The Cholesterol Odyssey with Arnold Meshkov, MD

Arnold Meshkov, MD

He was the greatest medical scientist of his time. But Rudolph Virchow, a German pathologist of the 19th century, was very perplexed. He saw more people who had died from some type of yellow “gruel” inside of the arteries of the heart, the aorta, and the legs. Virchow called this mysterious process “arteriosclerosis,” and he ruminated that the yellow material came from the human diet.

The smoldering suspicion that the material clogging arteries was from the diet remained for another 50 years, as the chemists dissected the molecular structure of the gruel, first called cholesterin and then cholesterol. The conundrum became more perplexing; cholesterol was already known to be a crucial “backbone” molecule of the membranes of every cell in the human body, especially for the nerves. Why was this essential component of life causing such catastrophic disease?

The answer would need to wait more decades. The bedrock belief that the diet was the cause came in the early 20th century; the impact of genetics ever later. The work of the scientist who confirmed the “diet hypothesis” remained hidden to Western medicine until the mid-20th century. In 1912, a young researcher named Nikolai Anichkov in St. Petersburg fed Russian rabbits various types of food—protein, fat, pure cholesterol, and carbohydrates. With meticulous science he proved that diet caused the process that was by then called “atherosclerosis.”

The main culprit was not fat in general; the cause was the cholesterol. Although cholesterol was vital to manufacturing cells, somehow the cholesterol that wasn’t needed was ending up inside of arteries. To this day, most doctors and scientists still don’t know Anichkov’s name.

The events of the last century, two disastrous conflicts, economic depression, and then a “cold war” between Soviet Russia and the West, shut down much of the scientific interchange of many nations. A nuclear physicist, inspired by the death of his father from a heart attack, resurrected Anichkov’s work in the late 1940’s, and took the old findings much further. John Gofman, MD, PhD, a man who had worked on the Manhattan Project to develop the nuclear bomb, knew how to use a unique machine at the time: a high-speed centrifuge.

Gofman knew much more about cholesterol by then. Its particular scaffolding of molecules made it challenging for the body to absorb. It didn’t mix with water, and it’s H20 that lords over all of the molecular traffic of the human body. Evolution needed to be clever. Once cholesterol entered the intestine, it was met with by a welcoming crew of protein molecules, ready to latch on to the cholesterol molecules and wrap them up into packages of several different types. Since cholesterol is a form of fat or lipid, it was logical to call these combination particles “lipoproteins.”

The lipoproteins came in different sizes, and Gofman knew that they had a variety of weights of their molecules. He had great success using his centrifuge to spin at high-speed raw uranium to separate out the tiny amounts of the radioactive atoms. Why couldn’t his machine do the same thing to the lipoproteins in the blood of humans?

Within a few years, Gofman separated the various types of lipoproteins by how they layered out in a tube after centrifugation. Of these specific lipoproteins, now four types named based on their “density,” might one be the specific cause of atherosclerosis? Through scrupulous work, both in the laboratory and using the blood of people with coronary artery disease, Gofman was convinced that it was just one of the lipoproteins that was the culprit agent of atherosclerosis. It was the low-density lipoprotein, the “LDL” molecule.

As groundbreaking as Gofman’s work was, how LDL got into the body, and then into the liver, the body’s manufacturing plant of molecules, was still shrouded. Gofman suspected that diet was a main driver of the body’s inability to deal with too much cholesterol intake. He was one of the first physicians to point the finger at the Western diet of too much animal fat and carbohydrates as a major cause of the “heart attack epidemic” of the mid-20th century.

Gofman was not alone in studying cholesterol and atherosclerosis by the 1950’s. The intricate metabolism of cholesterol was being elucidated, discovering that it was one particle liver enzyme that was “rate-limiting,” and ultimately determined that organ’s production of cholesterol.It had the tongue-twisting name of hydroxymethylglutaryl-coenzyme reductase; for “short” -HMG coenzyme reductase.

Still, the secrecy of how cholesterol was trafficked remained. The liver can make its own cholesterol but how does it deal with the diet’s contribution? It was two very sick children seeking help at the National Institute of Health in the late 1960’s that inspired two nascent researchers to crack the “cholesterol code.” These unfortunates had already suffered heart attacks and were not even ten years old.

Michael Brown and Joseph Goldstein were training to become metabolism scientists at the NIH, and were also spending a few hours a week seeing patients in a clinic. Goldstein was assigned the care of these two youngsters, discovering that their blood had hideously high levels of LDL cholesterol, undoubtedly the cause of their premature coronary artery atherosclerosis. He also knew that for his patients, eating too much cholesterol was not the cause of their malady. This disease was a genetic one, a fate determined by the DNA of their birth.

Goldstein knew that he had no therapy to offer the children, and shared his frustration with his close friend Brown. They set their skills to work to figure out the inherited metabolic disorder in these people in their laboratory. Within only a few years, the two had identified a particular molecule on the outer surface of cells that shepherd the LDL particle into the cell, and that in their two young patients, like the rare others with this genetic disease, had “LDL receptors” that were much fewer in number, or not present at all, unlike normal people. The cholesterol-laden LDL particles entering their body had no place to land, other than the wall of arteries resulting in atherosclerosis and heart attacks.

Brown and Goldstein were awarded the Nobel Prize in Medicine in 1985 for their discoveries, and combined with the understanding of the entire metabolism of cholesterol and LDL, led to the miraculous medications that are now used to prevent atherosclerosis and save lives, in people who have already suffered a myocardial infarction, and millions of others who are at risk of this often devastating disease. The foundation of basic science has led to the translation of difficult and intellectually trying work to rescuing so many from the heart attack epidemic.

The future is bright for more understanding and treatment options to blunt, and perhaps eradicate, the scourge of atherosclerosis. It is vital that the doctors and researchers of the present and the future understand the scientific underpinnings of how they treat patients every day.

------------------

Arnold Meshkov, MD, is a cardiologist based in the Greater Philadelphia area focused in adult congenital heart disease, interventional cardiology, and preventive medicine. Meshkov is also the author of the forthcoming book Chasing the Widowmaker: The Story Behind the Century-Long Battle to Vanquish the Heart Attack Pandemic.