The above image is of Bill and Melinda Gates of the Bill & Melinda Gates Foundation, a foundation dedicated to addressing worldwide disease and poverty by supporting access to quality healthcare and a reasonable education. Attacking malaria is on their list of initiatives. Bill and Melinda Gates are Earth’s avatar for philanthropy. Bill Gates along with Paul Allen founded Microsoft in 1975. Sadly Paul Allen passed away a few years back in 2018, age 65, from recurrence of non-Hodgkin Lymphoma. He had Hodgkin’s Lymphoma in 1982 which was successfully treated, he then developed non-Hodgkin lymphoma in 2009, successfully treated until it recurred in 2018.
Returning to evolution and what the heck that has to do with malaria and or sickle cell anemia, this is the gist of Darwinian evolution: whatever the genetic aberration that arose in human evolutionary history, if it provided a desirable mutation or adaptation that granted a favorable heritable trait, it was passed on, generation-by-generation, slowly, most assuredly. Remember that when we circle back to the connection between malaria and sickle cell anemia.
Symptoms of malaria infection, often episodic, include fever, headache, malaise, fatigue, nausea, night sweats, rapid breathing and shortness of breath; the breathing issue is due to the parasite’s life cycle through the lungs. And of course, there is the anemia. In severe cases, the skin turns yellow due to jaundice, the result of those busted red blood cells spilling their hemoglobin into the blood. As hemoglobin breaks down it imparts a yellowish hue which is what you see when a bruise resolves. When you bruise yourself, the color covers the rainbow spectrum from purple to red to green to yellow, it is hemoglobin being broken down and down, each diminishing chemical structure imparting its own unique color. Pictured here to the left is a microscope blood smear featuring a bunch of normal red blood cells plus right dab in the center a red blood cell with malaria parasites enjoying their parasitism.
In comparison to malaria, sickle cell anemia, which is an inherited blood disorder not an infection, shares a similar symptom palette with malaria, which likely explains why Dr. Irons’ presumptive diagnosis for dental student Walter Noel was initially malaria. Symptoms of sickle cell anemia include shortness of breath, rapid heart rate, episodes of joint pain, jaundice, abdominal pain, fatigue, chest pain, and back pain, a constellation of findings similar to malaria. And of course, there is the anemia. Pictured to the right is an art rendition between the shape of a normal red blood cell and a sickled red blood cell. Below is a real microscope view of a blood smear with mostly normal red blood cells and a few scattered sickled cells.
Malaria and sickle cell anemia present symptomatically similarly despite being two totally different diseases, their similarity based on the sanguine fact their primary disease process involves the blood.
Sickle cell crisis is a severe form of sickle cell anemia – why the red blood cells sickle will be further explained momentarily – and occurs when there is such a huge burden of sickled-shaped red blood cells that they occlude tiny capillaries in various organs, such as in the lungs, spleen, kidneys and articular joints causing severe ischemic pain. Walter Noel was in the throes of a sickle cell crisis that day in Chicago in 1904 when Dr. Irons examined him, and quite likely was suffering from malaria, too.
Symptoms of sickle cell disease usually occur six months after birth when the baby’s fetal hemoglobin F disappears, “F” for “Fetal” and is replaced with abnormal hemoglobin S; the “S” stands for “Sickle” of course. Abnormal S hemoglobin is what forces the red blood cell to change shape, from one of spherical to one of sickled. In farming, a sickle is an agricultural implement with a curved blade used to reap the harvest; and sickled red blood cells bear a resemblance to the sickle farm tool.
A person with sickle cell trait is a carrier of the gene – has one normal hemoglobin A gene, “A” for “Adult”, and one abnormal hemoglobin S gene – and is barely if at all symptomatic. Since the carrier state churns out both normal hemoglobin A and abnormal hemoglobin S both of which are inside a red blood cell, the cell is mostly copasetic. This is an important point, a person with sickle cell trait, inside a single red blood cell, has both normal and abnormal hemoglobin, the normal hemoglobin doing its best to prevent the abnormal hemoglobin from sickling the cell.
Not true in a person with sickle cell disease. In contrast, a person with sickle cell disease has both genes churning out the abnormal S hemoglobin so every single red blood cell is nothing but abnormal hemoglobin. In order to have the full-blown disease a person must inherit the abnormal S gene from both parents, not just one parent. Sickle cell disease occurs 1/365 Black Americans, 1/16,000 Hispanic Americans, and sickle cell trait exists in 1/13 Black Americans. The image on the left illustrates above a normal hemoglobin molecule that has four binding sites for oxygen molecules and even the hemoglobin molecule itself has a sort of spherical shape. The image below is meant to portray that the abnormal sickle S hemoglobin assumes a strange shape, a strangeness that is transferred to the red blood cell to sickle.
Your might be wondering why, if a person has sickle cell disease, shouldn’t all their red blood cells be sickled all of the time? But that is not the case. This is a key point about a person who has inherited both genes, most times despite having only abnormal hemoglobin, their red blood cells remain fairly spherical, they are not sickled. But certain conditions will trigger more and more blood cells to sickle, usually conditions that result in a decrease in oxygen in the blood. Such conditions could be stress, an infection, an injury or any of a number of events that lower oxygen. And the thing is this, once the blood oxygen levels drop low and the red blood cell sickles, even if oxygen levels are restored, a sickled cell will not un-sickle. It is a one-way event. It is like bending plastic beyond a certain point, it warps and it won’t unwrap by bending it back. Sickled red blood cells remain in circulation wreaking havoc until they are removed by the spleen, that is, if the spleen is still working, or they lyse from injury or they come to their 120 day or so life span.
Sickle cell anemia is genetic, and although it cannot be cured the symptoms can be managed. Malaria on the other hand is an acquired infection, it can be prevented, it can be cured, and its symptoms managed.
John Bershof, MD
John Bershof, MD is a plastic surgeon who has been in private practice for over 25 years. He is the author of numerous medical articles as well as the first textbook of medicine for mobile phones, entitled skynetMD 2005-2015. An essay entitled Gin & Tonics, Clerics, and Dr. Livingstone, I Presume?, which was extracted from one of his future as yet published books was featured in The Antioch Review.
While working on the medical textbook skynetMD for mobile phones, Dr. Bershof, perhaps not too surprisingly became more interested in the backstories of medical history, like who was Lou Gehrig, what is Lou Gehrig's disease, what was his lifetime batting average for the New York Yankees—.340, nineteenth overall—and who invented baseball anyway. Questions such as these piqued Bershof's interest. Having read At Home 2010 by Bill Bryson, his engrossing narrative journeys room-by-room through his Victorian English countryside home, a former rectory, where each room is a chapter about domesticity, about home. It occurred to Dr. Bershof that in similar vein he could take the reader disease-by-disease as jumping off points into human history, science, medicine—his canvas blank, no subject not within reach—and learn a little medicine along the journey.
The ability of a book that is heavily fortified with science and history to connect with a general readership can be challenging; Dr. Bershof through storytelling, humor, jumping off points and personal anecdotes, accomplishes it, written in a language fleeced of the jargon that normally accompanies such narratives. The first two books, The First History of Man published in 2020 and The Second History of Man published in 2021 are available in print, ebook and audio. The Third History of Man is in final stages of editing to be published in 2022, with more volumes to come after that.