Newsletter #5 - Henry Buchwald, Cholesterol Absorption, Is the Covid-19 mRNA Vaccine new tech?

Topics

1. One Surgeon’s Principles by Henry Buchwald, MD, PhD
2. Cholesterol Absorption Un-Simplified
3. Covid-19 Vaccine Update
4. My Vaccination
5. NYT Article
6. Is it New Technology?  

One Surgeon’s Principles by Henry Buchwald, MD, PhD

Two weeks ago when I began to prepare for this issue of the newsletter, I decided that I would write about cholesterol absorption. I went back to my files on this topic and began to read. Reading the medical literature sounds like a boring task, but with tools like Google Scholar and Pubmed, you can quickly follow one article to another via citations, and discover a treasure trove of research going back for more than a century. Within about twenty minutes, I found myself reading an article from the 1960s written by Dr. Henry Buchwald about partial ileal bypass. By that time, scientists and doctors had learned that cholesterol and fat are absorbed by a part of the small intestine called the ileum. The ileum is the distal most part of the small intestine before the small intestine becomes the large intestine (colon).

Buchwald, and other surgeons of his time, realized that if you bypassed part of the ileum, you might be able to decrease fat and cholesterol absorption. So, this is exactly what he did. In the 1960s, Buchwald began to treat patients with obesity, hyperlipidemia, and hypercholesterolemia with a surgical procedure called a partial ileal bypass. He would cut the intestine and sew the proximal opening to a new opening further down the line, effectively bypassing much of the part of the intestine that’s responsible for fat and cholesterol absorption.

As I read one article after another, it became obvious to me that this surgeon, Dr. Buchwald, was a pioneer in this field. I started to imagine being the first, or one of the first people to develop a new surgical technique, and then to have the confidence in my mind and my abilities to put reasonably healthy patients through the procedure. Whenever I think about “the first person” to do something this bold, I often wonder what these people were like. They’ve either got to be completely unhinged, or supremely principled geniuses. I wanted to know which one of these described Henry Buchwald.

Well, I found an article based on a speech that Buchwald delivered in 2015 at the age of eighty; it’s entitled “One Surgeon’s Principles.” In his speech, Buchwald said:

“I am in my 80s, and I know myself most fortunate to be able to make that statement. I have been a surgeon for nearly 50 years. I am grateful for those years of doing what I believe I was meant to do while enjoying almost every moment of that time. I am an academic who holds a dual appointment in surgery and biomedical engineering. In that role, I have attempted to be a mentor to residents in terms of surgical care, technique, and the attributes of practice that govern our discipline.”

“Over the years, based on my experience, I have formulated certain principles regarding the provision of care that have guided my career. I offer these 10 principles in the hope that they may be of interest to others.”

Buchwald’s Principles are As Follows: - It’s always your fault - Postoperative complications can be solved intraoperatively - Gentleness, not speed, is the cardinal surgical virtue - A learning curve can take time, but should not take lives - Venerate life - Be proud of your craft - Think creatively - Be of service to the community - Know where we are in our professional time continuum - Joy is in the process

I’ll give you two excerpts from his speech:

It’s always your fault

“Except for liability litigation, this precept is a good way to approach the acceptance of responsibility for the well-being and the life that a patient entrusts to you. Anticipate exigencies and attempt to prevent untoward events. Acknowledge bad decisions, even if they appeared to be the most rational choices when they were made. When assessing a bad outcome, recognize that there are no acts of God. I tell residents that if a patient falls out of bed, it’s their fault.”

Joy is in the process

“Successful outcomes are satisfying and awards are gratifying, but the joy of surgery is in the process—the daily events of caring for patients, thinking about a new problem and thinking anew about an old one, the unpredictability and ever-changing novelty of events, and the physical pleasure of working with your hands.”

“The word “surgery” is derived from the Greek words “cheiros,” a hand, and “ergon,” work. In essence, we are defined as hand laborers. Thus, as surgeons we live a continuous adventure, are physically active, and literally able to shape events not only with our minds, but with our hands. It is only fitting that my 10 principles conclude with the fact that a surgeon will spend the majority of his or her life in the practice of this chosen vocation. Therefore, take joy in the process.”

I think it’s obvious that Buchwald is the second type of person that I described above - a supremely principled genius. His principles are applicable to nearly all endeavors. I highly recommend reading this brief article in its entirety, both for those who are in medicine and those who are not. On top of his sage advice, for those who are in medicine, you’ll recognize much of what Buchwald says. For those who are not, you’ll get a little bit of an insider picture into the medical world - both the good and the bad.

Cholesterol Absorption

After I finished reading about Buchwald, I went back to the literature and read more about partial ileal bypass. The procedure was successful at reducing serum cholesterol and cardiovascular morbidity and mortality on the average, but I found one article in which Buchwald actually published data on individual subjects. This is relatively rare to find in modern medical literature, but was much more common decades ago when this article was written. Most modern studies only publish group statistics. What I noticed in reviewing the individual data is that, despite an average decrease of post-operative serum cholesterol levels, some individuals had almost no decrease in serum cholesterol after partial ileal bypass, while others had marked decreases.

In other words, sterol absorption at the ileum is not the only factor that determines serum cholesterol levels. In fact, despite the elimination of a large portion of an individual’s ability to absorb dietary cholesterol, they can still maintain a high level of serum cholesterol. There must be other factors.

I continued on to read articles from every decade between 1913 and today on cholesterol absorption. I’m hardly done with my research, but I’ve confirmed what I already suspected from earlier reading on the topic – cholesterol absorption is not simple and unifactorial, it is complex and multifactorial. It varies from individual to individual, across time (even within a day), and in response to different dietary modifications to varying degrees by individual, it is saturable, and even in the absence of dietary cholesterol, endogenous cholesterol can be reabsorbed. Here is an excerpt from an article written in 1987 by McNamara et al.

The preceding passage nicely sums up the complexities of cholesterol absorption on an individual level. So, when you read a headline that dietary cholesterol is either good, or bad, consider that it may be good for some individuals, bad for others, and neutral for the rest. Also consider that the dose makes the poison - some people may be able to down-regulate cholesterol synthesis and/or absorption in response to increases in dietary intake, but only to a point.

It turns out that the regulation of cholesterol absorption and synthesis is a very complex system involving enzymes, receptors, and pumps in the cells of the intestine (e.g. lipases, esterases, NPC1L1, ABCG5 and G8, ACAT, and others), in the liver, and on nearly every cell in your body.

Once cholesterol is inside the cells of the intestine, most molecules of cholesterol must undergo another reaction called esterification before being packed into blobs of fat called chylomicrons. These blobs are then released into lacteals, which are tiny ducts that eventually converge to form a lymphatic vessel, which leads to the thoracic duct, then into the superior vena cava, to the heart, to the blood vessels of the lungs, and then to the systemic circulation.

This process involves several other proteins, fats, and enzymes. Once in the systemic circulation, the fate of the cholesterol molecules depends on yet other blobs of fat (lipoproteins) and their constituent apolipoproteins. In addition, enzymes in the blood, and enzymes and receptors on cell membranes of every organ are responsible for uptake of cholesterol and secretion of excess cholesterol. Eventually, excess cholesterol is brought back to the liver for processing into neutral sterols and bile acids for excretion into the bowel. This excretion is the only way for your body to eliminate excess cholesterol. However, once cholesterol is excreted into the bowel in various forms, the small bowel can reabsorb much of this cholesterol once again.

Most individuals are able to up-regulate and down-regulate both cholesterol absorption and cellular cholesterol synthesis so that this entire system remains in equilibrium. However, an individual can have a dysfunction within any aspect of the system, which can result in the accumulation of cholesterol in places where it doesn’t belong - namely, the wall of an artery.

The complexity of the system is both good and bad news. The good news is that the system has multiple methods of regulating cholesterol levels and therefore multiple fail-safes. The bad news is that a lot can go wrong. One or more alterations to this system can lead to the retention of cholesterol that might cause an individual to be more susceptible to heart attacks and strokes. This is the main reason for studying cholesterol in the first place.

So, what can we do about this complexity? Should we throw our hands up and just say that it’s too complicated?

I don’t think so. It is very complicated, and it can be frustrating for people looking to improve their diet, or choose a medication. But, it may be possible to use blood work in conjunction with metabolic, dietary, and pharmaceutical interventions to find out what you respond to.

The primary dietary factors that will change cholesterol levels in some individuals are: the ratio of saturated to poly-unsaturated fat intake, cholesterol intake, plant sterol intake, and other factors of metabolic health - excess fat, liver fat, hyper-insulinemia, low muscle mass, and more. Fortunately, these factors are mostly within our control.

After metabolic health and diet interventions are utilized, the next place to look is pharmacology if a need exists. There are many drugs that can affect cholesterol synthesis and absorption: - Statins inhibit cholesterol synthesis. - Ezetimibe inhibits cholesterol absorption and reabsorption in the intestine, and reabsorption at the liver. - PCSK9 inhibitors increase clearance of cholesterol from the blood by increasing the number of LDL receptors on the cell surface.

It’s possible to obtain blood testing to find your genotype for various genes that can affect cholesterol absorption and metabolism, and also to measure your cholesterol synthesis and sterol absorption. This sort of testing might be useful in certain select cases, but for the vast majority of people, it’s likely sufficient to follow a lipid panel, an Apo B, and markers of cardiovascular and metabolic health as you make changes to the variables listed above. I expect in the next decade or two (but hopefully sooner) that the details of this system will become clearer, and blood tests more useful for tailoring nutrition and medication recommendations for individuals.

For those interested in even more detail on cholesterol metabolism, I highly recommend Peter Attia’s nine part series on cholesterol. It is very detailed but exceedingly well laid out and explained.

Covid-19 Vaccine Update

• My Vaccination
• NYT Article
• Is it New Technology?

My Vaccination

I received my first dose of the Pfizer-BioNTech mRNA vaccine eleven days ago. I had soreness in my left deltoid muscle for two days which was mild. I’ve had no other symptoms. Prior to vaccination, I confirmed that I was Covid-19 negative by nasal PCR, and IgG and IgM antibody negative by blood immunoassay (not the same as a rapid lateral-flow assay that you can have done on the spot at some pharmacies – these are much less reliable). I’m not suggesting that you need to do the same, I’m just giving this information for the context of my non-reaction to the vaccine. If you already had a Covid-19 infection, it’s possible you’ll have a stronger reaction to the first dose of the vaccine. I will schedule my second dose to be given in another ten days. I’ll report back in the next newsletter.

NYT Article

Since receiving my vaccine, I did learn of an unfortunate case of an OB/GYN doctor in Miami who died several weeks after vaccination. According to a New York Times article, the otherwise healthy 56-year-old doctor received the vaccine, and three days later developed a petechial rash.

He presented to the hospital and was found to have very few platelets in his blood stream. Platelets are tiny cell like membrane-bound entities that are essential for blood clotting. After two weeks of attempts to remedy the problem, he tragically died from an intracranial hemorrhage.

Pfizer-BioNTech, who manufactured the vaccine he received, commented that they believed his death to be unrelated to the vaccine. If the information in the NYT article is accurate, it’s certainly tough to swallow that the vaccine is unrelated based on the timeline alone. However, to my knowledge, there have not been any similar cases reported outside this one. At the time I’m writing this, 20.5 million doses have been administered. Of course this case is concerning and extremely sad, but however tragic, it does not eliminate the fact of the other 20 million successful doses.

Is it a new technology?

I’ve listened to a lot of people discuss the idea that the mRNA vaccine is a new technology, and therefore does not have a long track record of safety, like other vaccines. People have called the vaccine “experimental” as a sort of smear, and have been more afraid of it seemingly because of its “newness” alone.

I understand where this thought process comes from, and to some extent it is valid. However, there is really no aspect of this vaccine that is particularly unique in terms of its components or its mechanism of action.

The ultimate goal of nearly every vaccine is antigen presentation. An antigen is a molecule, often found on the surface of a virus or bacteria that can be recognized by your immune cells. Once an antigen is identified, the immune system can mount a series of defenses. One such defense is antibody formation. In the case of SARS-CoV-2, there is likely both antibody mediated, and immune-cell mediated immunity after either natural exposure to the virus, or exposure to the spike protein alone.

Therefore, you can imagine several different types of vaccine. And, in fact, different types of vaccines have been developed.

One way to induce immunity is to inoculate people with an attenuated or “inactivated” version of the SARS-CoV-2 virus itself. Live attenuated vaccines have been used in the past with excellent efficacy and safety. Examples of attenuated virus vaccines include measles, mumps, polio, zoster, tuberculosis, and others. In an attenuated vaccine, a weakened version of the virus is given to the patient. The virus is intended to be too weak to cause clinical infection, but has the proper antigens to confer future immunity.

To form an inactivated vaccine, the virus is destroyed using heat, chemicals, and/or radiation, and then given to the patient. This strategy has been used by Chinese vaccine makers for Covid-19. Both of these strategies involve injecting the actual antigen into the patient, along with most or all of the actual virus components.

Another method of getting an antigen into a cell is to invade cells with a virus that carries RNA or DNA which codes for the antigen of interest. This is the strategy used by AstraZeneca for their adenovirus vector vaccine. In this vaccine, a specific strain of avirulent adenovirus has its genome altered to contain a sequence of DNA that encodes for the SARS-CoV-2 spike protein. The patient is injected with virus. The virus then enters the recipient’s cells and releases DNA. The DNA is transcribed to mRNA, the mRNA is translated into spike protein, and eventually your cells present spike protein to your immune system. This is a second method.

The third method is the mRNA vaccine.

With this vaccine…

• There is no SARS-CoV-2 virus involved. In fact, there is no virus involved at all.
• There is no virus vector or DNA involved.
• Instead, with the mRNA vaccine, scientists skipped the first two steps, and instead deliver the mRNA directly into your cells using a lipid vehicle. The mRNA is then translated into spike protein. That’s it - there’s no virus at all, no DNA, no other proteins or antigens - just a lipid vehicle and mRNA.

With the first two approaches - you also have lipid and mRNA. Many viruses, including SARS-CoV-2 have lipid envelopes. So, if you use an attenuated, inactivated, or lipid-enveloped virus as a vector, you’ll still be dealing with a lipid vehicle of sorts that must fuse with your cell wall. With the other approaches, you have either RNA or DNA being delivered to the cell, just like you have with the mRNA vaccine.

So, there are many similarities between the different methods of immunity and vaccination, but ultimately, the end result is mRNA translation into spike protein. So, the mRNA vaccine is really a simpler but similar way of gaining immunity when compared to natural immunity and other methods of vaccination. The difference is in the engineering and development, but not really in the mechanism of immunity.

One potential concern is the components of the vaccine. But, the components of the mRNA vaccines are not particularly novel, nor are they even unfamiliar.

According to this information sheet from the FDA, “The Moderna COVID-19 Vaccine contains the following ingredients: messenger ribonucleic acid (mRNA), lipids (SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC]), tromethamine, tromethamine hydrochloride, acetic acid, sodium acetate, and sucrose.” The Pfizer vaccine has similar components.

Let’s go through each: - mRNA - you would come into contact with mRNA via any natural infection or any of the above vaccine methods except for the inactivated vaccine, which would likely have a damaged, non-functional version of the mRNA. - SM-102 - this is a proprietary lipid, which I believe is a version of sphingomyelin, which is a lipid synthesized by your own body and which is found in the myelin sheath of nerve cells, and in the cell membrane of many others. - PEG - polyethylene glycol - a mostly inert substance found in many medications both oral and injectable. - DMG - this is a type of phosphatidylglycerol that is either the same as, or similar to a glycerophospholipid that is synthesized by your own body, and is found in pulmonary surfactant. - Cholesterol - ingested and manufactured by your body every day. - DSPC - a type of lipid that has been used in other drug preparations for years - Tromethamine - a sort of acid buffer that is given in much higher doses to hospitalized patients under various conditions. - Acetic Acid - also known as vinegar when diluted in water. - Sodium Acetate - this is just sodium bound to acetic acid. - Sucrose - this is a sugar that you eat all the time. It’s a disaccharide of glucose and fructose.

That’s it. I really think this vaccine is likely to be safe in the short and long-term for nearly everyone who receives it. I’m sure there will be some unusual cases, and it’s even possible that unforeseen problems could occur, but there’s no evidence (to the best of my knowledge) for concern at this time.