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Rats and me
I was first introduced to a rat in a lab as a postdoc in 1971. It didn’t go badly. We observed each other with some caution as I looked into the “shoe box” cage with its wood chip bedding material. I wasn’t sure what to think, and neither was he. I’m a chemist and had not taken a biology course since high school. My professor, the late Ralph N. Adams at Kansas University, was “suggesting” it would be productive to observe neurotransmitters with an electrode sensor in the brain of that rat.
I was able to think of a dozen reasons why this would not work. The only way out of my dilemma was to try it. Many of my concerns were real, but it worked well enough to justify continuing the project and it went far further than I imagined was possible nearly five decades ago. Stopping prematurely was not an acceptable outcome, given all that has since evolved in the lab. I learned that both planning and doing had virtues, but most of all, do the experiment.
Today, my first thought on walking into a vivarium is “thank you.” Thanks for helping reduce my mild hypertension and helping to get my cholesterol under control. Thanks for helping with developing the imaging technology that was key to my care after a serious accident. Thanks for enabling my friends and family to get therapy that was completely unavailable to my grandparents.
I owe animals a debt of gratitude and have dedicated a good part of my career to giving something back by enabling more meaningful measurements on fewer animals.
On April 19, we celebrated Biomedical Research Awareness Day (BRAD), recognizing the valued contribution of laboratory animals to care for all the different mammals we rely on as family, friends, pets or food. BRAD is sponsored by Americans for Medical Progress (www.amprogress.org). AMP is needed to counterbalance organized efforts to disparage the use of any animals in research. Debate matters, and with this topic there are multiple sides, from the smallest fish to our companion pets and closest primate relatives.
Advances in our understanding of mammalian biology, disease and therapeutic interventions have been amazing over the past five decades and have accelerated apace over the past five years. Contrary to some daily press accounts, there is more yet to understand than what has been uncovered thus far. There is a long way to go with very little opportunity to advance therapies without both human subjects and laboratory animals. Some advocate using computers to simulate biology, some suggest cell cultures are enough and others think we can mimic a mammal on a microfluidic chip. The latter was featured in the May issue of DDNews. All of these can be helpful, but a brain is not a neuron in a dish and a liver is not isolated cells in a tiny flow channel. I am not going to discourage these innovations as a cynical luddite might, but I’d think it very foolish to either advance or cancel a human medicine project based on results from these early-stage in-vitro tools.
A mammal is much more than the sum of its parts. Only in intact mammals can we presently hope to learn of benefits (pharmacology) and risks (toxicology). Let’s not forget about concentration and time of exposure. We are dynamic. What we observe over a day will likely not hold true over a decade. What we observe in response to a 5 mg dose may well mean nothing much at 500 mg. If one pill is good, two will not reliably be better. The answers lie in preclinical and clinical trials over time with varying doses.
Most citizens do not understand the extent to which both preclinical and clinical trials are regulated. It is fair to say that regulations come from human failings. Yes, there have been terrible abuses with both animals and humans. Trouble occasionally happens today, but very rarely. The recipes (“protocols”) for projects are carefully vetted with respect to their purpose and their procedures. The welfare of both animal and human subjects is a top priority reviewed by Institutional Animal Care and Use Committees (IACUCs) and Institutional Review Boards (IRBs), respectively.
The validity and quality of data are most important. These trials are very costly. The best data results from carefully designed experiments that minimally disturb the subjects. Clinical trial participants review and sign an IRB-approved informed consent before participation. Animals unknowingly rely on the IACUC to consider their welfare and the risks and benefits to obtaining generalizable knowledge, such that the trial will not have been wasted. For both animal and human trials, we look to Refine, Reduce and Replace—meaning that we do not unnecessarily enroll participants with four legs or two until alternatives have been considered. As a result, trials improve year by year as the science advances.
Recently there were complaints from Europe that IRBs were not being sufficiently furnished with the animal efficacy and safety data preliminary to a human trial (Wieschowski et al., PLoS Biol 16(4): e2004879). This report was widely covered. The FDA uses the IND process for allowing advancement of a drug to human trials. IRB members have neither the time nor expertise to repeat the IND process.
Preclinical studies are necessarily imperfect on both the efficacy and safety fronts. Their reliability varies with both the disease (efficacy) and the adverse consequences (safety). A recent report demonstrated the decent concordance between toxicity observed in preclinical and clinical trials over the past 70 years (Clark and Steger-Hartman, Toxicol. Pharmacol. Regul. 96 (2018) 94-105). Regulatory bodies are not going to lighten up on the preclinical side or replace it with computer models anytime soon.
The debate between those supporting and refuting the value of animal work will continue. Both sides are right to an extent that remains ambiguous. The alternatives are also imperfect.
DDNews readers should be out front educating the public on this important topic. Too many of you fear the debate and are reluctant to join in. We shouldn’t encourage want “safe spaces” to hide from debating the question.
It gets even more interesting when we consider the reality of chimeric species, such as the mouse with a human-like liver. In my own career, I’ve been fortunate to participate in advances in bioanalytical chemistry and medical devices that enabled measurements on smaller and smaller samples from fewer and fewer research subjects undergoing dramatically reduced stress. I’m proud to have helped get better data to make better decisions while reducing animal use. This process continues.
Remember this: The first time a doctor prescribes a drug for you, your cat, or a relative, that’s the beginning of a trial with N=1. Pay attention. Your observations over time can contribute to generalizable knowledge for future patients. We are at the threshold of this possibility becoming manageable with electronic data communications. There are many details to work out, such as data security and properly managing large data sets. We have an opportunity to use more and better data to make better decisions. It’s not easy, but it’s possible.
Neither animal nor human research subjects are reliable predictors for all subsequent mammals. Diversity explains this. So it goes.
End Note: The book Bad Blood mentioned in my last column on the Theranos scandal is an excellent read. It is also a compelling reminder of why we have an FDA, an SEC, IACUCs, IRBs and a free press. People behave badly. Other people must catch and stop them.
Peter T. Kissinger (who can be reached at firstname.lastname@example.org) is professor of chemistry at Purdue University, chairman emeritus of BASi and a director of Chembio Diagnostics, Phlebotics and Prosolia.