Thursday, April 30, 2015

Asking for a Small Piece of the Nation’s Pie

By Rosalind Mott, PhD

This article was originally published in the Penn Biomed Postdoctoral Council Newsletter (Spring 2015).

Historically, the NIH has received straightforward bipartisan support; in particular, the doubling of the NIH budget from FY98-03 led to a rapid growth in university based research. Unfortunately, ever since 2003, inflation has been slowly eating away at the doubling effort (Figure 1). There seems little hope for recovery other than the brief restoration in 2009 by the American Recovery and Reinvestment Act (ARRA). Making matters worse, Congress now has an abysmal record of moving policy through as bipartisan fighting dominates the Hill.

Fig 1: The slow erosion of the NIH budget over the past decade
(figure adapted from:
Currently, support directed to the NIH is a mere 0.79% of federal discretionary spending. The bulk of this funding goes directly to extramural research, providing salaries for over 300,000 scientists across 2500 universities.  As the majority of biomedical researchers rely on government funding, it behooves these unique constituents to rally for sustainable support from Congress. Along with other scientists across the country who are becoming more politically involved, the Penn Science Policy Group  arranged for a Congressional Visit Day (CVD) in which a small group of post doctoral researchers and graduate students visited Capitol Hill on March 18th to remind the House and Senate that scientific research is a cornerstone to the US economy and to alert them to the impact of the erosion on young researchers. 

Led by post-docs Shaun O’Brien and Caleph Wilson, the group partnered with the National Science Policy Group (NSPG), a coalition of young scientists across the nation, to make over 60 visits to Congressional staff. NSPG leaders from other parts of the country, Alison Leaf (UCSF) and Sam Brinton (Third Way, Wash. DC), arranged for a productive experience in which newcomers to the Hill trained for their meetings.  The Science Coalition (TSC) provided advice on how to effectively communicate with politicians: keep the message clear and simple, provide them with evidence of how science positively impacts society and the economy, and tell personal stories of how budget-cuts are affecting your research. TSC pointed out the undeniable fact that face to face meetings with Congress are the most effective way to communicate our needs as scientists. With the announcement of President Obama’s FY16 budget request in February, the House and Senate are in the midst of the appropriations season, so it was no better time to remind them of just how important the funding mechanism is.

Meeting with the offices of Pennsylvania senators, Pat Toomey and Bob Casey, and representatives, Glenn Thompson and Chaka Fattah were key goals, but the meetings were extended to reach out to the states where the young scientists were born and raised – everywhere from Delaware to California. Each meeting was fifteen to twenty minutes of rapid discussion of the importance of federally funded basic research. At the end of the day, bipartisan support for the NIH was found to exist at the government’s core, but the hotly debated topic of how to fund the system has stalled its growth.
Shaun O’Brien recaps a disappointing experience in basic requests made to Senator Toomey. Sen. Toomey has slowly shifted his stance to be more supportive of the NIH, so meeting with his office was an important step in reaching the Republicans:

We mentioned the "Dear Colleague" letter by Sen. Bob Casey (D-PA) and Sen. Richard Burr (R-NC) that is asking budget appropriators to "give strong financial support for the NIH in the FY2016 budget". Sen. Toomey didn't sign onto it last year, especially as that letter asked for an increase in NIH funding to $31-32 billion and would have violated the sequester caps-which Sen. Toomey paints as a necessary evil to keep Washington spending in check. I asked the staffer for his thoughts on this year's letter, especially as it has no specific dollar figure and Sen. Toomey has stated his support for basic science research. The staffer said he would pass it along to Sen. Toomey and let him know about this letter.

Unfortunately, three weeks later, Sen. Toomey missed an opportunity to show his "newfound" support for science research as he declined to sign a letter that essentially supports the mission of the NIH.  I plan to call his office and see if I can get an explanation for why he failed to support this letter, especially as I thought it wouldn't have any political liability for him to sign.

Working with Congressman Chaka Fattah balanced the disappointment from Toomey with a spark of optimism. Rep. Fattah, a strong science supporter and member of the House Appropriations Committee, encourages scientists to implement twitter (tweet @chakafattah) to keep him posted on recent success stories and breakthroughs; these bits of information are useful tools in arguing the importance of basic research to other politicians.

Keeping those lines of communication strong is the most valuable role that we can play away from the lab.  Walking through the Russell Senate Office building, a glimpse of John McCain waiting for the elevator made the day surreal, removed from the normalcy of another day at the bench. The reality though is that our future as productive scientists is gravely dependent upon public opinion and in turn, government support. The simple act of outreach to the public and politicians is a common duty for all scientists alike whether it be through trips to the Hill or simple dinner conversations with our non-scientist friends.

Participants represented either their professional society and/or the National Science Policy Group, independent from their university affiliations. Support for the training and experience was provided by both the American Academy of Arts & Sciences (Cambridge, MA) and the American Association for the Advancement of Science (AAAS of Washington, DC).

Friday, April 3, 2015

Dr. Sarah Cavanaugh discusses biomedical research in her talk, "Homo sapiens: the ideal animal model"

Biology and preclinical medicine rely heavily upon research in animal models such as rodents, dogs, and chimps. But how translatable are the findings from these animal models to humans? And what alternative systems are being developed to provide more applicable results while reducing the number of research animals?
Image courtesy of PCRM

Last Thursday, PSPG invited Dr. Sarah Cavanaugh from the Physicians Committee for Responsible Medicine to discuss these issues. In her talk entitled, “Homo sapiens: the ideal animal model,” she emphasized that we are not particularly good at translating results from animal models into human patients. Data from the FDA says that 90% of drugs that perform well in animal studies fail when tested in clinical trials.  It may seem obvious, but it is important to point out that the biology of mice is not identical to human biology. Scientific publications have demonstrated important dissimilarities in regards to the pathology of inflammation, diabetes, cancer, Alzheimer’s, and heart disease.

All scientists understand that model systems have limitations, yet they have played an integral role in shaping our understanding of biology. But is it possible to avoid using experimental models entirely and just study human biology?

The ethics of studying biology in people are different from those of studying biology in animals.  The “do no harm” code of medical ethics dictates that we can’t perform experiments that have no conceivable benefit for the patient, so unnecessarily invasive procedures can not be undertaken just to obtain data. This limitation restricts the relative amount of information we can obtain about human biology as compared to animal biology.  Regardless, medical researchers do uncover important findings from human populations. Dr. Cavanaugh points out that studies of risk factors (both genetic and environmental) and biomarkers are important for understanding diseases, and non-invasive brain-imaging has increased our understanding of neurodegenerative diseases like Alzheimer’s.

Yet these are all correlative measures. They show that factor X correlates with a higher risk of a certain disease. But in order to develop effective therapies, we need to understand cause and effect relationships - in other words, the mechanism. To uncover mechanisms researchers need to be able to perturb the system and measure physiological changes or observe how a disease progresses. Performing these studies in humans is often hard, impossible, or unethical. For that reason, researchers turn to model systems in order to properly control experimental variables to understand biological mechanisms. We have learned a great deal about biology from animal models, but moving forward, can we develop models that better reflect human biology and pathology?

Using human post-mortem samples and stem cell lines is one way to avoid species differences between animals and humans, but studying isolated cells in culture does not reflect the complex systems-level biology of a living organism. To tackle this problem, researchers have started designing ways to model 3D human organs in vitro, such as the brain-on-a-chip system. Researchers also have envisioned using chips to model a functioning body using 10 interconnected tissues representing organs such as the heart, lungs, skin, kidneys, and liver.
Image from:

Dr. Cavanaugh explained that toxicology is currently a field where chip-based screening shows promise. It makes sense that organs-on-a-chip technology could be useful for screening drug compounds before testing in animals. Chip-screening could filter out many molecules with toxic effects, thus reducing the number of compounds that are tested in animals before being investigated clinically.

A major counterpoint raised during the discussion was whether replacing animal models with human organs on a chip was simply replacing one imperfect, contrived model with another. Every model has limitations, so outside of directly testing therapeutics in humans, it is unlikely that we will be able to create a system that perfectly reflects the biological response in patients. The question then becomes, which models are more accurate? While ample data shows the limitations of animal models, very little is available showing that alternatives to animal-free models perform better than existing animal models. Dr Cavanaugh argues, however, that there is an opportunity to develop these models instead of continuing to pursue research in flawed animal models. “I don’t advocate that we end all animal research right now, rather that we invest in finding alternatives to replace the use of animals with technologies that are more relevant to human biology.”

This topic can ignite a passionate debate within the medical research community. Animal models are the status quo in research, and they are the gatekeepers in bench-to-bedside translation of scientific discoveries into therapeutics. In the absence of any shift in ethical standards for research, replacing animal models with alternatives will require mountains of strong data demonstrating better predictive performance. The incentives exist, though. Drug companies spend roughly $2.6 billion to gain market approval for a new prescription drug. Taking a drug into human trials and watching it fail is a huge waste of money. If researchers could develop new models for testing drugs that were more reliable than animal models at predicting efficacy in humans, it’s safe to say that Big Pharma would be interested. Very interested.

-Mike Allegrezza

"Wistar rat" by Janet Stephens via Wikimedia Commons