To the YSM Community:
Since 1839, the thesis requirement has been the capstone of a Yale medical education. Through the thesis process, students learn the importance of observation and formulation of a question leading to the expression of a testable hypothesis. They learn the importance of study design, and rigor, validity, and reproducibility. They come to understand the impact of bias on the interpretation of observations. Most importantly, they learn the value of curiosity and how to pay attention to the outlier.
The thesis serves as a way of inculcating curiosity and an appreciation for the scientific method and reflects a fundamental belief that only through science will we make progress in improving human health. Yet, the Sars-CoV-2 (COVID) pandemic unmasked a skepticism among some in this country about the value and reliability of science, even as scientists, industry, and patients came together to develop vaccines against Sars-CoV-2 in record time. The proportion of Americans who express “at least a fair amount of confidence” in medical scientists has dropped from 89% in the spring of 2020 to 77% in October of 2023 (Kennedy and Tyson, Pew Research Center, 2023).
To reestablish trust in science, we must change how we communicate with and engage communities in the scientific process, and we will need to double down on our commitment to unbiased hypothesis testing, rigor, and reproducibility. As scientists, we must recognize that we are also human beings who often fall in love with our hypotheses. We forget that our job is not to prove hypotheses but to test them, and that falsifiability is a crucial element of rigorous science. Science and advocacy do not mix well. In addition, we too often conflate technology with science and lose sight of the fact that some of the most impactful discoveries have been made when investigators apply simple, elegant methods to address profound questions.
As physicians and practitioners of medicine, we often take comfort in “evidence-based medicine,” without understanding the quality of the evidence or gaps in our understanding. We confuse observation and correlation with causation. Yet, over the course of my lifetime and career, our assumptions about the etiology of numerous diseases have been stood on their head by questioning the evidence to admit new observations and formulate and test new hypotheses. Consider the case of peptic ulcer disease. In 1974, authors of an epidemiological study published in New England Journal of Medicine affirmed an association between smoking and peptic ulcer disease but noted that studies of the effect of smoking on acid secretion and gastric motility had produced conflicting results (Friedman et al., 1974). Just 10 years later, Marshall and Warren systematically identified the presence of a new species of Campylobacter in the stomachs of patients with gastritis and peptic ulcer disease and went on to demonstrate the ability of H. pylori to produce gastritis (Lancet, 1984 and Australian and New Zealand Journal of Medicine, 1984). Through careful observation and experimentation, they disrupted gastroenterology.
We must guard against confirmation bias by taking an agnostic approach to understanding mechanism. This has been driven home in recent years by paradigm-shifting studies related to health disparities. For example, in the last year a group of investigators performed a combined ancestry genome-wide association study to identify single nucleotide polymorphisms associated with diabetic retinopathy ( Breeyear et al., Nature Medicine, 2024 ). They discovered a powerful association with a variant in the glucose-6-phosphate dehydrogenase (G6PD) gene that causes G6PD deficiency and hemolysis but also protects against malaria, resulting in increased prevalence in individuals of African descent. Because the variant leads to a shorter half-life of hemoglobin, levels of glycosylated hemoglobin (HbA1c) are lower in carriers of the variant for any given level of glucose. In a health system in which HbA1c is the primary metric for diabetic control, the authors estimated that 12% and 9% of diabetic retinopathy and neuropathy cases, respectively, in individuals of African ancestry are due to underdiagnosis of poor glucose control in carriers of this variant. This one discovery could dramatically reduce retinopathy and neuropathy if we change how we screen patients for this variant and alter diagnostic criteria in carriers of the variant.
Times of change present wonderful opportunities to conduct an agnostic and constructive appraisal of our hypotheses and processes. As we face skepticism about science in the coming years, we must approach it with the same curiosity that we ask questions in science. This requires us to listen with humility. We will win over doubters by demonstrating unwavering commitment to rigor and the scientific method and by communicating the impact of our discoveries in clear and transparent ways.
Sincerely,
Nancy J. Brown, MD
Jean and David W. Wallace Dean of Medicine
C.N.H. Long Professor of Internal Medicine