COVID-19 and Prioritizing Human-Based Research

{Mandatory preamble: As with all of my blog posts, the views espoused herein are mine alone and should be construed as neither shared nor endorsed by any organization with which I have an affiliation.}

Today I had the honour and privilege of participating in a US congressional briefing on prioritizing human-based research for COVID-19, sponsored by the Washington, DC-based Physicians’ Committee for Responsible Medicine. The content below represents the more verbose version of what I communicated at the briefing, and constitutes what I consider to be a critical conversation in our pathway out of this pandemic. As a physician and scientist who specializes in neglected tropical diseases – most of which are situated in low-resourced equatorial parts of the planet – I have come to learn over the past 12 years of practice that all diseases – whether communicable or not – end up being diseases of poverty and disadvantage. This blog post aims to weave a story about why I think that may be the case.

Medicine and science have a longstanding diversity problem. According to the Pulitzer-prize winning science writer, Laurie Garrett, “from the 1960s to the 1980s, nearly every major direction in the field of global health, including allocation of hundreds of millions of dollars given by institutions such as the Rockefeller Foundation, World Bank, and WHO, were decided by a handful of Western men” (1). As of September 2019, 76% of tenured scientists across the NIH are men, despite that since 2008 more than half of American PhD graduates in the biological sciences have been women (2). On April 17th of this year, the NIH issued a press release about its launch of a public-private partnership to speed vaccine and therapeutics development (3). Four of the 5 scientists quoted in the press release are White men. All six directors or deputy directors of the NIH are men, five of whom are White (4). Only 23% of labs in the NIH’s National Institute of Child Health and Human Development are led by women (2). In 2018, Donna Strickland, a Canadian physicist, was hastily promoted to the rank of Full Professor by the University of Waterloo. Why? She was receiving the Nobel prize and people were wondering why she was only ranked an Associate Professor. In 1910, the American Medical Association issued the Flexner Report, and in it discouraged schools of medicine from training Black students. At the time, the AMA ranked medical schools, so in 1918, in an effort to improve its reputation, Queen’s University in Canada voted to ban Black students from its medical school (5). Ethelbert Bartholomew was a 4th year medical student at Queen’s when the ban on Black students took effect. He was forced out and went on to become a porter with the Canadian Pacific Railway, and died in 1954 never having completed his medical training. In 1943, after 60 years of exclusion, White women were welcomed back to Queen’s, and in 1965 Black students were welcomed back, but it wasn’t until 2018 that the ban on Black medical students was officially repealed from the books. In 2019, 101 years after the abrupt cessation of his medical training, Ethelbert Bartholomew was awarded his medical degree posthumously after the University issued a formal apology (6,7).

Inexplicably, Black voices continue to be absent or severely under-represented in the overall conversation of science. A key analysis published in a prominent academic journal demonstrated that Black applicants to an NIH-funding program comprised only 1.4% of the applicant pool (8). Forty percent of research topics proposed by Black applicants were less likely to be funded, and key words used in proposals that were inversely associated with funding success included: disparity, socioeconomic, and, most gallingly – patient (8). Black scientists were far more likely to be engaged in clinical and community-based research with human subjects than that conducted in a basic science lab (8). After all, it is not health problems of a predominantly cellular or molecular nature that plague Black communities. But when concerns such as food security, police violence, and access to high quality primary health services are immaterial to a grant adjudication panel comprised mostly of experienced, affluent White male academics, the narrative of science – even that ostensibly being done to improve health – continues to be skewed in ways that perpetuate systemic racism, sexism, and intergenerational trauma.

Because the locus of decision-making power in science and medicine has been situated in the hands of a single demographic, entrenched biases have defined its cultural narrative, and this has had grave consequences for those who exist outside that dominant phenotype. Racism, sexism, and nepotism have all intersected to enable continued over-representation of White men in leadership of academia and medicine (9). Why is this a problem? Well, humans have no foresight; hence the adage “hindsight is 20:20”. We are also universally terrible at identifying our knowledge gaps a priori. In other words, we don’t know what we don’t know. There is something called the Founder Effect (10), which is a biological concept that explains how populations of genetically similar individuals end up being vulnerable to certain disease threats. When a population of animals – cheetahs, for example – can be traced back to just a few “founders”, it means they lack the genetic diversity needed to withstand population level insults, like cancers or viruses, so that when these insults occur, the whole population is imperiled. This concept of uniform “founders” – who are so demographically and experientially similar as to have no knowledge of something that may seem tremendously obvious to a more diverse group of thinkers – extends to scientific leadership as well. One of my favorite illustrations of this concept is the story of a Hungarian doctor named Semmelweis (11).

At Vienna General Hospital in the late 1840s, there were maternity wards respectively staffed by either doctors or midwives. The maternal mortality rate on the doctor-staffed wards was many times higher than that on the midwife wards. This fact was widely known and women would beg to be cared for by the midwives. Semmelweis – a young physician at the time – investigated this discrepancy and his sleuthing led him to the pathology suite. Back in the 1840s, doctors would routinely juggle the work of delivering babies and performing autopsies all in a single day, so Semmelweis speculated that some sort of corpse particle was leading to what is now recognized as sepsis in women delivering on the doctor-staffed wards. He implemented a chlorine-based hand-washing protocol and over a 3-month period, saw the maternal mortality rate fall from 18% to 2%. Semmelweis was vocal to his colleagues that it was the collective medical practice of touching corpses and then touching women that was leading to their demise. The overwhelmingly affluent White, male medical community at the time did not welcome this news, and Semmelweis was roundly denounced and derided. Doctors were gentlemen, after all. And a gentleman’s hands were clean.

Belief perseverance is our psychological tendency to clutch on to even discredited beliefs. Despite Semmelweis’ objective successes at saving the lives of women and their babies, he was ostracized and eventually died in an asylum at the age of 47. Only after Louis Pasteur confirmed his germ theory in the 1860s did the work of Semmelweis gain recognition and acceptance. The Semmelweis reflex is the reflexive rejection of innovative ideas and theories that misalign with prevailing scientific dogma, paradigms, and approaches, and, along with a Founder effect in leadership, represents one of the greatest threats to disruptive scientific innovation. As with COVID-19, the simple intervention of hand-washing saved lives, but even in the face of irrefutable evidence that the status quo was killing women, the entitlement and privilege of the gentlemanly doctors enabled them to continue to lay their bacteria-laden hands on women who were doing the work of perpetuating the species. If this privilege and entitlement of the medical establishment sounds familiar, it should, as it was the exact same entitlement to the bodies and lives of others that characterized the experimental unanesthetized surgeries of enslaved Black women by J. Marion Sims (12), also in the late 1840s, and the tragic Tuskegee syphilis trials 100 years later (13,14).

The continued disparity and inequity within scientific leadership and decision-making power needs to be urgently corrected to truly reflect the diverse interests of the communities science is designed to serve. The data are clear. Diversification of leadership and organizational structure pays dividends (15,16) and equips institutions with the resilience and thought diversity needed to withstand events that would be otherwise catastrophic. Prioritizing our default approaches to solving scientific and health problems creates a fallout that is not only very costly, but disproportionately borne by those who are marginalized to begin with. We need to bring more voices to the table and find out what’s material to the communities we serve, particularly the ones that have been over-represented in this pandemic.

When implicit biases and structural and systemic racism collide with social disadvantage on a national scale, we end up with devastating statistics like 71% of COVID-19 deaths in Louisiana occurring among Black residents, who comprise only 32% of the state’s population (17). Or take Michigan, where 40% of COVID-19 deaths have occurred among Black people despite that only 14% of state residents are Black (17). All told, Black counties have 6-times the COVID-19 mortality rates than those that are predominantly White (18). Indigenous Americans living in Arizona and New Mexico have COVID-19 mortality rates that are 5 to 8-times as high as their White counterparts (19). These disparities apply not just to COVID-19, but to chronic disease mortality (20), access to primary care for illnesses like childhood asthma (21), and even immunization coverage (22). With numbers such as these existing in the context of a monochrome leadership and a long legacy of non-consensual engagement of minoritized communities in medical research, is it any wonder that we also have a major trust issue (23,24) in public health?

There are no absolutes in science and medicine. Science is about getting closer to the truth of how we exist in this world. We don’t know the whole truth, but for so many communities, even coming close to the truth is impossible because we’ve systematically denied them access to even asking the questions. Communities have been trying to speak their truth and tell us what they want and need out of science – we just haven’t listened. Now is the time to listen.

At the risk of anthropomorphism, so too have the animals been speaking their truth – just not in a language that we have understood. Perhaps the most compelling case of a fantastic regulatory failure is that of thalidomide (25). In 1953, the drug was first synthesized and thereafter prescribed to pregnant women with morning sickness. By 1960, a large number of newborns were being identified with specific and function-limiting limb malformations. Within the year, thalidomide was implicated as the cause, but not before 10,000 infants had been severely affected, and countless others had died. At the time of thalidomide’s licensure, regulatory agencies did not require pre-clinical animal testing for fetal damage – called teratogenicity – but even if they had, it is unclear if the fetal malformation risk would have emerged anyway. This is because there are significant limits to how closely another animal species can truly model our natural biological processes and diseases. Thalidomide, as it turns out, causes the same fetal malformations in rabbits and monkeys, but not in mice, rats, hamsters, dogs, cats, pigs, or ferrets. Similarly, the known teratogen alcohol causes similar fetal effects in mice and dogs, but not in rats, pigs, or guinea pigs. In fact, of 22 major teratogens, 8 were not discovered to be harmful at all until they were used in humans (26), which is explained by the fact that no single animal or combination of animals perfectly models our biology. A dozen commonly used mammals model the human teratogenicity reaction only 25-70% of the time (26).

The inverse is also true: something may be harmful in animals but not in humans. Fluoride is one such example that causes fetal malformations in dogs, but not in people. Anyone who lives with a dog knows that they not us and we are not them. When the RMS Titanic sank in 1912 in the North Atlantic, no human survived immersion in the icy waters for more than 30 minutes. Thankfully, a Black Newfoundland named Rigel swam around in the water for 3 hours, eventually alerting the captain of the rescue vessel – the RMS Carpathia – to a lifeboat of passengers too weak to alert him themselves (27). I have personally witnessed a Labrador retriever happily cleansing his palate on the entire contents of an outhouse. He was absolutely fine. I was traumatized, of course, but he was okay. On the other hand, consuming just a handful of grapes could land both dogs in the veterinary intensive care unit. We are not the same, humans and animals, and that simple fact is the common thread tying together every historic example of how an animal model failed to predict an adverse outcome in humans.

We need not abandon trusted approaches in favor of systems that are completely experimental and unvalidated, but rather, we can seek the truth by prioritizing the human-based clinical and community research that is historically underfunded and conducted by minoritized scientists, as well as the truly elegant and sophisticated non-animal based laboratory models that already exist. The closing remark of the chapter on public health renewal in the 2004 Naylor report following the original SARS epidemic states “If not now, after SARS, when?” (28) Embracing the unknown is anathema to human nature, particularly during times of extreme psychological stress during which gravitation to security and known quantities prevails as a coping mechanism. But when it comes to the science that will steer us out of COVID-19’s path, we need a cognitive reframing so as not to wind back the clock on progress and innovation. Reputable public and private organizations have embraced non-animal based testing and human organs-on-a-chip as a new global standard. The UK-based Wellcome-Sanger Institute, famous for decoding a third of the human genome, closed its world leading animal facility, recognizing the superiority of non-animal alternative technologies (29). The EPA will completely replace mammals in toxicity testing by 2035 (30), ending a long legacy of unfathomable waste and inefficiency, and in doing so, promoting animal welfare. Both the FDA and EMA have signaled their willingness to accept data from non-animal based models in applications for licensure and emergency use authorization scenarios. In March of this year, both agencies convened to discuss clinical trials of SARS-CoV2 vaccines (31), and while the requirements for animal model data prior to human trials was emphasized, there appeared to be consensus that adherence to the “3R principles” of reduction, refinement, and replacement (32) of animal-based testing would be encouraged. It was further recognized that significant delays would ensue if non-human primate data, for example, were required for testing of vaccine candidates prior to use in humans.

Exemplifying the 3R principles is something called the rFC test for toxins in vaccines. The historic standard has been based on the blood of horseshoe crabs, but the synthetic alternative – rFC – has been optimized and is allowed by the FDA so long as companies can prove its equivalence to the animal based test (33). Due to their commitment to replace animal models where possible, Eli Lilly is one such company that has moved to rFC testing for new injectable products since 2016. A plethora of well characterized human organs-on-a-chip are available and have precedent for evaluating the toxicity, immune responsiveness, and effectiveness of new drug treatments and vaccines. The Wyss Institute of Harvard (34) has been a particular pioneer in this field and has published results of toxicity and other studies using their various human organ-on-a-chip models (35,36,37). Their work has already pivoted to solving some of the most pressing problems related to COVID-19 (38).

In 1690, the British philosopher John Locke defined a person as a “thinking intelligent being, that has reason and reflection, and can consider itself the same thinking thing in different times and places” (39). The 2010 Declaration of the Rights of Cetaceans grants whales and dolphins the right to life, freedom, and protection of their natural environment, and has led to foundational legislation in India (40,41), Canada (42), and California (43,44) granting their right to freedom and self-determination. Personhood was also granted to great apes by the Belearic islands of Spain in 2007 (45), and the World Declaration of the Great Apes in 1994 aimed to secure right to life, individual freedom, protection, and prohibition of torture for chimpanzees and other great apes. It is commonly stated that when one is accustomed to privilege, equity feels like oppression. However, rights and protections are not zero sum propositions. Granting such privileges to cetaceans and non-human primates has neither incurred great cost to humans nor has it eroded our inherent rights to life, liberty, justice, and pursuit of peace. Men lost no rights through the Women’s Rights movement. Abolishing child labor erased no rights of adults. Unfortunately, when the dominant cultural narrative enables dominion of one group over another, that narrative wholly defines the opportunities, roles, and permissible activities of those being oppressed. Despite the aforementioned gains for dolphins, whales, and apes, speciesism continues to disadvantage those to whom rights and freedoms should be considered. We are not the same as animals, but we are not so different that prejudice should foster a narrative that defines their right to life, that downplays their sentience, and ignores their fundamental complexity as we humans execute our larger mission, which on many days feels like incinerating the planet.

With great power comes great responsibility. That responsibility needs to extend beyond the duty of care owed to those most vulnerable amongst us to our animal kin who entrust us with their welfare, and to handle them with the care to which they are rightfully entitled; care that has unfortunately fallen well below standard expectations on countless occasions (46,47,48,49). The best approximation of human biology and illness are human-based models and human subjects research. When those holding the power exercise a homogeneous thought process due to a common demographic or phenotype, the lived experience of those marginalized by their otherness remains external to the narrative that will best approximate their truth. And in extreme times like these, the truth is what we need.

 

Acknowledgments: I thank the Physicians’ Committee for Responsible Medicine for inviting me to participate in the briefing today. Additionally, I would like to sincerely thank the phenomenally talented members of my research team who contributed to fact-checking content for today’s presentation and this blog post: Anacaona Hernandez, Anjola Ogunsina, Candice Madakadze, Celine Lecce, Christian Lecce, Chelsia Watson, Hira Raheel, Ikeade Adeyinka, Jason Kwan, Mahmud Sam, Mariyam Nebil Mohammed, Milca Meconnen, Priyanka Challa, Ranie Ahmed, Sabrina Yeung, Shveta Bhasker, and Stefanie Klowak. #Gratitude

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