by Aleks Prochera
figures by Shreya Mantri
The past year and a half have been a time of profound uncertainty. We all wish we could gaze into a COVID crystal ball and get answers to our burning questions. Some of us would want to know how long the pandemic will last. Others, however, especially those who have never received a positive result, would likely seek an answer to a more personal question – how would infection with SARS-CoV-2 affect me?
Suppose you are eighty years old and suffer from type II diabetes. In that case, you have a partial response to that question – your chances of serious illness are relatively high. If you are a healthy thirty-something, on the other hand, statistically you are less likely to experience severe COVID-19. Yet, we’ve all heard of young people who ended up in the ICU despite their weekly gym visits and impeccable health history. If not age, pre-existing conditions, and socioeconomic status, why is it that some otherwise healthy people end up in hospitals with their bodies shuttered by the infection?
Although (to my knowledge) no COVID crystal balls exist, scientists and patients from all over the world are teaming up to figure that out. One answer to this question, it turns out, is written in four letters – A, C, T, G; the letters that make our genetic code.
Infectious diseases – it’s not all about microbes
Since its conception, the field of infectious disease has centered on microbes. In contrast to genetic disorders, which have been known to result from mutations in the genome one is born with, infectious diseases have been known to be caused by external villains – bacteria, fungi, and viruses. The equation was simple – when attacked by such villains, we, the hosts, succumbed to the infection and developed diseases.
Over time, our understanding of what causes one to get sick evolved tremendously. It turned out that microbes are not the whole story; our bodies’ behavior when exposed to a pathogen is as important as the nature of the pathogen itself. And this behavior – what happens inside us when external villains strike, is shaped by a variety of factors (Figure 1).
Even with this expanded view of infectious diseases, however, it seemed that something was missing. Although age, disease history, diet, or medications could explain many of the differences in how people experienced infections, these factors fell short of accounting for the extremes of infection outcomes. Specifically, why some people don’t get sick when exposed to pathogens and why some suffer greatly with supposedly benign infections remained a conundrum. It has only been in the past few decades that scientists started to shed light on these questions. The answers, it turned out, have been within us all along – they are encoded by our own genomes (Figure 1).
Genetics matters – the case of P
One of the cases that brought genetics to focus in the field of infectious disease has been the case of a two-and-a-half-year-old girl called P (“P” being used to protect her privacy). In early 2011, P was brought to the hospital with fever, severe cough, and difficulties breathing; her condition quickly got worse. In search of the reason for her deteriorating state, the doctors pricked and probed, testing her for various bacterial and viral infections. The only hit – the influenza virus.
For most of us, the word influenza brings to mind the annual flu – muscle aches, fever, fatigue. For others, however, infection with this virus is a matter of life and death. P turned out to be one such patient. Fortunately, after a grueling three weeks in the hospital, having been put on mechanical ventilation and various medication regimes, P was brought back to health and released home. Her case, however, puzzled everyone.
Over five years later, that puzzle was on the mind of Jean-Laurent Casanova, a scientist-clinician who, for decades, has been studying the influence our genomes have on how we weather various infections. Having previously discovered genetic underpinnings of severe cases of other infectious diseases, so-called inborn errors of immunity to infections, Casanova wondered: could the life-threatening infection that P had undergone have anything to do with what’s hidden deep within her cells?
To answer that question, he and his collaborators asked P’s family to participate in a study that would dive into their genetics. With their consent, they collected not only P’s blood but also her parents’. The scientists then returned to the lab to isolate and sequence everyone’s genetic material. From then on, the efforts moved to the computer bench, where the bioinformaticians took over. Working with gigabytes of genetic data, they zoomed in on various regions of P’s and her parents’ DNA, comparing them to other healthy individuals, looking for meaningful differences.
After long days at the lab benches and in front of computers, the results emerged. Both P’s parents carried a single mutation in a specific gene, an integral component of the antiviral machinery that protects the organism against viral invasion. P, in turn, came to inherit two faulty copies of that gene, one from each of her parents. Further laboratory investigation revealed that, indeed, it was these changes in P’s genome that likely caused her to succumb to life-threatening influenza a few years back.
Genes and COVID
Fast forward to 2020. While most of us were checking news and hunkering down in our homes, biomedical scientists have been gathering on Zoom and venturing into their labs to try to better understand the disease caused by the newly emerged coronavirus – SARS-CoV-2. The early epidemiological data suggested that certain factors, including age and sex, as well as specific conditions, such as type II diabetes, predisposed one to a severe case of the disease. Since the beginning of the pandemic, however, cases of otherwise healthy, young people who underwent life-threatening COVID-19 pneumonia have been reported in the medical literature, media, and passed as cautionary tales. Such cases were something experts in the study of genetic underpinnings of susceptibility to infectious diseases have seen before. Could it be, the scientists wondered, that at the base of those cases laid an error in the genetic code, not unlike the one discovered in P?
With this guiding hypothesis, an unparalleled international collaboration was formed. Formally known as The COVID Human Genetic Effort (Figure 2), the initiative united scientists and clinicians who shared a goal of finding inborn errors of immunity that led to life-threatening COVID-19.
From the USA to France, Italy, and hospitals worldwide, scientists and clinicians searched for individuals willing to participate in the study. Over six hundred patients who ended up in the ICU, even though on paper they should have exhibited at most moderate symptoms, were recruited. Almost as many individuals who had undergone COVID-19 with little or no issues were also enrolled in the study.
In a span of several weeks, teams around the world collected and processed patients’ samples. Then, the bioinformaticians took over. Using the results from previous studies, including P’s case, they narrowed down the analysis to specific “antiviral” genes, thus advancing the project in a record time. After only a few months, a time span shorter than it took to crack P’s case, the results were in. In a paper published in October 2020, the scientists reported the discovery of mutations in a fraction of the individuals with severe COVID-19. The sequences encoding components of the same antiviral machinery that P’s mutations were found in turned out to be altered in some severe COVID-19 patients. Based on this and other studies, these changes are likely to blame, at least partially, for a fraction of the observed severe cases of SARS-CoV-2 infection.
From bench to bedside and back
Do these results make genome sequencing the scientific equivalent of gazing into a crystal ball? Not really — or better said, not yet.
For one, even though the price of partial or whole genome sequencing dropped significantly since the early days of this technology, the practice is by no means widespread in the clinic. More importantly, the discovered mutations account for a small fraction of life-threatening COVID-19 cases; there are likely numerous other genes that shape how we respond to this novel coronavirus.
The discoveries from these studies, however, are a significant contribution to our understanding of basic immunology. The findings from both the single case study of P and the massive collaboration of The COVID Human Genetic Effort solidify our knowledge of how our bodies respond to infection and have the potential to provide new insights into the workings of our immune systems.
Of as much importance is the fact that such investigations advance how we think about therapeutic approaches to the disease. The insights from this and other studies have the power to shape the nature of treatment patients receive and have already informed how we treat individuals with severe symptoms of the infection. So though you might not be able to peek into your “COVID future”, you can be sure that researchers around the world are doing their best to make sure it’s as bright as it can be.
Aleksandra Prochera is a Ph.D. student in the Harvard Immunology Program. You can find her on Twitter as @Aleks Prochera.
Shreya Mantri is a PhD student in Biological and Biomedical Sciences at Harvard Medical School.
For More Information:
- Want to know more about how genetics shape individuals’ response to SARS-CoV-2? Check out this webinar professor Cassanova gave on that topic.
- Interested in finding out what exactly is the machinery that is so important in the fight against viruses that its dysfunction increases one’s risk of severe viral disease? This article provides a short and sweet overview of these antiviral tools. You might also want to read this piece which dives into the clinical importance of these molecules in the fight against SARS-CoV-2.