An Interview with Professor Manuel Varela: Statins and an Unsung Hero

Jul 8, 2019 by

Alfred Alberts in his laboratory at the National Institutes of Health in the early 1960s. When he began his research, cardiologists and public health experts had been at a loss to help people with high cholesterol levels.

Michael F. Shaughnessy –

1.     Alfred Alberts is most known for his discovery of a cholesterol lowering drug called lovastatin.   Where was this “unsung hero” educated and where did he initially work?

The “unsung hero” whom you speak of, Alfred William Alberts, noted for having discovered the famous cholesterol-reducing drug called lovastatin, was an American scientist born in Manhattan, New York, on the 16thday of the month of May, in the year 1931. During Alfred’s childhood years the Alberts family moved to Brooklyn, where Alberts later attended a high school called Erasmus Hall. Alberts then enrolled in Brooklyn College, taking his degree in the field of zoology. 

A short while later, in 1953, Alberts married Helene Cuba, nicknamed Sandy, his high school sweetheart, whom Alfred had met a few years earlier on a blind date. Shortly after this, Alberts signed up for the Army, working 2 years in a military laboratory while serving duty. After an honorable military discharge and using the GI bill as a source of funding for his education, Alberts entered graduate school, joining the PhD program at the University of Kansas, in Lawrence, Kansas, focusing his interests in the field of cell biology, a fledging area of the biomedical sciences. 

Before finishing his graduate degree, however, young Mrs. Alberts apparently had a strong dislike of living in isolation at Lawerence as a “laboratory widow,” a seemingly common occurrence amongst spouses of scientific investigators. The young married couple consequently moved to the less isolated University of Maryland, at College Park, MD, where Alberts continued his graduate studies. 

While enrolled in the PhD program at Maryland, Alberts had progressed as far as completing his graduate courses and, importantly, completing his experiments for the dissertation project, which was a also requirement for the doctorate degree. Unfortunately, however, the GI bill funding for graduate school was slated to terminate, and Alberts had yet to write up his dissertation even though his experimental work for the doctorate had been largely finished. 

His status, frequently a common one encountered by students in graduate school, was considered ABD, that is, “all but the dissertation,” a situation characterized by having essentially all necessary data collected but the final write-up coalesced into a dissertation or a thesis not yet completed and approved by a graduate committee. Alberts had yet to finish writing the dissertation. Thus, the doctorate remained elusive.  

At about this time, in 1959, with funding being a critical issue for Alberts, a biochemistry professor by the name of Dr. Earl Stadtman, had casually announced one day in lecture about a job opening at the National Institutes of Health (NIH), a nearby research-intensive institution, in Bethesda, MA, where Dr. Stadtman had been working as a research scientist. Alberts realized this was an excellent opportunity to acquire funding in order to support his growing family. He consequently quit the doctoral program, abandoning his dissertation project without finishing his graduate degree at the University of Maryland in order to work as a laboratory technician at the prestigious NIH. For Alberts, it was a fateful move that would change his life forever. 

The end result was that he never again would have the chance to earn the coveted doctorate. 

At the NIH, Alberts met and eventually began working under the direction of Dr. Pindaros Roy Vagelos, known also as P. Roy Vagelos or simply Roy Vagelos, a physician scientist working initially as a postdoctoral fellow in the NIH laboratory of Dr. Stadtman and later as an independent investigator, still at NIH. Dr. Vagelos taught biochemistry to Alberts, who partook in studies pertaining to the discovery of acyl-carrier protein, known simply as ACP. It is at this point in the career of Alberts in which he made another fateful decision. 

In 1966, Alberts chose to accompany Dr. Vagelos to the Washington University where they had 

a School of Medicine, in St. Louis, Missouri. Dr. Vagelos was appointed chair of their biochemistry department, and Alberts was appointed an instructor of biochemistry. While at Washington University Alberts had been promoted to an assistant professor of biochemistry, and later to associate professor, with tenure.  

In 1975, Alberts made another fateful decision. Leaving a tenured positon as an academic faculty at a prestigious research institution, Alberts followed Dr. Vagelos to Merck Research Laboratories, in Rahway, New Jersey, where Dr. Vagelos later became their CEO, and Alberts later became director of Merck’s department of biochemical regulation. 

The move to Merck by Alberts had been undertaken despite the advice not to do so by Dr. Vagelos, who had encouraged Alberts to stay on at Washington University, where he had an established research program. It is, however, at Merck, later in 1979, where Alberts would make his world-changing discovery, namely, that of mevinolin, a fungal metabolite which later became known as lovastatin. This discovery by Alberts not only changed the course of history for countless millions of patients suffering from coronary artery disease, it was a discovery that Dr. Vagelos attributes solely to Alfred Alberts, who never got a doctorate. 

2.     It seems that like many others- collaboration was a major part of his work. Who did he work with and where, and what were some of their discoveries?

Indeed, one of the first key papers to be published regarding the lovastatin discovery had 20 authors.  Alfred Alberts collaborated with several key individuals, all devoted to the same task, testing the hypothesis that cholesterol had a role in conferring cardiovascular disease. Working towards testing this idea with Alberts was Julie S. Chen. Alberts and Chen set out to find inhibitors of the key enzyme that was committed to the biosynthesis of cholesterol. 

The key enzyme of interest was called HMG-CoA reductase. The acronym HMG-CoA stands for 3-hydroxy-3-methylglutaryl coenzyme A, an important substrate for the metabolic enzyme. 

The letter A of coenzyme A (CoA) stands for “activation of acetate,” a biochemical phenomenon discovered (and name coined by) the great Dr. Fritz Lipmann, in 1946. In any case, the idea considered by Alberts and colleagues was that if indeed cholesterol build-up was associated with (or, indeed, a cause of) cardiovascular disease, then inhibition of cholesterol biosynthesis would then alleviate the detrimental effects of the disease. 

An important task to perform was the screening of microbes, such as in this case the fungus called Aspergillus terreus, as sources for potential inhibitors of the HMG-CoA reductase. The microbial screening process was developed for Chen and Alberts by another Merck colleague, Dr. Art Patchett, who had taken his PhD from Harvard and had just completed a postdoctoral fellowship at NIH before moving to Merck. This fungal screening technique permitted Alberts and Chen to conduct a high throughput experimental method for testing large numbers of samples from the screened fungi for rapid measurement of enzyme inhibition. 

Although the method was capable of analyzing thousands of potential enzyme inhibitors in a short amount of time, the team found a promising candidate after testing fungal compound number 18!  The precise chemical name for this compound was 1,2,6,7,8,8a-hexahydro-β,δ-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthaleneheptanoic acid δ-lactone. The shortened named for this fungal-derived agent was mevinolin, and later the metabolite’s name was changed to lovastatin. 

Interestingly, the lovastatin breakthrough by Alberts and colleagues was not the first of the statins to be discovered. That credit goes to another biomedical investigator by the name of Dr. Akira Endo, who screened over 6,000 distinct fungal samples of Penicillium citrinumin the mid-1970s at Sankyo drug company, searching for the elusive HMG-CoA reductase inhibitor, a compound which he later called compactin, known in 1976 as ML-236B. 

The compactin discovery almost destroyed the progress with lovastatin, not because compactin was first to be discovered, but rather because a rumor had emerged that the compactin caused cancer. It did cause lymphoma in experimental dogs, but only if given at 200 times the proper dosage. It did not cause cancer at regular doses, but the damage had been done—it killed all further progress for compactin development. Furthermore, the rumor almost threw a permanent wrench in the works for lovastatin, except that it was provided to patients only at normal physiological and therapeutic doses, not in the excessive amounts like those given with the compactin fiasco.

3.     Why is the discovery of this “lovastatin” important?  

Lovastatin and other “statins” lower the production of cholesterol, which is widely believed to combine with the so-called fatty acid protein called low-density lipoprotein (LDL).  The buildup of the LDL-cholesterol occurs in the form of plaques that materialize within the interiors of coronary arteries which oxygenate the heart, resulting in the blockage of these arteries. This coronary artery blockage of the oxygen-containing blood supply to the heart is called atherosclerosis. This cholesterol-LDL complex, the so-called “bad cholesterol,” is, thus, associated with the formation of atherosclerotic plaques. 

These arterial plaques contain the LDL-cholesterol complexes plus cellular debris, fibrous-like proteins, and deposits of calcium. Together, these accumulated arterial fatty cholesterol deposits will narrow down the insides of the coronary arteries that provide oxygenated blood to the heart. The occluded coronary arteries are less able to supply the heart with its required oxygen, leading to cardiovascular disease. As with all or most living tissues in mammals, oxygen is necessary for heart muscle to function properly. Without the oxygen, the cardiac muscle will be damaged and die in the process. The risk of stroke and heart attack is enhanced. In developed countries, coronary heart disease is the number one cause of human death. 

The development of lovastatin was a major discovery that for the first time in history permitted the lowering of blood cholesterol on a massive scale. It allowed clinicians to directly confront the detrimental effects of coronary artery disease. Lovastatin was shown in massive clinical studies to lower the incidence numbers of strokes and heart attacks, both of which were hypothesized to be due to high blood levels of the bad cholesterol. Thus, lovastatin changed the course of medical history.

4.     As I understand it, today there are a number of “statin” drugs- that seem to all reduce cholesterol- but how do they really work? What exactly do they do?

In short, the statins function to reduce blood cholesterol by directly binding to the HMG-CoA reductase enzyme, thereby preventing the enzyme from eventually making cholesterol. This enzyme works normally by converting the substrate called β-hydroxy-β-methylglutaryl coenzyme A (HMG-CoA) to the product called mevalonate. The molecular structures of the statin family display a close resemble the structure of the mevalonate. As a result, the statin binds to the HMG-CoA reductase enzyme in such a fashion that it (statin) competes with the HMG-CoA substrate and the mevalonate binding for the active site of the enzyme. 

The active site of an enzyme is the location where the catalytic chemistry takes place, converting the substrate to the product in a biochemical reaction. Interference of an enzyme’s active site by, in this case, competitive inhibition, prevents the enzymatic biochemical activity and thus prevents the catalytic formation of the product. This phenomenon is frequently referred to as competitive inhibition. In our case here, the complex between a given statin (competitive inhibitor) and the enzyme prevents the formation of the mevalonate. This then results in the lowering of the cholesterol levels later on down the biochemical biosynthetic pathway. 

Normally, the biosynthesis of cholesterol starts with a key metabolite called acetyl-CoA, which is then converted to HMG-CoA in multiple biochemical steps. From the mevalonate production, the biosynthesis pathway proceeds through another series of biochemical reactions making intermediate metabolites along the way and eventually producing the cholesterol in the end of the pathway. The statins serve to inhibit this cholesterol-making pathway by inhibiting the key metabolic enzyme, the HMG-CoA reductase. The statin-mediated lowering in the cholesterol manufacture process thus lowers the atherosclerotic plaque production which in turn prevents coronary artery occlusion and, therefore, permits the heart to acquire its needed oxygen. 

While lovastatin is a naturally produced compound, made from a fungus, other members of the statin family are made artificially, such as in the case with atorvastatin (commonly known as Lipitor) or with rosuvastatin (known as Crestor).  

The statins play important functions in improving the flow of blood through an individual’s arteries. These statin molecules also help to stabilize the plaques that may already be in the patient’s coronary arteries, preventing them from becoming larger or from breaking off into pieces which might cause a stroke otherwise. Lastly, the statins are known to reduce vascular inflammation, another morbid process that can be associated with heart disease. 

The statins, however, may not be perfect. In patients, the statins have been documented to cause a rather lengthy list of albeit rare but negative side effects. 

Some of these otherwise rare side effects can be serious, such as in the case where patients may suffer from debilitating muscle weakness and pain, as a result of taking statins.  

5.     Some individuals do not seem to respond to statin drugs (or maybe they are eating all the wrong stuff on the sly) but is there a genetic component to cholesterol?  Are there some individuals who seem to be genetically predisposed to cholesterol- and in your mind- why is cholesterol important? Other than it seems to block arteries, veins, capillaries etc.

While a diet that is low in saturated fats and cholesterol can certainly play a prominent role in reducing blood levels of the so-called bad cholesterol, the LDL-cholesterol, there are certain individuals who are nonetheless genetically pre-disposed to very high cholesterol concentrations. In rare cases, dieting may not always help such patients. Such individuals may have, for instance, a genetic-based disease, such as the one called familial hypercholesterolemia. These individuals exhibit quite elevated levels of blood cholesterol. It is these very types of patients for which the statins play an important role in alleviating such cholesterol levels in their blood sera. The statins have been shown in clinical studies to significantly reduce blood serum levels in familial hypercholesterolemia patients. 

Regarding your question about the importance of cholesterol, it is perhaps not so well known that there are various good aspects to this seemingly pathological molecule. For example, cholesterol is the starting point for the biosynthesis of steroid hormones, such as the glucocorticoid called cortisol, which functions in regulating metabolism and the immune response.  

Cholesterol is also a metabolic starting point for the mineralcorticoids called corticosteroine and aldosterone, which function in kidney absorption of key electrolytes, like sodium, chloride or bicarbonate. Cholesterol is also a precursor for the production of the sex hormones testosterone and estradiol.  

Cholesterol resides in the membranes of our cells. In the plasma membrane, cholesterol controls the fluid nature of such membranes. In this sense, cholesterol is having a positive biological effect. Often dietary cholesterol will go the membranes of our cells, and when these cellular membranes become saturated from consuming an overabundance of fats and cholesterol, the cholesterol will be shunted to the LDL-cholesterol pathway and form the basis of the patient’s atherosclerosis.  

There is, for instance, the so-called “good cholesterol,” which is in the form of a complex with high-density lipoprotein (HDL). The HDL-cholesterol is readily transported to the liver where it is degraded into another form like bile salts which are then stored in the gall bladder. Ultimately these bile salt end products are excreted into the gastrointestinal tract when an individual consumes a meal. The bile salts may be taken back to the liver and cycle back to the gall bladder. 

Another positive aspect of cholesterol is that a variant of it can be converted to the necessary vitamin D with the help of sunlight. Suitable exposure of the skin to sunlight will facilitate the conversion. The vitamin D in turn then plays a role in regulating phosphorous and calcium metabolism. 

6.     I understand he recently died- did he ever receive the acknowledgement that he so truly deserves?

It is estimated that over a dozen Nobel prizes have been awarded for studies pertaining to cholesterol, a molecule that two of these Laureates, Joseph Goldstein and Michael Brown, have described as the “most celebrated molecule” ever.  It seems rather odd, therefore, that the Nobel did not ever go to Alberts for his contribution to the statin discovery and the lowering of blood cholesterol for countless millions of suffering patients. As your chapter title aptly states, this may be a primary reason why Alberts was referred to as an “unsung hero” of cholesterol reduction efforts. 

Despite the inability of Alberts to obtain his sought-after PhD, the University of Maryland nevertheless bestowed an honorary doctorate upon him in later years, in 1994. Back in 1959, however, Alberts had had to abandon his PhD dissertation research at this same institution in order to acquire a paying position (at NIH) to support his family. He was never able to go back to his doctorate project to finish it. 

Interestingly, the so-called Alfred Alberts Biochemistry award was established and given to outstanding biochemistry, biology, or chemistry students at the City University of New York (CUNY) in Brooklyn.  

7.     What have I neglected to ask about Alfred Alberts? 

The statin story actually starts first with Dr. Nikolay Nikolaevich Anichkov, an experimental pathologist who was housed in St. Petersburg, Russia, in 1913. Dr. Anichkov treated laboratory animals, namely rabbits, with high dietary cholesterol and observed the atherosclerosis pathology in the experimental animals. The findings later became known as the lipid hypothesis, characterized as an association between blood serum levels of cholesterol and the production of the atherosclerotic plaques. While the work took a fair amount of time for widespread acceptance, verging on decades, Dr. Anichkov’s work nonetheless turned out to be backed up by many reports of supporting experimental evidence. 

For a number of decades, a controversy had been in the works with the cholesterol connection to cardiovascular disease. The main sticking point was the putative neglect for other associated risk factors such as diet, smoking, exercise, genetics, etc., all factors of which are also known to be important in the development of cardiovascular disease. 

Sadly, Alfred Alberts died of coronary artery disease. Though he had been living in New Jersey, he became ill while visiting his son Eli in Colorado. While still in CO, Alberts had suffered a heart attack, and he underwent an emergency coronary artery bypass surgery. Unfortunately, neither the surgical nor the statin treatments were to be useful for Alberts. 

He passed away in Fort Collins, Colorado, at the age of 87 years on the 16thday of June, in the year 2018. Alberts left behind his adoring wife, Sandy, their three children, Heather, Mitchell, and Eli, plus two grandchildren, Jacob and Nellie.

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