Lluís Montoliu: “No one suffers from Covid in the same way. At the genetic level, we still don’t know why”
At MAPFRE, we are committed to scientific research. As such, we approached experts in genetics from the CSIC (Spanish National Research Council), Lluís Montoliu (*), Chairman of the organization’s Ethics Committee, and Anna Planas (**), researcher at the Barcelona Institute of Biomedical Research (IIBB-CSIC), to discuss some questions related to genetics and serious cases of COVID-19, the most advanced technologies and the latest advances in genome editing and epigenetic understanding. Like all the scientists consulted, they are calling for a firm commitment to research.
How do genetics relate to the effects of COVID-19?
Lluís Montoliu: A lot. Everyone experiences a different severity of COVID-19. Unfortunately, around 1 percent of cases resulted in fatalities. Some people have a genetic predisposition to develop a severe case of COVID-19. However, others are able to keep the virus from replicating in their body without showing any symptoms. There are various different projects (financed by the Carlos III Health Institute, led by Pablo Lapuncina and Ángel Carracedo), studying cohorts of people who have had the virus asymptomatically or with minor severity, as well as those who had to go to the ICU and have died. This involved analyzing their genomes to see if there is a correlation between this different evolution of the disease and certain genetic variants. This falls under the so-called Precision Personalized Medicine, which seeks to treat patients, not diseases. This is what genomic and epigenetic techniques can provide us: discovering the genetic background and the multiple genetic variables that are present in a person, which, by chance, determine whether they are more or less resistant to the virus. In volume 3 of the white paper (The researcher is a coordinator of Vol. 3 of the CSIC’s white paper on Genomics and Epigenetics), we discuss different aspects of genomics and epigenetics, which by nature are important in understanding these differences in COVID-19, though we still don’t understand why they occur. We must continue to investigate. No one suffers from Covid in the same way.
Phylogenetic estimates suggest that zero infections could have been achieved in October 2019. Haven’t the last five months felt like an eternity in terms of the spread of the virus?
Anna Planas: Even though it was not my focus of research, I became interested in the subject from the outset, when concern among society wasn’t yet a reality. I was seeing the news about the virus in China and I found it rather worrying. That piqued my interest in this topic. Some characteristics of this infection were curious: Why do some people suffer from the disease so severely and others are asymptomatic? We now think that this is likely to happen in other infections, although there aren’t usually infections at a pandemic scale that affect so many millions of people at one time. We also had never observed an asymptomatic case of flu before. Within the CSIC and the Hospital de Sant Pau and the Clinic, we began to think about studying it and, like many other scientists around the world, are working on studies that relate genetics to the disease. What lies ahead is to find out what percentage of serious cases can be explained by genetic causes. A recent seminar discussed how genetics could explain up to 50 percent of severe cases. That is perhaps on the high end, but genetics clearly plays a key role in explaining serious cases, particularly genetic alterations in the type I interferon pathway.
Where does the immune system fail and what role do interferons play? The virus itself has mechanisms to reduce the production of interferons. When produced to a lesser extent, does this give the virus an advantage?
Anna Planas: Interferons are a weapon we have to fight viruses. They are our first containment measure and an essential protein in our defense against viral infections. We have seen that people unable to develop a good interferon response, because they have a mutation in a gene in the type I interferon pathway, for example, have experienced more severe cases. We continue learning more and more, and studies currently underway will find more genes involved in the clinical severity of COVID-19. The signaling or response pathways are very complex. It’s not just a gene, the interferon pathway is the front line, but a complete accompanying response is then needed. If any step along the way does not work, the response to the virus is highly reduced. That is the crux of the matter. Genetic factors will be discovered in people who, for example, have a small gene variant that makes them less efficient in fighting the virus. In addition to genetic factors, if we add age and risk factors with vascular and cardiovascular morbidities, etc., the risk of developing severe COVID-19 increases. Genetic risk is certainly an important factor.
Where do we have to be most vigilant, with the elderly, the immuno-compromised, or another group that should be more protected?
Anna Planas: There are factors involved that are emerging but are not fully understood. The virus not only attacks the lungs, but the entire body. The virus binds to a protein called ACE2, which serves as a gateway for the virus to enter our cells. ACE2 is not only expressed in the lungs, although this is the most severely affected organ and is usually fatal. In some people we are seeing that the virus causes other long-term complications, thrombotic phenomena, etc. This virus seriously affects endothelial cells, which line our blood vessels. Diseases that lead to a weakened vascular system, such as diabetes mellitus or cardiovascular disease or morbid obesity (these people may have basal inflammation which could perhaps be conducive to a cytokine storm), are a huge risk factor.
Where do we stand in terms of genetics?
Lluís Montoliu: Expect treatments to become increasingly personalized, and for there to be personalized medicine. Knowing if a person has genetic determinants that will presumably cause them to develop a more serious Covid is very important. If we know this in advance, we can start treatments and prepare this person to prevent failure. The same is true for any type of cancer or any type of rare congenital disease. If a treatment exists, if we know what the mutation is and the person’s genetic variety, and we know the other genetic varieties of the genome, we can give them an appropriate, personalized treatment. In the immediate future we can expect—and in many cases this is already a reality—that women with breast cancer, for example, will receive treatment tailored to the genetic variants they have, which will be known following a quick biopsy to give them what they need. That is one of the benefits that genomics has provided.
To what extent are genetics responsible for the most lethal diseases compared to life habits?
Lluís Montoliu: There are many types of diseases. In monogenic and congenital diseases, a single gene is capable of producing a pathology. Here, the genetic origin is unquestionable. Then there are very complex diseases, such as arthritis, Alzheimer’s and diabetes, whereby we can have a genetic predisposition, but interaction with our environment and surroundings can either stimulate them or protect us from them. Different elements come into play here, such as age and aging. The older we are, the more likely we are to develop a cancer. Other factors include our lifestyle—if we are sedentary, we’ll likely develop cardiovascular problems sooner— as well as our diet or where we live, whether in the forest or in a city. Not everything is genetic. As people, we have a lot to do to prevent the onset of disease. Improve our diet, exercise, avoid drug abuse, etc. This is the complex interaction of our habits with genetics.
In the future, will we be in completely different circumstances in the event of any other pandemic?
Lluís Montoliu: It would be a stretch to say “any other pandemic.” Viruses have been part of the world for much longer than we have. They have demonstrated their ability to adapt in multiple circumstances. The next may well be a virus that has little or nothing to do with it. Hopefully we will be able to leverage some of what we know now to recreate a preventative vaccine or proactive treatment or antiviral strategy as quickly as possible. We must remain committed to science being strong and there being enough investment even in matters that today may seem “exotic.” Luis Enjuanes spent 35 years working with coronaviruses. A large part of the population had never even heard of them and some people might well ask why continue investing in Luis’ lab? But thanks to continued investment, he was the first to determine what happens and which are the best vaccines that can be developed.
What unknowns still need to be cleared up?
Anna Planas: Every time a gene is found to be associated with the clinical severity of the disease, there is still a long way to go before understanding how that relationship works and finding out why people who have a genetic deficiency or alteration suffer from a disease more seriously. We need to study how that gene works, what the coding protein is doing, how it relates to other proteins, how the cells respond. There’s so much to do! Different CSIC groups, such as the CNB (National Centre for Biotechnology), with Marta López de Diego, collaborate as a team to work with the virus, and infect cells in which the deficiencies or gene variants detected in patients can be reproduced. In reality, we can learn a lot from biology to unravel the underlying molecular mechanisms and identify possible therapeutic targets, ways to prevent the virus from spreading, find possible treatments. Research, not just current research, but knowledge accumulated over many years, notably in AIDS, has allowed antivirals to be developed that have been used to treat COVID-19. Research has enabled us to obtain COVID-19 vaccines in record time. Research will always help us tackle new infections in the future. Covid has shown how vulnerable we are to a viral infection that can change the lives of the entire world.
What have we learned?
Anna Planas: It’s amazing what has been achieved: developing Covid vaccines, which are already proving their effectiveness, in just one year. For example, the Pfizer and Moderna vaccines, which are messenger RNA-based, are an entirely new technology (for which Katalin Karikó might even be a Nobel Prize candidate) that will allow for a new generation of vaccines not only for this virus, but for other viruses too. At the moment, all approved vaccines seem to be very effective against COVID-19, but we don’t know how long the immunity will last. This is something we’ll only find out over time. There may be variability in the vaccine response that may have a genetic component. We don’t know whether the duration of immunity will be the same for everyone. We also can’t rule out whether future mutations in the virus will require regular vaccination, as is the case with the flu virus. However, new COVID-19 vaccines are being developed, here at CSIC too, that are still being studied and will have a wider spectrum of action and are expected to provide immunity even when the virus undergoes specific mutations.
For us, the lesson is clear: we are researchers, but the situations in which we work are very precarious. The lesson is that we must not lower our guard, we must invest in research. I think the population has learned a lot during this time. However, what is most concerning is that vaccination will not reach everyone equally. It will take time for the global population to achieve immunity, as there will still be areas of the globe where it will take years to vaccinate the whole population.