An Interview with Professor Manuel Varela: Cholesterol and its Antecedents- and who was Joseph Goldstein?

Sep 24, 2019 by

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Joseph L. Goldstein

Michael F. Shaughnessy –

1) We have all heard that nasty word—cholesterol, and it sends shivers and shakes into our minds and spines. However, what exactly IS cholesterol, where does it come from, what does it do? Moreover, what can we do about it?

Indeed, the term cholesterol evokes a sense of fear amongst the masses of people, especially those who are concerned about their heart health. Cholesterol is widely known to be involved in coronary artery disease, such as atherosclerosis. This type of heart disease involves the arteries that supply oxygen-laden blood to the heart. These coronary arteries are blocked to varying degrees by atherosclerotic deposits containing cholesterol and fats. The numbers of human deaths every year is staggering, both at the national level, in the U.S., where it is the number one cause of mortality, and on a worldwide scale.

Cholesterol, an organic molecule, is a biochemical steroid in its nature. In humans, cholesterol is obtained as part of the regular diet, but it is also made in the liver.

In the liver, the starting molecule for the biosynthesis of cholesterol is called acetyl-coenzyme A (i.e., acetyl CoA), which will have been made from our dietary intake of sugars, protein, and fats, during metabolic catabolism. During the cholesterol synthesis, several molecules of acetyl CoA are condensed with each other to make a vital precursor called 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). Then, the HMG-CoA is converted into another metabolite called mevalonate. From mevalonate, the cholesterol molecule will be biosynthesized in a pathway that requires over two dozen additional biochemical reactions.

The enzyme that catalyzes the biochemical conversion to mevalonate is called HMG-CoA reductase. This enzymatic step is a crucial committed stage, and it is regulated naturally in the body.  The enzyme, however, is also a good target for regulation by pharmaceutical drugs, the statins being an example that comes to mind. The statin drugs will target the HMG-CoA reductase enzyme to prevent the overproduction of the cholesterol.

Combined with diet and exercise, the levels of blood cholesterol can usually be kept in check. In the case where a patient is suffering from hypercholesterolemia, a conditional where the blood cholesterol levels are abnormally elevated, the statins and other cholesterol-reducing medicines may be utilized.

Incidentally, it may interest our readers to know that while cholesterol certainly has its pathological circumstances, there are also positive aspects to this famous molecule. While cholesterol is generally found within the cell membranes of individuals, it serves a regular physiological role in regulating the fluidity (i.e., flexibility versus rigidity) of these membranes at the molecular level. It is also a metabolic precursor to the biosynthesis of certain steroid hormones, such as cortisol, estrogen, and testosterone. Another interesting fact is that cholesterol can be converted to vitamin D by the action of ultra-violet light in the skin of humans.

2) Now, LDL and HDL—I look at my blood work, and I use the memory device—LOUSY DL and Healthy DL—-but what is DL? So what do these terms mean?

The LDL and HDL acronyms refer to high-density lipoprotein and low-density lipoprotein, respectively. Both of these biomolecules are found in the body, and they serve to carry cholesterol throughout the various regions of the body. Using your amusing vernacular, lousy, the LDL is indeed lousy because LDL transports cholesterol from the liver to the tissues like the heart, where cholesterol, together with fats, can build up in the coronary arteries to occlude them, increasing the risk of heart attacks. The occluded or blocked coronary arteries are prevented from providing needed oxygen to the heart, causing an increased risk of heart disease. A heart that is deprived of its oxygen may create a situation where the cardiac muscle is damaged or where heart muscle cells may even die.

On the other hand, the HDL, the “healthy DL” as you so aptly put it, serves to carry the cholesterol to the liver.  This cholesterol transport to the liver is a necessary, healthy process.  Excess cholesterol that’s brought to the liver by the HDL can, in turn, be degraded. For example, cholesterol in the liver can be converted to bile acids or a compound called coprostanol, which can then be excreted from the individual. Alternatively, as I mentioned above, cholesterol can be converted into any of a variety of useful hormones, or to vitamin D, or sent to the cell membrane.

Obviously, then, one would (or should) like to optimally have their lousy DLs as low as possible and their healthy DLs correspondingly as high as possible.

3) How does one go about balancing the healthy and unhealthy? And is the American diet utterly CRUMMY?

If one wishes to harbor healthy levels of cholesterol, then proper diet is indicated. Such a diet is low in both cholesterol and certain fats. Fats, especially those that are saturated, serve to maintain potentially unhealthy blood cholesterol levels. Thus, a low saturated-fats diet is essential. Second, exercise helps to get the blood circulation going to healthy levels. The practice helps better to supply oxygen to the tissues to keep them healthy. If diet and exercise do not keep the cholesterol and saturated fat levels down, then chemotherapy may be indicated. This is where cholesterol-reducing drugs can come into play.

The short answer to your question about the poor quality of the American diet is: yes. While one’s version of a healthy diet may vary in detail from individual to individual, a consensus amongst clinicians seems to be that a healthy diet is rich in fruits, vegetables, nuts, legumes, fish, polyunsaturated fatty acids, and low in carbohydrates, saturated fats, and processed foods. The American diet is crummy because of overeating during meals, excessive snacking between meals, and consumption of so-called fast-foods, much of which are rich in unhealthy saturated fats and cholesterol.

4) Now, who was Joseph Goldstein, and where was he born? (I understand he is still alive).

Dr. Joseph Leonard Goldstein has been a world-class medical geneticist, biochemist, and 1985 Nobel laureate, sharing the honor with Dr. Michael Stuart Brown, for their discovery that cellular receptors for LDL serve to reduce the levels of blood-laden cholesterol. Goldstein was born in Sumter, South Carolina, in the U.S., on the 18th day in the month of April, during the year 1940. His parents were Isadore and Fannie Alpert Goldstein. His parents were owners of a clothing store. He was raised as a child in Kingstree, S.C., in the U.S. As of this writing he is presently 79 years of age.

5) His early years and medical training- where did he receive his education and under who- and what got him studying cholesterol?

Goldstein attended elementary school and a small high school (about 60 enrolled students) in Kingstree, S.C., the latter of which was known to be an all-white school that was steeped in segregation. A central topic of interest for Goldstein included chemistry, and he attributed this scientific interest to his high school science teacher.

After high school graduation, Goldstein went to a private, liberal arts institution called Washington and Lee University, which was located in Lexington, Virginia, in the U.S. Majoring in the discipline of Chemistry, Goldstein took his undergraduate degree, with highest honors, summa cum laude, in 1962.

After graduating from university, Goldstein enrolled in medical school at the Southwestern Medical School Health Sciences Center, which was part of the University of Texas, in Dallas, TX, in the U.S. While in medical school, Goldstein became interested in the area of academic medicine. He has attributed this new interest to medical school teacher and mentor Dr. Donald W. Seldin, who at the time was the departmental chair of Internal Medicine. Dr. Joseph L. Goldstein took his M.D. degree in 1966.

The newly minted Dr. Goldstein then moved from Dallas, TX, to Boston, Massachusetts, in order to take up a new post as an intern and later a medical resident at the prestigious Massachusetts General Hospital, where he stayed until 1968.  It is at Mass General where Dr. Goldstein first met Dr. Michael Brown, both of whom became friends and scientific collaborators.

After the conclusion of his residency training at Mass General, in 1968, Dr. Goldstein moved to Bethesda, Maryland, in the U.S., where the National Institutes of Health (NIH) had been housed. Dr. Goldstein became a clinical associate studying molecular genetics at the National Heart Institute in the NIH research laboratory of the famous Prof. Marshall W. Nirenberg, who in 1968 became a Nobel Laureate with Dr. Har Gobind Khorana and Robert W. Holley, for their solving of the genetic code.

At the NIH Dr. Goldstein participated in the clinics, where he and Dr. Brown had first encountered patients with presented with the genetic disease called familial hypercholesterolemia (FH). The severe medical condition much interested Dr. Goldstein and his good friend and collaborator, Dr. Brown, who had also moved to the NIH, working in the laboratory of Prof. Earl Stadtman, studying the chemistry of enzymes. Encountering these FH patients was the prime spark the started their Nobel Prize-winning cholesterol work.

6) I understand he worked with a Michael S. Brown- what do we know about this chap?

Biomedical scientists Brown and Goldstein shared the Nobel Prize in physiology or medicine in 1985 for their collaborative work on cholesterol biochemistry. The scientific duo had first met while they had been young medical interns at Mass General, in Boston, MA. Thanks to their pioneering studies, countless millions of lives have been saved from the ravages of coronary artery disease.

Michael Stuart Brown was born in Brooklyn, New York, in the U.S., on the 3rd day of April, in 1941. His parents were Harvey and Evelyn Brown. Having been raised in Wyncote Pennsylvania, Brown went to Cheltenham High School and attended the University of Pennsylvania, where he took his undergraduate degree in Chemistry, in 1962. He then attended the School of Medicine at the University of Pennsylvania, and he received his M.D. degree in 1966.

After interning at Mass General, Boston, MA, where he met Dr. Goldstein, Dr. Brown moved to the NIH in 1968. Dr. Brown worked in the laboratory of Dr. Earl R. Stadtman, focusing on the biochemistry of enzymes. Next, Dr. Brown moved to Dallas, Texas, where he studied the HMG-CoA reductase enzyme at the University of Texas Southwestern Medical School.

In 1974, Drs. Goldstein and Brown shared a research laboratory, choosing to combine their previously independent laboratories into one collaborative lab. The move was to result in astonishing research successes. Together, the research teams wanted to focus on FH disease in order to solve the problem of high blood cholesterol.

The Goldstein-Brown researchers found out that cells from humans have in their membranes the LDL receptors, which function to lower the cholesterol levels from the blood and that in the FH patients these LDL receptors were lower than usual. Thus, the cholesterol concentrations in the blood of the FH patients were abnormally high, leading to the severe condition of hypercholesterolemia. 

7) On some T.V. commercials, I hear them talking about “genetics” and blaming genetics on high LDL. Is there any truth to this?

Indeed, it is true. The Goldstein and Brown research laboratory discovered the LDL receptor in the membranes of cells from FH patients with hypercholesterolemia. They found that the gene which encodes the LDL receptor in humans with the FH condition was defective, leading to lower than normal levels of this receptor. In examining more closely the nature of the defect, they discovered the mechanism of the LDL receptor’s disappearance from the cellular membranes. This mechanism is referred to in the textbooks as receptor-mediated endocytosis. As the LDL ligand binds the receptor on the membrane, the membrane invaginates and pinches off to form an intracellular vesicle enclosing the LDL receptor within the internalized endosome. With the LDL receptor missing from the plasma membranes of cells, the LDL-cholesterol builds up and collects in the blood and its vessels. This is especially troublesome in the arteries that feed blood to the heart, the so-called coronary arteries. The LDL-cholesterol build-up in the blood may result in the formation of atherosclerotic plaques in the vessels, which block the flow of oxygenated blood to the heart, increasing the risk of heart attacks.

8) Apparently, they have won a number of prizes for their work- can you name a few?

Drs. Goldstein and Brown made their Nobel Prize-worthy discoveries relatively early on in their careers, and they consequently garnered a significant number of other accolades. Each of these awards is bestowed to investigators for making substantial scientific contributions to the biomedical sciences.

One, in particular, is the Albert Lasker Award, 1985, for basic medical research, which is considered by many to be a preamble to the Nobel Prize. The Lasker prize was established in the mid-1940s by Albert D. Lasker, who was a prominent advertising magnate and dedicated philanthropist. Another leading accolade is the Warren Alpert Prize, 1999, which is awarded by its associated Foundation and is run by a committee composed of biomedical scientists at Harvard Medical School. Another distinguished honor is their inclusion as Fellows, in 1991, into the prestigious Royal Society. This Royal Society Fellows list, established in 1663, has a large number of world-renowned scientists, such as Isaac Newton, himself, plus Albert Einstein, Francis Crick, Dorothy Hodgkin, and Tim Hunt, to name only a few. One of my favorites is the Herbert Taylor Research Award, in 2005, established in 2004 by the American Society for Biochemistry and Molecular Biology (ASBMB). The ASBMB-based award was given to both scientists for their excellent contributions in the areas of biochemistry and molecular biology. One last tribute is the National Medal of Science, which is bestowed by the president of the U.S. and was given to Drs. Goldstein and Brown in 1988.

9) Goldstein and Brown did work on the SREBP family of “membrane-bound transcription factors.” What does SREBP stand for, and why is it important?

The acronym SREBP stands for sterol regulatory-element binding protein, and Drs. Goldstein and Brown discovered it in the early 1990s. The pathway to its discovery began in 1933, when a biomedical scientist by the name of Dr. Rudolph Schoenheimer, sealed laboratory mice in bottles with plenty of air and fed the mice a diet that completely lacked cholesterol. The jars then exhibited a higher cholesterol content.

But when Dr. Schoenheimer sealed his lab mice in the jars and gave them food with plenty of cholesterol in it, he found that the mice inside the jars did not produce any additional cholesterol. These findings suggested (1) that mice, and by extension other animals like humans, can make cholesterol on their own and (2) that when cholesterol is already present in sufficient amounts, it prevents the further biosynthesis additional cholesterol, i.e., that cholesterol production was regulated by cholesterol. Such a regulatory mechanism is known as feedback inhibition by the product that’s made at the end of the pathway.

This is where the SREBP mechanism discovered by Drs. Brown and Goldstein comes into play. This SREBP discovery of theirs was performed in the early 1990s, after they had received the Nobel, in 1985. First, they had purified the SREBP family of proteins. The SREBPs are DNA-binding factors that turn on the gene expression programs for a variety of new genes, making a set of proteins that function in making cholesterol and fatty acids. Since the activation of gene expression by the SREBPs are at the level of transcription, i.e., RNA synthesis is turned on for a variety of genes, the SREBPs are also referred to as transcription factors.  In general transcription factors bind to promoter elements on DNA and turn on the transcription of specific genes.

Drs. Brown and Goldstein found that members of the SREBP family are bound to the membrane of the intracellularly located endoplasmic reticulum (ER) but in an inactive form. When cholesterol levels are low, however, the SREBP comes out of the membrane. The newly loosened SREBP molecule moves to the Golgi complex, where it is cut into two fragments and becomes active as a putative transcriptional activator. Next, the freshly activated SREBP moves to the nucleus of the cell where it binds to its DNA and stimulates the gene expression of elements that encode enzymes for cholesterol biosynthesis. One essential protein is the HMG-CoA reductase, which then proceeds to make the needed cholesterol in the ER. 

When cholesterol levels are too high in the blood, the SREBP is kept in an un-fragmented state, thus maintaining itself in an inactive form. The genes that encode cholesterol and fatty acid biosynthesis consequently are not expressed. 

10) Apparently, Goldstein has been involved with the Salk Institute and the Rockefeller University in New York City. What kind of work did he do at these excellent places?

In 1983, Dr. Goldstein was elected as a so-called non-resident fellow for biological sciences at the Salk Institute, which is located in La Jolla, California, in the U.S. One activity that Dr. Goldstein partook in at the Salk Institute was that of a symposium presenter at the 40th anniversary of the founding of the famous institution.

In 2015, Dr. Goldstein became a life-long member of the board of trustees at the Rockefeller University. The institution was established in 1901 by the oil magnate and philanthropist John Davison Rockefeller.

Along these lines, Dr. Goldstein also became a member of the board of trustees for the Howard Hughes Medical Institute, established by another wealthy entrepreneur Howard Hughes, in 1953. Each of these institutions is laden with many prominent biomedical scientists. A great deal of biomedical research is conducted at these institutes.

11) Goldstein seems to be a model of someone who has done a great deal of clinical research and investigation. What would you say are his most significant accomplishments? And how does he seem to be able to discern such important factors and variables and discoveries?

The discovery of the LDL receptor was a tremendously important finding. His involvement in the scientific breakthrough of its regulation, its feedback mechanism for controlling cholesterol biosynthesis via the SREBPs, constitutes another hugely significant mark on the biomedical science field. This more recent discovery has led directly to the saving of countless millions of lives from the detrimental effects of heart attacks.

Another significant discovery by Dr. Goldstein that I have not yet mentioned is that of Scap.

Scap stands for SREBP cleavage-activating protein. Like the SREBP, the Scap molecule is also an ER-associated protein. But the Scap is also associated with the SREBP, as well. Together, they form a complex called SREBP-Scap. The membrane-bound SREBP-Scap complex in the ER functions as a sensor of cholesterol levels. The Scap molecule aids in the feedback regulation of the cholesterol biosynthesis.

It is my contention that Dr. Goldstein’s medical training in the clinical field is the prime factor in his discernment regarding what is essential from a biomedical standpoint. Obviously, studying medical diseases is vital for discoveries of underlying cellular and molecular mechanisms. Knowledge of such fundamental life-associated machinery is then critical for its manipulation in order to realize effective treatments. With heart attacks still being close to being number one as a leading cause of morbidity and mortality, if not number one itself, the work of Dr. Goldstein and others in this area of biomedical science will continue to be of great importance, possibly for generations to come.

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