Yves here. This KLG offering on the state of education in medicine sets up a discussion on statins that he will continue in his next post.
To add to what KLG describes, a good friend, a biomedical engineer and daughter of an MD whose first job was at the NIH, said, “Medicine is a medieval art.” Yet the teaching of medicine does not acknowledge its limited scientific foundations.
By KLG, who has held research and academic positions in three US medical schools since 1995 and is currently Professor of Biochemistry and Associate Dean. He has performed and directed research on protein structure, function, and evolution; cell adhesion and motility; the mechanism of viral fusion proteins; and assembly of the vertebrate heart. He has served on national review panels of both public and private funding agencies, and his research and that of his students has been funded by the American Heart Association, American Cancer Society, and National Institutes of Health
For most of my professional working life I have been a biochemist and molecular cell biologist whose interests did not require any serious acquaintance with biomedical science as applied to the actual practice of medicine. I was interested in protein evolution, structure, and function; how cells move; and how they evolved to form complex multicellular organisms. I taught graduate students and directed the projects of graduate students in a similar vein.
My professors, both undergraduate and graduate, had little interest in understanding or teaching “human biochemistry,” which is now one of the most useful science courses taught at my home institution. They generally looked down on the subject, which in retrospect was more than a bit precious.
This all changed for me when I moved to my current institution and began tutoring first- and second-year preclinical medical students in small groups. I learned quickly that although I was comfortable understanding the basics of metabolism, nutrition, heart disease, and cancer from 20,000 feet, things changed when I had to introduce emergent physicians to the molecular and cellular intricacies of Type 1 and Type 2 diabetes, cancer progression, hematology, and cardiovascular disease.
In retrospect, it is somewhat embarrassing that I might have known at one time the intricacies of glycolysis and the TCA cycle and muscle contraction, while at the same time having not one meaningful clue about the biochemistry and cell biology of diabetes. Many of the canonical medical textbooks seemed to go around their subjects instead of getting straight to the heart.
So, I began to do what I had been taught when faced with a new problem and a new project: Dig into the literature and build a foundation for the new knowledge and understanding my students required of me. And this led, after a few false starts and sojourns in a cluttered desert to my question: What if medicine were taught like a science?
At first glance this is a perfectly ridiculous thing to ask. Of course, medicine is taught like a science! After all, except for students at NYU, premedical students must master General Biology, General Chemistry, Principles of Physics, and Organic Chemistry in preparation for medical school.
Nevertheless, I found that much of the current teaching and practice of medicine shows that the principles of the biomedical and human sciences are not as foundational in the teaching of medicine as they should be, and this perhaps can be illustrated by the hegemony of evidence-based medicine (EBM). I hope to cover this in more depth as this series continues, but the more I reflect on EBM, the more it seems that the inverted pyramid of EBM, with the meta-analysis viewed as the source of true knowledge, is analogous to the inverted totalitarianism Sheldon Wolin uses to describe our “managed democracy.” Granted, that is a bridge too far for now, but it is not a bridge to nowhere.
Anyway, how can this be? An answer, if not the complete answer, finally dawned on me when my continuing education led me to read The Case Against Sugar, by Gary Taubes:
History is critical to understanding science and how it progresses. Moreover, in many (all) scientific (scholarly) disciplines – physics (biology), for example – the science is taught with the history attached. Students learn not only what is believed to be true and which conjectures have fallen by the wayside, but on the basis of what experiments and what evidence, and by whose authority and ingenuity…Medicine today though, as with related fields such as nutrition is taught mostly untethered from its history. Students are taught what to believe but not always the evidence on which those beliefs are based, and so oftentimes the beliefs cannot be questioned…(nevertheless) Students of any science need to know why they are being asked to believe a particular idea, or why not, and on what grounds. Without the history of the idea, there’s no way to tell, and by implication, no reason to ask.” (modified, p. 21-22).
If we are telling the students what is true, then we are not teaching them to understand. Thus, all understanding develops from the history of a discipline. Which is not to say that every practitioner must know the complete history of her discipline, which is impossible, but she must understand the foundations of the practice, where they are strong and where they are weaker.
The scientific foundation of medicine is alive and well in some places, such as cancer biology as illustrated in The Emperor of All Maladies: A Biography of Cancer by Siddhartha Mukherjee. Dr. Mukherjee covers the history of cancer, but more importantly this book describes the progress made and in the treatment of cancer, what works and what doesn’t.
What doesn’t work: The radical mastectomy, first performed by William S. Halstead, one of the four doctors who founded the Johns Hopkins Hospital. A similar operation was 100 years old at the time, and 100 years later it was still largely a futile and violent gesture visited upon women, for no good reason.
What does work, on the other hand, is the treatment of childhood leukemia, which came out of the long and difficult work of Sidney Farber and colleagues beginning in the late-1940s. Many other cancer treatments also work, such as the combination of chemotherapy and focused radiation on oropharyngeal squamous cell carcinoma. The use of imatinib (Gleevec) was a revolution in its targeting of oncogenic protein kinases, although resistant mutants of the Abl tyrosine kinase are sometimes a complication leading to recurrence.
One of the most important points to remember regarding successful cancer treatments is that if remission/cure is the goal, the clinical endpoint is exact and the patient lives. However, it does seem that the clinical endpoints in cancer therapy have been fairly mobile lately, if the commercials I see when I (seldom) watch television are indicative.
One might also say, correctly, that clinical endpoints have been mobile during the current pandemic, which is not over and has not been blunted particularly well by mRNA vaccines that are repeatedly described as “safe and effective,” even if they do not prevent infection and transmission of SARS-CoV-2.
Here we will be concerned with the practice and teaching of nutrition and the health consequences of same over the past 60+ years using the following sources: Gary Taubes, Good Calories, Bad Calories: Fats, Carbs, and the Controversial Science of Diet and Health and The Case Against Sugar; John Yudkin, Pure, White, and Deadly: How Sugar is Killing Us and What We Can Do to Stop It; Nina Teicholz, The Big Fat Surprise: Why Butter, Meat & Cheese Belong in a Healthy Diet; Richard David Feinman, Nutrition in Crisis: Flawed Studies, Misleading Advice, and the Real Science of Human Metabolism. Each of these books is available and all are accessible, with good bibliographies for those like me who go down rabbit holes.
The primary focus here is what can be called the Diet-Heart Hypothesis, which for the past 60+ years has been a (the) ruling framework for understanding diet and health. The history of the Diet-Heart Hypothesis is straightforward, with several landmarks, of which your choices may vary, but the results remain mostly the same:
(1) 1955: President Eisenhower has his first heart attack and widespread attention was focused on heart health. Nevertheless, his “melba toast diet” did not work, except to make him miserable for the next and final 14 years of his life.
(2) 1957: Seven Countries Study led by Ancel Keys of the University of Minnesota
(3) 1961: Ancel Keys is on the cover of Time
(4) 1968: Minnesota Coronary Study
In the Seven Countries Study, Ancel Keys, who was a leading nutritional physiologist of his day (World War II K-rations were said to be named after him) and his coworkers reported results from Italy, Yugoslavia, Greece, Finland, The Netherlands, Japan, and the USA. Their data (minimally) supported the hypothesis that a diet high in fat led to heart disease.
The subsequent history of the Seven Countries Study has been fraught, including criticism of the methods (e.g., Greece was studied during the extended Orthodox Lent when most of the subjects were fasting) and speculation about why these seven countries were included and others, such as France, where a rich diet high in fat did not lead to and increased burden of heart disease, were excluded.
From 1968-1973, the Minnesota Coronary Study compared the typical “American Diet (eggs, bacon, meat, whole milk, butter, cream, one starch-one vegetable)” with a “Cholesterol-lowering Diet.” 9,000 men and women participated in the study, which found no correlation between heart health and diet. Over the course of the study, 269 deaths were recorded in the Experimental Group (cholesterol-lowering) while 206 deaths occurred in the control group on the American diet. The results were not published until 1984. When Ivan Frantz, Jr., the principal investigator for the project, was asked why it took so long to go public, he replied, “We were just disappointed in the way it came out.” An analysis of the recovered data published in 2016 showed:
(1) No mortality benefit for the intervention group
(2) A 22% higher risk of death for each 30 mg/dL decrease in serum cholesterol
(3) No evidence for protection against cardiac atherosclerosis or heart attack
(4) No evidence of benefit on mortality from coronary heart disease
(5) No support for the hypothesis that replacement of saturated fat with linoleic acid translates into a lower risk of death
(6) Incomplete publication “has contributed to overestimation of the benefits of replacing saturated fat with vegetable oils rich in linoleic acid.” Nevertheless, the unquestioned dogma became “eat fat, get fat, have a heart attack.”
In 1993, the Women’s Health Initiative (a study of 49,000 post-menopausal women) spent $725M (approximately $1.3B in current dollars, or enough to support approximately 1000 NIH research grants, 5 years each at $250,000 per year) on the health consequences of a low-fat diet, hormone replacement therapy (HRT), and vitamin D/calcium supplementation.
The results ranged from underwhelming to alarming. Dietary modification did not reduce the risks of coronary heart disease (CHD), stroke, cardiovascular disease (CVD), colorectal cancer, or breast cancer. Vitamin D/Calcium supplements did not reduce the risk of hip or other fractures while showing a small improvement in bone density and may have had a marginal effect on the risk of colorectal cancer. HRT did not reduce the risk of CHD. HRT did increase the risk of breast cancer in some subjects, however. When these results came out, Elizabeth Nabel, then Director of the National Heart, Lung, and Blood Institute (NIH) stated, “The results of this study do not change established recommendations on disease prevention.” (Good Calories, Bad Calories, p. 75). Okay, then. What might, one could ask…
While Ancel Keys was closing the circle on the conclusion that fat is bad and must be replaced, necessarily by carbohydrates, John Yudkin was working independently in the Department of Nutrition of Queen Elizabeth College (Kings College, London) on the largely correct, in my view, Carbohydrate Hypothesis that heart health was harmed by the overconsumption of carbohydrates, particularly refined sugar. For various reasons, Keys was lionized while Yudkin was marginalized. The (High Fat) Diet-Heart Hypothesis won out while the Carbohydrate Hypothesis languished. Alas. The Carbohydrate Hypothesis (short version) can be summarized as follows:
(1) Dietary lipids (including cholesterol, which is not a lipid) are demonized based on little more than “That makes sense: Eat fat, get fat (and die of a heart attack). The public follows the Great American Food System (sic), because it has no real choice, and fat calories in the diet are replaced by refined carbohydrates present in food-like substances marketed by Big Agriculture and Big Food.
(2) Insulin dysregulation ensues in a large subset of otherwise normal, healthy people.
(3) Obesity, Type-2 diabetes, and Metabolic Syndrome are the result, which we can see all around us.
Which brings us to the work of Gerald M. Reaven, who introduced Metabolic Syndrome (Insulin Resistance Syndrome) to the world. In a nutshell, people with metabolic syndrome have 3 of 5 of the following: (1) waist circumference greater than 40 inches in men/35 in women, (3) elevated triglycerides, (3) reduced HDL – “good” cholesterol, (4) elevated blood glucose, and (5) elevated fasting glucose. The pathobiology Metabolic Syndrome can be summarized in this frank but useful oversimplification:
(1) Metabolic Syndrome is caused by dysregulation of the glucose – insulin axis.
(2) Our (recommended, inescapable, default) high carbohydrate diet leads to the chronic elevation of insulin.
(3) Insulin is our major anabolic hormone.
(4) When insulin levels rise our bodies are in the fed state and the storage of energy in the form of fats (fatty acids in triacyl glycerol).
(5) Chronic elevation of insulin eventually leads to insulin resistance, which results in an abundance of the unhealthy diagnostic criteria for Metabolic Syndrome listed above.
Insulin resistance is a hallmark of Type 2 Diabetes, which is responsible for much of the “diabesity” seen where the “Western Diet” is common.
So, which diet is healthier? The balanced diet that includes protein, fat, vegetables, and dairy, which is the healthy diet those of us of a certain age were taught to eat? Or our current diet in which calories from the demon fat have been replaced by carbohydrates?
Another useful oversimplification, but one that is based in biochemistry is this: The 2-cabon fragments obtained from fatty acids are used as acquired, especially in the never resting heart, while the 3-carbon fragments obtained from carbohydrates, when consumed in abundance are stored as fat.
My view is that we have basically been poisoned by Big Ag and Big Food for the past 50+ years. As an example, when I was in elementary school a full serving of Coca-Cola was 6.5 ounces in reusable(!) bottle (about 75 calories). That has increased to 140 calories in a 12-oz (perhaps recycled) can, 280 calories in a 20-oz. single-use(!) plastic bottle, and as much as 400 calories in a Super Big Gulp (styrofoam cup), depending on how much ice you add. The way back to health is to return to that balanced diet, which will also have positive environmental impacts, as soon as we prohibit the industrial production of meat, a coming story for another time. Also on deck is that other demon of our diet, cholesterol, which I have mostly left out of the current discussion.
Finally, there is the question of carbohydrates themselves. Are they toxic? Is there such a thing as “carbotoxicity”? A well-written perspective article, Carbotoxicity – Noxious Effects of Carbohydrates,” appeared in the journal Cellin October 2018 addressing this very question:
Modern nutrition is often characterized by the excessive intake of different types of carbohydrates ranging from digestible polysaccharides to refined sugars that collectively mediate noxious effects on human health, a phenomenon that we refer to as “carbotoxicity.”
Epidemiological and experimental evidence combined with clinical intervention trials underscore the negative impact of excessive carbohydrate uptake, as well as the beneficial effects of reducing carbs in the diet. We discuss the molecular, cellular, and neuroendocrine mechanisms that link exaggerated carbohydrate intake to disease and accelerated aging as we outline dietary and pharmacologic strategies to combat carbotoxicity.
This paper appeared shortly before I began considering the nature and causes of our epidemic of obesity and ill health that is surely connected with our diet and our so-called “food system.”
I was particularly interested in the potential toxicity of fructose. Like glucose, fructose is a 6-carbon sugar molecule. Sucrose – table sugar – is made up of one molecule of glucose connected to one molecule of fructose, making sucrose a disaccharide. The history of sugar as a commodity is a fascinating subject, and it appears that the biochemistry of sugar during metabolism may be just as interesting, but with immediate interest to everyone who consumes sucrose.
This paper introduces fructose as a potentially toxic molecule and covers the subject well. Perhaps by following the lead of these authors, the nature of fructose and high-fructose corn syrup, which was replaced sucrose in many of our processed foods, will be revealed. Fineman in Nutrition in Crisis disregards this idea as “fructophobia,” but I think he is wrong. The fructose found in an apple is not present in the same dose and the fructose in a Super Big Gulp, and “the dose makes the poison.”
“Carbotoxicity” also considers the benefits of the ketogenic diet, which is rich in fat (those 2-carbon units from fatty acids are used to make the ketones during ketogenesis). A consensus has not been reached, and the article has been cited only 41 times in nearly 4 years. A modest response, but the truth sometimes takes a while to come out, especially in the era of Evidence-Based Medicine. As time allows and I read the references in this paper, I am increasingly confident the authors (all European, and that is not a coincidence) are on to something that will make a very big difference.
But this difference will be felt only when medicine is once again taught like a science and not considered an edifice of received wisdom.
 Too harsh. Upon repeated reading they are generally good, but they tend to leave out too much of the foundational detail. The only way around that is for the teachers of medical students to add that back.
 Included as judicious review of both the book and the evidence. We all have our priors. The key is to recognize them. Mine are that the dysregulation of the insulin response is the culprit in obesity, heart disease, and metabolic syndrome. Correlation and causation can be linked by a plausible mechanism, which is the primary take-home lesson of Nutrition in Crisis, Chapter 13.
 Saturated fatty acids have no double bonds in their alkyl side chains, which means they are “saturated” with hydrogen atoms. Linoleic acid is the 18-carbon “polyunsaturated omega-6 fatty acid” with two double bonds. Unsaturated fats are widely believed to be healthier, according to the labels in the nutrition supplement store.
 Which is a hallmark of EBM as practiced then and now.
 Insulin rises immediately after we eat a sugar/glucose/carbohydrate-rich meal, and this causes the glucose to be taken up by the liver and skeletal muscle where it is stored as glycogen (glucose polymer) for later use. Excess glucose is ultimately converted into fatty acids and then transported to fat cells where it is stored.
 Type 1 diabetes mellitus (T1DM, previously caused juvenile diabetes) is the result of insulin insufficiency caused by the autoimmune destruction of the beta cells of the pancreas, where insulin is produced. It commonly presents at age 8-10 but can appear at any age. Type 2 diabetes is caused by insulin insensitivity, in which cells and tissues that are supposed to take up plasma glucose are unable to do so because they do not respond to insulin. T2DM is distinctly an age-onset disease.
 I am loathe to support any kind of argument from authority, but for a variety of reasons,mostly good, Cell, founded in 1974, is considered to be the best and most important journal in cell and molecular biology.