopes that it would lead to new treatments for illness-induced appetite loss that is common in many chronic illnesses like cancer and HIV/AIDS.

Not only is this research inefficient and unethical, it’s utterly insignificant. Animal research does not translate to knowledge about humans. Not only that, but we already know that, when exposed to cannabis, a human’s hypothalamus triggers the release of ghrelin, which stimulates the appetite. This isn’t new science; this is another example of researchers taking advantage of animals who aren’t protected by the Animal Welfare Act

Unfortunately, studies of this type aren’t isolated events. In 2017, the National Institutes of Health (NIH) supported 330 cannabinoid research projects totaling almost $140 million. Many of these studies involved the use of animals for experimentation, including mice, rats, dogs, and non-human primates. It’s common in these studies that, after being trapped inside inhalation chambers, the animals are killed so that researchers can extract the animal’s organs (typically the brain) to study more closely.  

There are currently 30 states where cannabis is available for use as a therapeutic agent and nine that have approved cannabis for recreational use. With cannabis policy shifting, the number of studies and amount of funding dedicated to scientific research in this area will increase. However, that doesn’t mean animals have to suffer. There are numerous humane and human-relevant alternatives that can be used to address the current research gaps.

In 2017, the National Academy of Sciences (NAS) conducted an extensive review of the current evidence regarding the health effects of using cannabis and cannabis-derived products. In its report, The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research, the committee presents nearly a hundred research conclusions and outlines recommendations to improve future cannabis research. The report concludes that there is limited evidence that cannabis is effective at increasing appetite and decreasing weight loss associated with HIV/AIDS and insufficient evidence that cannabis is an effective treatment for cancer-associated anorexia nervosa.

The NAS committee formulated recommendations to improve the quality and advancement of cannabis research. The experts endorse prioritizing a research agenda to support the investigation of the long- and short-term health effects of cannabis use, using human clinical and epidemiological studies. They also recommend the development of novel diagnostic technologies that permit rapid, accurate, and noninvasive assessment of cannabis exposure. This report demonstrates the need for more human-based research (such as this report) in order to advance our knowledge of cannabis.

Opportunely, other researchers have identified the benefits of conducting more efficient research in humans. According to ClinicalTrials.gov, there are 437 and 732 current or recently concluded human clinical and observational studies in the United States and worldwide, respectively, investigating cannabis. These types of studies use human volunteers who consent to participate in research in order to make advancements in medical knowledge.

With technology continuously advancing, there is no justification to explain the use of animals to study human diseases. The research at Washington State University that used animals to study how brain changes from cannabis exposure are responsible for changes in eating behavior could have been done with human volunteers. Advanced neuroimaging techniques like functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), and positron emission tomography (PET) are able to reveal functional brain activity in response to stimuli, including peripheral signals with central effects (like ghrelin).

With cannabis studies on the rise, researchers and funding bodies must prioritize the use of humans and human-based methods for more promising scientific research.

September 7, 2018   animal testing

 

As a child, Max Ritvo climbed into his mother's bed to watch cartoons every Monday, a ritual so important to Max that he named his dog Monday. As a 16-year-old high school wrestler with a black belt in karate, Max was diagnosed with Ewing sarcoma. Over several years, he suffered through toxic chemotherapies, including an immunotherapy drug that only seemed to accelerate his tumor growth. Finally, a sample of Max's sarcoma was injected under the skin of a mouse to create an avatar of his cancer. This is called a patient-derived xenograft or PDX. When a drug that succeeded in controlling Max's mouse avatar sarcoma was given to him, it did not work. More about Max later.

Acknowledging decades of mouse research failures in cancer treatment, scientists in recent years have sought answers from mouse avatars like Max's—mice who have fragments of specific human tumors injected under their skin. The promise is that by studying actual human tumors rather than standardized cancer cell cultures, tumor characteristics and treatment responses mimicking those of the patient may be produced in mice.

This approach seems to be an improvement in the standard but failed xenograft model of cancer research, whereby preserved cancer cell cultures are injected under the skin of mice—until the fact that mice cannot be made to behave like humans dooms the method. After the initial enthusiasm and hype from researchers and media, some of the species-specific discrepancies that make all animal research unreliable for human medicine have emerged for PDX models.

So what has dimmed the prospects for mouse avatars of human cancers? First, because not all human cancers will grow in mice (a strong hint that mice are not a good model), only about half of human cancers can produce PDX models. Because those PDX models can take months to be developed, this approach is too late for many patients with limited survival. And because of the expense and time lag for applications in clinical medicine, PDX production is a shaky business model.

Meanwhile, the genetics and biology of PDX avatars revealed why this has not been a reliable approach to replication of human cancer biology. Researchers at the Broad Institute of MIT and Harvard analyzed the genomes of 1,110 PDX models representing 24 cancer types. They discovered that PDX tumor genetics changed during generations of implants, that those changes occurred in 88 percent of PDX models by the fourth passage, that about 12 percent of the total tumor genome was changed, and that those changes are quite different from genetic changes occurring in the corresponding human cancers. For example, human glioblastomas (lethal brain tumors) tend to gain extra copies of chromosome 7, whereas mouse PDX models of those glioblastomas tend to lose those extra copies.

Further, some of the avatar tumor genetic changes affect the response to chemotherapy drugs, making these models even less reliable for prescribing patient treatments. So the cancer in the mouse avatar, despite being taken from the patient, is not the same cancer that threatens the patient, and may not respond to treatments as the patient would.

Other research has discovered that the human connective and vascular tissues in the PDX mice are replaced by corresponding mouse tissues as they pass between mice. Thus, the "humanized" cancer environment is not even maintained in the PDX model. Another disabling problem is that mice without immune systems must be used to permit tumor growth in the PDX models. Aside from the obvious divergence from the human tumor environment, this precludes testing of immunotherapy drugs—a promising and growing therapeutic class of cancer agents.

PDX-derived cancer treatments are not the answer to the wide translational barrier between animal research and patient outcomes, a barrier called by researchers "the Valley of Death." Lead Broad Institute researcher Todd Golub agrees. He does not think that PDX mouse research is any better than the discredited xenograft mouse model, stating: "I just don't see the PDXs as being some magically different thing."

In a cruel reversal, Max's mother Ariella sat at her son's bed to keep watch as he died in August 2016. Neither standard treatments nor Max's PDX-derived treatment could save him. Ariella had almost frantically led the family foundation's efforts to accelerate progress in cancer therapies, but she said after Max's death: "And I now have the horrible luxury of time."

Cancer patients do not have the luxury of wasted time, funding, and hope buried in the PDX paradigm. The answer is human-specific cancer research. The longer it takes to get there, the more unnecessary cancer deaths will occur.

September 7, 2018   animal testing

 

Diabetes researchers sat up straight in 2017 when two mouse studies reported the ability to increase pancreatic insulin production with drugs: the neurotransmitter GABA and the anti-malaria drug artemisinin that works through the GABA pathway. Appearing in the prestigious journal Cell, these reports caused excitement that a means for reversing type 1 diabetes mellitus was at hand.

But hold the headlines—neither outcome could be replicated in carefully designed studies at the University of Pennsylvania Perelman School of Medicine and the University of California Davis, both published in another prestigious journal, Cell Metabolism. These reports led pancreatic biology researcher Fred Levine to state: "These two recent papers in Cell Metabolism have shown definitively that the two earlier papers in Cell are completely irreproducible."

This failure to replicate is not unusual. The irreproducibility of animal research seems to be present wherever it is investigated, and it is underestimated because replication attempts seldom occur and failures are rarely published.   

David Rimm's report of melanoma antibody staining that identified the need for specific chemotherapy could not be replicated in his own laboratory, a failure attributed to contaminated commercial antibodies and costing millions of dollars in wasted research funding. A 2008 report claimed that fewer than half of 6,000 routinely used antibodies recognized only their specific targets, and a 2015 report (with 110 co-signatories) on commercial antibodies called them "wildly variable."

Bayer Healthcare researchers reported in 2011 that fewer than one-fourth of 67 drug target validation studies could be replicated, and that more than half of attempted validations resulted in project terminations. A much-referenced report in 2012 from biotech giant Amgen found that its scientists could not replicate 47 of 53 "landmark" cancer papers from high impact factor journals. An unpublished 2015 survey by the American Society for Cell Biology found that more than two-thirds of responding researchers had experienced inability to replicate their research findings, and an accompanying comment was: "In many laboratories, the incentives to be first can be stronger than the incentives to be right."

When more than 270 researchers collaborated to replicate 150 reports from the most respected psychology journals, they rejected 50 as too difficult to replicate and found concordant outcomes in just 36 of the remaining 100 studies. The mean effect size of the replications was just half of that in the original studies, confirming much weaker results. The even worse replication rate for any but these top-rated reports can only be imagined.

Ninety percent of surveyed preclinical researchers reported that a research replication crisis exists. More than 70 percent of 1,576 surveyed researchers have tried and failed to replicate other scientists' experiment(s), and more than half of those surveyed reported failure(s) to reproduce their own experiments. Investigations of high-quality research results from leading academic institutions have shown a pathetic 11-25 percent replication rate for published preclinical research (here and here). The economic impact has been estimated at $28 billion annually for the more than half of preclinical research results that cannot be replicated.

John Ioannidis' claim that most science research results are false, controversial when it appeared in 2005, is now widely accepted. That the problem has nonetheless grown over the ensuing years is attributable to resistance from the research enterprise toward a reality that threatens their very existence. The status quo seems more important than the truth when careers and funding are at stake.

The many reasons for the failure to replicate most animal research results include a litany of laboratory procedural issues and the inherent variability of research involving nonhuman animals. In such an environment, the unethical practice of selective reporting of random successful outcomes is tolerated—often silently or overtly facilitated by institutional, career, and funding considerations that favor provocative claims over good science.

Critically however, underlying all this is the fundamental genetic and evolutionary reason for animal research irreproducibility and the failed translation of animal research findings to human medicine, which is immutable even if all other factors are eliminated—nonhumans cannot even predict or reproduce outcomes for their own species, never mind for humans.

Would better animal research replication mean better translation to human medicine? No, because no matter how reproducible or consistent animal research findings may be, those findings will not predict or explain human outcomes. Then why do we care about laboratory replication, other than presenting an honest picture to the public? We care because the fundamental inability even to replicate animal research outcomes contributes to the abundant evidence that such research in the interest of human medicine is scientifically irrelevant.

In other words, although we know that any animal testing results will have no reliable scientific link to human outcomes, the inability to conduct this bad science in a reproducible manner means that even the exercise itself has no scientific foundation. In even simpler words, the Emperor has no clothes. 

The replication crisis includes the animal research that often leads to FDA approval for clinical trials that—because of false preclinical results—cannot succeed. Thus, patients and volunteers are subjected to fruitless interventions and their consequences, years are lost to this doomed research, billions of dollars are wasted that may have been put to good scientific use, people die perhaps needlessly while bad research persists, and the once-hallowed scientific endeavor suffers a justified major credibility hit.

The NIH has recognized the replication crisis and suggested reasons and solutions. NIH director Francis Collins has stated: “Preclinical research, especially work that uses animal models, seems to be the area that is currently most susceptible to reproducibility issues.” So the crisis in animal research replication is no secret.

The proposed NIH approach is described:

"Clearly, reproducibility is not a problem that the NIH can tackle alone. Consequently, we are reaching out broadly to the research community, scientific publishers, universities, industry, professional organizations, patient-advocacy groups and other stakeholders to take the steps necessary to reset the self-corrective process of scientific inquiry."

Noble-sounding as it is, this is a formula for failure, as the elements solicited for resolution are precisely those who created and perpetuate the crisis. Self-interest mitigates against a cooperative effort, just as self-interest sustains an animal research enterprise that is an abject failure scientifically and ethically. The solution to the replication scandal does not appear to be at hand, but it can be eliminated by replacing animal research with human-relevant research methods.

A good single source review of the replication crisis in science research is here.

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