The Codebreakers of Disease

by James L. Blackburn

One of the few good things to come out of the COVID-19 pandemic was increased interest in, and therefore increased funding for, research into the role genetics plays in disease. It has long been known that genes can greatly influence the body's susceptibility to infections and the course these infections take. COVID's seemingly capricious choice of and effect on victims drew our attention to an uncomfortable truth usually on the minds of only geneticists and immunologists: our DNA code can make life and death decisions for us.

Background

Immunology, the study of our bodies' defense mechanisms against the critters that would make a meal of us, has been around for a couple of centuries. Genetics, the study of our cellular code that we inherit from our parents and pass on to our children, and how that process influences our physical characteristics, has been a focus of science since the monk Brother Mendel was studying pea plants in the mid-19th Century. During the latter half of the last century, the two fields came together with a common goal: to learn what it is in our genetic coding that makes us susceptible to certain terrible diseases, and how we can protect ourselves. The result of this marriage of interests is called immunogenetics.

Modern immunology is considered to have had its start at the end of the 18th Century. Several British doctors, working independently, were investigating the idea that our bodies were somehow capable of acquiring resistance to disease. They experimented with a procedure called variolation, a predecessor to our current inoculation, in cases of small pox. A tiny bit of fluid from a small pox patient's pustules would be applied to a healthy person. This seemed to give them a degree of protection, though this practice was very dangerous. Not only could the patient die, but he could spread the disease.

Small pox variolation had been practiced in the Orient for some time. It was introduced to the British Isles by Lady Mary Wortley Montagu, writer and wife of Britain's ambassador to Turkey, upon their return to Britain in 1718. But modern inoculation - the deliberate introduction of microbes or vaccine to gain immunity - began with experiments by an English country doctor, Edward Jenner.

Jenner was intrigued by folklore among farmers that milkmaids who contracted cowpox, a similar but less virulent disease, would not get smallpox. Cowpox was a rash of cow udders which infected the people who milked them. At this time, and throughout history until only recently, smallpox was a threat to truly fear. The 18th century French writer Voltaire said that during one outbreak, 60% of the local population were infected, and one out of five victims died from it. And if you see photos of victims, you will never forget them.

Jenner took a big risk that garnered him historical significance, but today it would have put him behind bars. He went to a milkmaid infected with cowpox and scraped pus from some of her pustules. He then went to the son of his gardener, a perfectly healthy eight-year-old, and infected him. The boy became a typical case - developed pustules, had a slight fever - and a week later was healthy again. Jenner then went to another girl who had smallpox and repeated the procedure with the boy. Nothing happened. The boy didn't get sick. Jenner repeated the procedure, and still the boy remained healthy. This proved that inoculation was possible with a similar but less virulent disease. With this, Jenner secured his place in the history of vaccination. So did the cow, as a matter of fact. The milkmaid's cow was named Blossom, and her hide now hangs in the St. George's Medical School library in London. (The word vaccine comes from the Latin word for cow, vacca.)

Immunogenetics grew out of the increased understanding that our bodies defenses against disease were in large part affected by inherited traits. Since the cracking of the DNA code in 1953 and the subsequent advances in genetics, we are building a knowledge base ever more extensive and refined. Researchers are investigating questions like, How do our bodies distinguish between enemy cells that must be attacked and our own healthy cells? And why does this sometimes go wrong, such as with cancer and autoimmune diseases like type one diabetes, wherein our defensive cells turn against us? In just the last few years great strides were made in our understanding of these processes thanks to, unfortunately, a new biological threat, SARS-CoV-2, commonly called COVID.

COVID-19

Immunogenetics was already a burgeoning field of research before December, 2019, and then COVID-19 descended on us. It spread rapidly, and the race was on to develop a vaccine. This sense of urgency catapulted immunogenetic research into the front lines of the COVID combat. By February of 2022, according to WorldoMeter.info, globally we were seeing nearly 4,000,000 new cases a day. What made COVID a perfect study for immunogenetics was its variability. There were obvious risk factors - age, sex, pre-existing conditions - but there was wide variability in this. People considered high mortality risk, e.g. elderly men with a pulmonary condition, were exposed but never tested positive, or if they did were asymptomatic or their symptoms were mild. Meanwhile, a healthy young girl anticipated to recover easily, fell into a coma and died. What was going on at the cellular level with this dreadful disease?

Answers to these questions were being sought by virologists worldwide. A resource for them was a highly specialized team of immunologists, geneticists, computer programmers and artificial intelligence experts at the University of Montpellier in Montpellier, France. A unique system of information in the field of immunogenetics was developed there in 1984 by immunologist Prof. Marie-Paule Lefranc. The system stores, organizes and provides access to immunity and genetic data. It is called ImMunoGeneTics or IMGT®.

ImMunoGeneTics®

Today, the IMGT group is part of the Institute of Human Genetics (Institut de Génétique Humaine) which is overseen by the France's National Scientific Research Center (Centre National de la Recherche Scientific) and the University of Montpellier. While the Center explores many fields of scientific research, the Institute focuses on genetics and pathologies. The IMGT group concentrates on immunogenetics: the study of the role our genes play in our immunity to disease. IMGT was the 2023 recipient of the coveted Cristal Collectif award for excellence in research.

"The COVID-19 pandemic was a huge impetus to the field of immunogenetics", says Prof. Sofia Kossida, the director of IMGT since 2015. "Virologists, public health experts, medical doctors, geneticists and, of course, immunologists were all scouring for data on the genetics of immune systems. The faster COVID spread, the greater the need for hard, clean, organized data."

Prof. Kossida's multidisciplinary team gathers information from databases worldwide and organizes it to provide quick, customized access for physicians and researchers. But a shortage of data is not necessarily the biggest obstacle to new research.

"Today we are witnessing an explosion of data in this field," says Gaoussou Sanou, doctoral candidate at IMGT. ""ning everywhere today, but most notably in our field of genetic research thanks to progress in DNA sequencing - I'm sure you've heard of the Human Genome Project - as well as the reduced costs in these new technologies." Mr. Sanou tries to give us a perspective on the numbers: "For example, the international ‘1000 Genomes' project has generated one million billion bytes of data. Any way you look at it, that's a lot of data."

Mr. Sanou says the big problem has become working with this quasi-infinite supply. "We are asking ourselves today, ‘How do we store this mass of information? How do we present it to IMGT users? And how do we update it dynamically while maintaining optimum access?' These are the questions which challenge us."

The IMGT team has introduced a few brilliant ideas to help manage this task. "We rigorously developed a proprietary vocabulary at the heart of our system," says Mr. Sanou, "thus allowing different components - databases, tools - to communicate clearly, distinctly, without ambiguity. By doing so we have enabled an ‘open science context' that users can mine, examine and share. Access and usage now has skyrocketed."

COVID-19 lent itself to such focused and deep investigation of accumulated knowledge. "The IMGT team hit the ground running, giving users the power and opportunity to investigate the structure and function of our immune system at a molecular level and how it responds to the COVID-19 viral attack," says Mr. Sanou. Prof. Kossida echoes her team member, "Our models allow us to perform simulations, to see how one molecule interacts with another, for example our defensive cells with the COVID virus. We can turn speculation into experiment and experiment into fact."

Immunotherapy

One of the most important areas of immunogenetic research is immunotherapy. This is a type of biological therapy wherein substances called monoclonal antibodies are used to boost or inhibit our bodies' immune system. The current focal point for immunotherapy is cancer. Finding a cure for cancer, and even just treating it, is hampered by cancer's variability and complexity. Cancer cells may attack the body, or they may cause the body, via the immune system, to attack itself. Some biotherapies, then, stimulate the immune system to attack cancer cells, while other biotherapies suppress the immune system to keep the body from seeing healthy cells as the enemy. Current research is being done on using immunotherapy to alleviate cancer treatment side effects and on predicting how patients will respond. This latter is important because only a small portion of patients respond well to immunotherapy, and side effects can sometimes be severe.

Artificial Intelligence

For immunotherapy to work, and indeed at the heart of the immunity process, is our bodies' ability to distinguish "self" from "non-self", that is to say, the good guys from the bad guys. Dr. Anjana Kushwaha, doctorate in artificial intelligence and member of the IMGT team, explains, "The immune response to pathogens and malignant cells - the enemy - begins at the molecular level. Molecules must nest, bind to the appropriate site. However, due to the vast possibilities and subtle differences among molecules, predicting a specific binding probability is beyond normal human intelligence. This is where artificial intelligence comes in. AI can do analytical computations in minutes that we … well, that we might never be able to without it."

AI is not without controversy. Even Stephen Hawking, the late great cosmologist, urged caution in developing AI. But with respect to medical research, it is a tool of discovery we cannot ignore. Dr. Kushwaha says, "In a Stanford study of classifying skin lesions as benign or malignant, AI was as accurate as dermatologists. How can we ignore this? If doctors have at their disposal a tool that can relieve the suffering of their patients, they would be in violation of their Hippocratic Oath not to take advantage of it." And so it goes that we, with some trepidation, must accept artificial intelligence as a powerful weapon in our arsenal against the afflictions of mankind.

Opportunities for discovery are wide open in this field. It is still relatively young, and there is no limit to the possible applications. Current research is focused on such varied afflictions as multiple sclerosis, diabetes type I, rheumatoid arthritis, Crohn's disease, bipolar disorder, asthma, autism and tuberculosis. Research is also looking into forecasting the course of diseases, selecting the most efficacious therapy, as well as susceptibility to and likelihood of acquiring maladies.

The way forward

"With the completion of the Human Genome Project in 2003," says Prof. Kossida, "we have at our disposal the tools we need to find the genetic contribution to diseases. We have the databases, the maps, the technologies and the talent. Important research is now being done in the form of genome-wide association studies. Basically, these involve comparisons of the genes of two very large groups of people: one with a disease and a similar group without it. In this manner, we can get an idea of the genetic component, if any, in the acquisition, course and outcome of that disease."

One outcome of all this directly relevant to the reader is personalized medicine. With the knowledge acquired from research into human genetics and our immune systems, medicine will become more customized to the individual, not the one-size-fits-all approach as it is today. If we have certain genetic knowledge of a patient, we can tailor the drugs, therapies, scans, tests, etc. that will work best for that particular person. "Immunogenetics is the way forward," says Prof. Kossida. "It has the potential to be the biggest contribution to the relief of human suffering since Dr. Jenner's work with the small pox vaccine."

Mr. Blackburn can be reached at gringoviajero@hotmail.com

The author wishes to express his deepest gratitude to Prof. Kossida, Mr. Sanou, Dr. Kushwaha, Mr Zeitoun, Dr. Giudicelli, Dr. Duroux and the rest of the IMGT team for their contributions to this article.