An Interview with Professor Manuel Varela: Blood and its Variants?

Jul 15, 2019 by

Karl Landsteiner

Michael F. Shaughnessy –

1) Who was Karl Landsteiner? And what did he discover about ABO blood groups?

Nobel Laureate Dr. Karl Otto Landsteiner was a famous immunologist and biomedical scientist. His world-wide fame arises from his milestone discovery of the so-called ABO blood types, a blood classification scheme. His discovery revolutionized the course of human medicine because it permitted physicians for the first time in history to conduct safe life-giving blood transfusions, based on his ABO system.

Prior to Dr. Landsteiner’s groundbreaking discovery that there were different blood groups, medical transfusion of blood between individuals was fraught with potential disaster. The blood-transfused patient might succumb to a dramatically fatal outcome, and, worse, the types of outcomes (death versus survival) from the transfusions were unpredictable. Dr. Landsteiner’s discovery that human blood consisted of three (and later 4) different types changed the course of medical history and ushered in a new era of clinical medicine. Thanks to Dr. Landsteiner’s pioneering work, it became possible to determine the blood types of a patient and of a blood donor, before the transfusion would take place. This allowed properly matched blood types to be identified beforehand. Thus, it permitted clinicians to provide blood to their patients in a safe manner.

In his experiments during the late 19th and early portions of the 20th centuries, Dr. Landsteiner collected samples of blood from many individuals, including his own blood and those of his colleagues. Next, he purified the red blood cells, separating them from the white blood cells and clotting factors, a substance he called serum. Then, he mixed each of the red blood cell samples with each of the various sera samples, examining the mixtures for the occurrence of clotting, a process now called agglutination. Some mixtures of blood and sera “clotted” (agglutinated), and others did not show this agglutination.

After analyzing the various blood clotting data, Dr. Landsteiner devised the ABO system. He proposed that the various types of blood harbored what he called the agglutinogens, now known as antigens. He said that type A blood had A antigens whereas type B blood had so-called B antigens. He also proposed that the agglutinating sera had antibodies, like anti-A and anti-B antibodies. If the blood harbored neither A nor B antigens, he referred to the blood as type C, later called type O. Shortly thereafter, he found a fourth blood group, called type AB. In November of 1901, Dr. Landsteiner published his findings in a scientific journal called Viennese Weekly Journal of Medicine.

More recently, the ABO system has been revised such that the antigens are now considered the ABH system to better reflect the molecular nature of the blood antigens. These blood antigens are found on the surfaces of the red blood cells. Surprisingly, the blood antigens are mainly sugars! The sugary blood antigens consist of molecules like galactose, fucose, N-glucoseamine, N-acetylgalactosamine, plus, a platform of lipid or protein.

Type O individuals (i.e., those lacking both A and B blood antigens) nevertheless harbor H antigens on their red blood cell surfaces. In fact, all humans, independent of blood type, have antigen H on their red blood cell surfaces.

2) Where was he born and where did he go to school?

An only child, Karl Landsteiner was born on the 14th day of the month of June, in the year 1868, to parents Leopold and Fanny Hess Landsteiner, in the small town of Baden Bei Wein, in the province of Lower Austria, Vienna. When the child Karl was only 6 or 7 years old, his father, a noted journalist and lawyer, died suddenly of a heart attack at 56 years of age, leaving his wife to care for the young child. Mother and child were known to have been close for the rest of her life, and when Fanny Landsteiner herself passed away, in 1908, her devoted son was known to have displayed her funeral death mask in his bedroom for the rest of his life.

He was recognized at an early age as being intelligent. Young Karl attended State grammar school in Linz and then at Wasagasse Austrian Imperial high school in Vienna, graduating in 1885 with honors. He subsequently enrolled in medical school at 17 years of age and graduated with his M.D. degree in 1891 from the University of Vienna Medical School. During his tenure in medical school Karl and his mother Fanny converted to Catholicism from Judaism, in 1890, hoping to escape persecution by the rising anti-Semites of Vienna. Landsteiner managed to keep his Jewish heritage a secret and went through great lengths to maintain the secret, even expensive litigation, in 1937, to avoid exposure. He lost the lawsuit, however, and his inclusion into a Jewish-based encyclopedia was published.

Having fully developed an interest in chemistry while in medical school, Dr. Landsteiner continued post-graduate study in the research laboratory of an inspirational teacher, Prof. Ernst Ludwig, in an effort to further his interest in conducting investigative research, as opposed to clinical medicine. Dr. Landsteiner’s first publication entails work performed in Dr. Ludwig’s laboratory.

Dr. Landsteiner’s post-graduate pursuits were extensive, gaining advanced training from various investigators, such as Drs. Arthur Hantzsch and Roland Scholl, both of whom were from Zurich, Switzerland, plus, Nobel Laureate Prof. Emil Fischer, from Wurzburg, Germany, Dr. Eugen von Bamberger, from Munich, Germany, and Prof. Eduard Albert, from Vienna, Austria. In Dr. Fischer’s laboratory, Dr. Landsteiner synthesized a compound called glycolaldehyde.

Dr. Landsteiner started a research assistant post, in 1896, at the laboratory of Dr. Max von Gruber, a prominent scientist who was housed at the Institute for Hygiene at Vienna General Hospital, in Austria. Prof. Gruber was famous for having earlier pioneered the discovery of a serology-based laboratory test for the presence of typhoid fever. It is here in Dr. Gruber’s lab where Dr. Landsteiner learned the basics of immunology and, importantly, of serology, the science of blood serum.

Dr. Landsteiner’s discovery of the ABO blood system, in 1901, occurred after he entered the laboratory, in 1897, of Anthony (Anton) Weichselbaum, who was then director of the Institute for Pathological Anatomy. In 1903, Dr. Landsteiner took his Ph.D. degree studying pathology and histology of the parenchyma.

3) Today we are very careful about blood transfusions because Landsteiner linked human blood transfusions to shock (often resulting in death) jaundice and a number of other conditions. Tell us about this?

Great care must be taken to ensure that blood transfusion recipients receive the correct blood types. If, God forbid, a patient receives an incorrect blood type, then a severe, perhaps fatal consequence can occur as a result of the incompatible blood transfusion. Providing to a patient a blood transfusion that is of the incorrect blood type (an incompatible blood transfusion) will generate a serve immune response called a transfusion reaction. The particular kind of immune response that occurs is called a Type II hypersensitivity reaction. The magnitude of this response can be profound, possibly inducing strong physiological responses such as the jaundice and shock that you mentioned. The outcome might possibly lead to death.

During a transfusion reaction, an antibody that is specific for a particular blood antigen, will bind to that antigen, forming an antibody-antigen complex on the surface of a red blood cell. This so-called immune complex (antibody-antigen) will then initiate a physiological mechanism called complement. The activation of the complement system in turn stimulates the insertion of giant membrane attack complexes into the membranes of the red blood cell target, resulting in lysis of the blood!

Another blood rejection mechanism that’s stimulated by an antibody-antigen complex on the red blood cell surface is called antibody-dependent cell-mediated cytotoxicity (ADCC). The incompatible blood transfusion triggers the ADCC system to recruit another specialized type of cell, called natural killer (NK) cells, which have specialized proteins on their surfaces called the Fc receptors that bind to the Fc portion of the antibody. The Fc part of the antibody forming part of the immune complex on the wrong blood then is bound by the Fc receptor of the NK cells. The NK cell binding to the red blood cell of the incorrect type will then release mediators that destroy the red blood cells!

4) He was awarded the Nobel Prize for his classification of blood types: A, B, AB, and O. Can you tell us about each?

The type A blood has A antigens on their red blood cell membrane surfaces. The A antigens can be recognized by anti-A antibodies. Such individuals can safely receive blood from individuals who are also type A, or type O (as type O does not have the A or B antigens). Type A people, however, can make anti-B antibodies. These type A individuals can, nevertheless, donate blood to those who are type A or AB.

The type B blood has B antigens on their red blood cell surfaces. The B antigens are recognized by anti-B antibodies. Individuals of type B blood can safely receive type B or O blood. Type B individuals make anti-A antibodies. Type B people can donate blood to those who are type B or AB.

The type AB blood has both antigens A and B on the surfaces of their red blood cells. The A and B antigens can be recognized by anti-A and anti-B antibodies, respectively. Individuals with type AB blood do not make anti-A and anti-B antibodies and can, thus, safely receive transfusions from types A, B, AB, and O. Thus, type AB persons are considered so-called “universal recipients” of blood. However, type AB people can donate blood only to similarly typed individuals with type AB blood, because they have the A and B antigens.

The type O blood has neither A nor B antigens. (Though they do harbor the H antigens. All individuals harbor the H antigen on their red blood cells.) Neither anti-A nor anti-B antibodies will recognize type O blood, as the A and B antigens are missing. Type O individuals will produce both anti-A and anti-B antibodies. Thus, type O people can receive only type O blood. However, an individual who is type O is considered a “universal donor” because they lack the A and B antigens. Thus, type O people can donate blood to those who are A, B, AB and O.

5) Now we often hear about Rh factor. What does this mean in this regard?

In 1940, Dr. Landsteiner discovered the Rh factor system. It represents another very important blood group classification system. Before its discovery, however, clinicians who used the ABO system to cross-match blood donors to their recipients still encountered transfusion incompatibilities. These transfused blood rejections had to do with the Rh factors!

A person will either have or lack the Rh factor antigen, and such individuals are referred to simply as Rh-positive (Rh+) or Rh-negative (Rh-), respectively. The term Rh originates from the Rhesus monkey (Rh for Rhesus) because about 85% of humans share the Rhesus factor with the Rhesus monkeys. The Rhesus antigen resides in the membrane of the red blood cell and transports glucose and anions across the membrane. In modern times, the Rhesus factor is also called D antigen.

The ABO and Rh blood classification schemes are intertwined. For example, the blood of certain individuals may be A-positive (A+) or A-negative, (A-). Likewise, others may be B+, AB+, and O+, or A-, AB-, or O-, depending on whether they have or lack the Rh antigen on their red blood cell surfaces.

Although the Rh factor incompatibility rejections during mismatched transfusions are relatively minor compared to those with ABO incompatibilities, the Rh factors nevertheless play a prominent role in a drastically more considerable life-threatening situation.

Rh factor mismatches can cause a terribly serious condition called hemolytic disease of the newborn. It’s a dreadful disease involving the Rh blood antigen incompatibility. The consequence involves incompatible blood types between a mother and fetus. During a mother’s second pregnancy, if a fetus inherits an Rh+ blood type from the father, and the mother is Rh factor minus (Rh-), the mother can develop antibodies that are directed against the Rh+ fetus itself and attempt to destroy it! The baby may be stillborn. However, the pregnant mother can take RhoGAM, a preventative medicine consisting of helpful anti-Rh antibodies. These antibodies will find any incompatible blood and clear them from the system before immune cells are activated and memory cells are made for the next encounter. Thus, during the mother’s next pregnancy, she will not make the dreaded anti-Rh antibodies, resulting in the protection of the fetus from a potentially disastrous consequence.

6) Apparently he was known for his meticulous scientific work- can you elaborate?

One can certainly envisage the great need for a meticulous nature when conducting scientific experiments in the field of biomedical sciences because such studies can directly have profound impacts on the general health of human beings across the world. While scientists in general have to be rather meticulous in their work in order to collect reliable data that’s repeatable and accurate, many biographical and scientific sources, especially in a description by the Nobel Commission, attest to this particular character trait about Dr. Landsteiner as being quite profound.

In the case of Dr. Landsteiner, the accuracy of the blood grouping data was enormously important. Lives literally depended on getting the particular blood categories absolutely correct. The meticulous work of Dr. Landsteiner is evident if one examines the work that was involved during the ABO blood type system discovery. He collected many blood samples, keeping careful notes about whose blood was whose. He even collected his own blood! He prepared sera from each of the blood samples, as well as having isolated the red blood cell samples and keeping them separated from the sera samples. He mixed different blood samples with different sera and carefully (meticulously) observed whether an agglutination reaction occurred.

The work had to be repeated and in much the same way as before. Minor variations in the methodology or the laboratory protocols might mean enormous and confounding differences in outcomes. Furthermore, great care had to be taken to ensure that no contamination occurred between samples.

One account reports that Dr. Landsteiner was viewed by colleagues as an enormously critical investigator and educator. His laboratory personnel were made to repeat each of their most important findings while he stood over them observing their methods. He painstakingly checked and verified all of their data.

Others were more critical of Dr. Landsteiner. Another narrative describes him as having been a “stubborn tyrant” as a fellow colleague. More often than not, he was characterized as being rather a pessimistic and skeptical old crab!

Having a meticulous nature is exceedingly important in science, and the biomedical sciences are no exception. Great scientific investigators, regardless of their specific scientific discipline, will want to know the truth. Without question, conducting experiments meticulously will aid in ensuring that accuracy is maintained and that eventually the truth is uncovered. Other investigators will repeat important findings and confirm or revise the conclusions made in earlier biomedical studies. Therefore, invoking a meticulous nature keeps the paces of science moving in positive ways.

7) In a sense, his blood work permeates much of modern medicine today. Is there any real way to assess his contributions to modern medicine?

Historians of medicine and the biomedical sciences have attributed the discoveries of Dr. Landsteiner has having made one of the most important scientific discoveries in the 20 century if not in the entire scientific history of the world. I’m sure these previous recorders of scientific and medical history are not far off the mark.

The ability to save lives based on life-giving blood transfusions changed everything in medicine. Countless millions of lives have been saved. Billions more lives are slated to be saved on account of Dr. Landsteiner’s ABO and Rh factor discoveries.

Dr. Landsteiner’s contributions in discovering these blood groups is epic, and they provide a tremendous challenge to those wishing to assess the degree to which the enormity of the impact in modern medicine and biomedical sciences has been made.

8) Plasma- how does this fit into the picture?

Blood is a complex liquid-based tissue that contains cells and fluid. Plasma may be considered the fluid part of blood, i.e., blood without its red blood cells. Plasma is actually a complex liquid-based substance. It consists of water, ions (called electrolytes), certain gases (oxygen and carbon dioxide), nutrients (e.g., sugars), formed elements like white blood cells, and a complex mixture of various proteins.

For example, this fluid plasma part of blood also contains the protein factors that cause clotting. If the plasma is further treated in such a way that these clotting factors are removed, then the remaining substance is called serum. Multiple serum samples are called sera.

Other proteins include antibodies, which are specifically induced by an antigen and will function to protect the body from foreign (non-self) substances, such as tissues, microbial pathogens and cancer. If an individual is immunized with an antigen, the blood will harbor responsive antibodies, and the material without clotting factors will be referred to as antiserum. There are many types of antisera.

Plasma can also harbor iron-binding proteins, such as transferrin or certain cytochromes. Iron is necessary for maintaining proper oxygen-binding properties of hemoglobin in red blood cells and in ensuring that certain iron-binding enzymes function properly.

Plasma contains complement, which is a physiological cascade system of proteins that work to protect the individual from pathogens by lysing bacteria or stimulating inflammation. The complement system serves a useful purpose as an innate immune system-based form of protection.

Plasma harbors certain white blood cells, also referred to as leukocytes. These types of cells also function immunologically. For instance, some leukocytes called B-lymphocytes develop into plasma cells when antigen is recognized, and these plasma cells then become antibody factories. Such B-cells play an important role in humoral immunity, a sub-category of the adaptive immune response. Other leukocytes such as the T-lymphocytes also function as useful adaptive immunity components, during cell mediated immunity. The leukocytes represent a member of the formed elements of plasma.

Other formed elements of plasma include the erythrocytes, which are stem cells that are underdeveloped, immature forms of red blood cells. The erythrocytes bind to oxygen and carbon dioxide in the blood and transfer these gases throughout.

Another formed element is called the platelet, which is a cell fragment that can play a role in the clotting of blood. Platelets are derived from larger cells called megakaryocytes and harbor bits and pieces of their membranes as part of these formed elements.

9) What have I neglected to ask? 

Dr. Landsteiner’s body of scientific work was not limited to blood grouping. He made other important contributions to the biomedical sciences.

In 1904, he studied a medical condition called paroxysmal hemoglobinuria, in which levels of hemoglobin in the urine are elevated under extreme cold temperatures. He showed that the condition is brought about via an autoimmune reaction in which self-antibodies induce complement. Some reports indicate that this study represents one of the first known of the autoimmune diseases.

Working with Dr. Erwin Popper in 1908, Dr. Landsteiner was the first to demonstrate that polio is caused by a filterable virus! He and Dr. Popper injected the brains of monkeys with a saline-based suspension of spinal cord and brain tissue from a human child who had died from poliomyelitis. No bacteria were detected in the brains of the injected monkeys, suggesting that the causative agent was a virus. Dr. Landsteiner was a key figure in the finding that polio was caused by poliovirus.

In 1906, he developed a new microscope-based method for examining the causative agent of syphilis, Treponema pallidum, as a useful tool for diagnosis. He successfully developed an animal model using monkeys for studying syphilis. He discovered that the mechanism behind the famous Wassermann reaction, a test for syphilis, was based on an agglutination of lipid-specific antibodies. He found that the targets of the Wassermann antibodies were phospholipid in nature.

In 1917, Dr. Landsteiner studied small molecules called haptens, which could not provoke an antibody response on their own, but could be made to provoke an immune response, a property called immunogenicity, if combined with a larger inert carrier molecule. The combined hapten and carrier together, called a conjugate, constituted the intact antigen. The part of the antigen to which an antibody binds is called an epitope, or antigenic determinant. Interestingly, his work showed that the haptens could bind specific antibodies, and he felt that Nobel should have been bestowed to him for his hapten-antibody work.

In 1926, he discovered the MNP blood grouping system, which was used early on forensically in criminal cases and for settling paternity disputes. While not widely used today, this system and the ABO groupings were used to award Dr. Landsteiner the Nobel.

Interestingly, Dr. Landsteiner became good friends with another prestigious scientist, Nobel Laureate Dr. Linus Pauling, discoverer of the famous alpha helix and proponent of the virtues of vitamin C. The two investigators even collaborated together in which Dr. Pauling contributed a chapter in a revised book originally written by Dr. Landsteiner. The book edition was called “The Specificity of Serological Reaction.

Dr. Landsteiner was known to have played the piano. However, when neighbors complained they couldn’t hear the radio, he sold the piano. Dr. Landsteiner’s wife, Helene Leopoldine Wlasto Landsteiner, whom he married in 1916, developed cancer of the thyroid later in life. Dr. Landsteiner devoted his time to researching her disease. Unfortunately, he suffered a heart attack and died two days later, on the 26th day of June, in 1943, at the age of 75, leaving behind his wife Helene and his son, Earnest. Helene passed away of her malignant illness a few months later, on Christmas.

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