Navigating the COVID-19 Pandemic: Glycans, Biological Age and Inflammation with Prof. Gordan Lauc

Podcast published on 7/4/2023 • Show notes written by Vanja Maganjic & Rina Bogdanovic

433 minutes reading time
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Episode summary

In an era defined by COVID-19, understanding the intricacies of our immune response and the profound role our lifestyle choices play in shaping our resilience or vulnerability to future pandemics is of great importance. In this episode, we unravel the influence of glycans, complex carbohydrates instrumental in immune response regulation, on our understanding of COVID-19 susceptibility and severity. We explore the role of lifestyle in disease prevention, particularly focusing on diet and obesity. Gordan Lauc is a Professor of Biochemistry and Molecular Biology at the University of Zagreb Faculty of Pharmacy and Biochemistry and founder and CEO of Genos Ltd. Listen in as he shares valuable insights into pandemic regulations, the spread of misinformation, and vital lessons for the future. 

Conversation timestamps

We Discuss:

• The Role of Glycans in Promoting and Suppressing Inflammation [03:11]
• Biological Age as a Predictor of COVID-19 Severity [09:48]
• Behind the Scenes of Study Design: Stratifying COVID-19 Patients [12:17]
• The Role of Proinflammatory Glycans in COVID-19 Severity [16:24]
• Impact of Lifestyle Choices on Disease Risk [22:22]
• Glycan Biomarkers in Disease Prediction [28:58]
• Biobanking: A Vital Tool in Pandemic Preparedness [41:39]
• COVID-19 Regulations and Responses: A Croatian Perspective [43:48]
• Vaccine Mandates and Universal Masking: Is It Too Much? [50:13]
• Lessons for Future Pandemics [53:51]

 

About the guest

Articles, books, and other media discussed in the show

Biomarkers of biological age as predictors of COVID-19 disease severity | Aging (2020)

Composition of the immunoglobulin G glycome associates with the severity of COVID-19 | Glycobiology (2021)

Differences in Immunoglobulin G Glycosylation Between Influenza and COVID-19 Patients | Engineering (2022)

IgG N-glycome changes during the course of severe COVID-19: An observational study | eBioMedicine (2022)

Altered IgG glycosylation at COVID-19 diagnosis predicts disease severity | European Journal of Immunology (2022)

 

Conversation highlights

"And the other problem is that you know, whenever we look for advice, we get advice for a standard human. A standard human does not exist, there is no standard human. So at the moment, there are some attempts to do things like nutrigenomics, meaning we will look at your genes and tell you what to eat. These things still don't work, one day, maybe. But today, we do not have enough knowledge to say which genetic polymorphism will make a specific diet good for you. The only thing we can do is try it and see whether something works for us. And we cannot see it by looking in the mirror. Because we cannot tell the difference between how we look now and tomorrow. So these biomarkers could actually help motivate people. And it works. So we are doing it already. So the glycans are being used as a personal navigator for longevity by I think over 15,000 people so far globally."

"Inflammation is sometimes good, and sometimes it is bad. And in particular, it becomes worse as we get older. Because one thing we should always keep in mind is that our genome is optimised for a lifespan of maybe 35 years. Because this was the period when humans were getting offspring until maybe 100-150 years ago. So nothing in our genome is optimised to keep us alive after the age of 35. And then the damages start to accumulate. And one of these long-term damages is low-grade chronic inflammation. So inflammation gets out of control. Instead of doing the very important task of destroying pathogens, inflammation starts to cause small little damages all around our body, which then needs to be repaired, which costs a huge amount of energy. And ultimately, it's involved in the development of most chronic diseases we have today. So inflammation is underlying cancer, metabolic diseases, and inflammatory diseases. So too much inflammation is actually what is making us age faster and eventually die."

"We know that approximately 40% of this IgG glycan composition would be heritable. Heritable means it is something we got from our parents, we cannot change it. 60% is changeable. It's affected either by epigenetics or direct environment. So epigenetics is a kind of memory during most of our lifetime, including prenatal life, where information from the environment from our mother is telling our immune system how to behave, and this can be maintained for decades. And then there are environmental factors, meaning if we are overweight, the fat tissue, especially the old fat tissue, does not have maintenance mechanisms."

 

Episode transcript

Rina’s Intro

Rina Bogdanovic [00:05] Hello, hello, and welcome back to GlycanHub - the podcast in which we explore health, disease, and longevity through the lens of glycobiology. My name is Rina, and I am your host. In a world reshaped by COVID-19, recognizing the intricacies of our immune response to such threats, and understanding how our lifestyle choices can tip the scales between vulnerability and resilience in the face of future pandemics, has never been more imperative. As listeners of our podcast, you’ll already know that chronological and biological ages do not always progress at the same pace. And one of the primary determinants of one’s biological age is the level of low-grade chronic inflammation in the body. Glycans on IgG – the most abundant antibody in humans – are considered functional effectors which can either promote or suppress inflammation. My guest today has conducted numerous studies looking at IgG glycans of individuals infected with COVID-19 and tracked the severity of their symptoms – what he found is that there is no such thing as a standard human. There are a multitude of factors which should be considered before giving generalised advice about disease prevention and implementing one-size-fits-all restrictions. In fact, the glycans on IgG could predict how severely the patients were going to be affected by COVID-19 – which offers hope that such measurements could one day be used as prognostic biomarkers and tools for better patient stratification. In this episode, we're offering a retrospective on the Covid-19 pandemic. We're not only comparing the different national responses but also discussing the role of the media in propagating misinformation and contemplating the strategies we could employ to be better prepared for future pandemics. My guest today is a Professor of Biochemistry and Molecular Biology at the University of Zagreb Faculty of Pharmacy and Biochemistry and founder and CEO of Genos Ltd. He is also the chief scientific officer at GlycanAge. His lab performs large-scale studies of the human glycome and genome-wide associations, aiming to understand the role of protein glycosylation in health and disease. His work primarily focuses on plasma glycoproteins and Immunoglobulin G in particular. A warm welcome to Gordan Lauc. Hello and welcome to our Podcast. 

Gordan Lauc [03:08] Hi Rina, thank you for the invitation.

The Role of Glycans in Promoting and Suppressing Inflammation

Rina Bogdanovic [03:11] So we are going to be discussing your research on COVID over the last three years, but I think a good place to start is to set the stage by first talking about inflammation and discussing some of the key terminology when it comes to the immune system. Glycans coat our cells, they are present on most proteins in our body. So, why did you choose to study glycan composition of immunoglobulin G, or IgG, antibodies in particular?

Gordan Lauc [03:39] Antibodies or immunoglobulins have a very important role in our immune system. And glycans have a very important role on antibodies. So, normally, we think about antibodies as a tool or as the weapon which will recognise foreign antigens, molecules or foreign organisms, but after antibodies bind to foreign antigens, the immune system has to mobilise some form of response, different molecular events, which will lead to the destruction of that antigen. And this form of response depends on the type of antigen. So, we'll have a different immune reaction to a virus, to bacteria or to some kind of dietary antigen. And this response is very largely defined by glycans. Because the antigen part, the so-called the FAB or fragment antigen-binding of antibodies is defined very early in our lifetimes. So, we have all these rare combinations. We generate the sequence of amino acids early, and then there is fine-tuning later, but in principle, our repertoire is set early. Before we make antigens, the decision of what to do with antigens has to be made later in life, so once we meet an antigen. And actually, it can change with time. So we can, for example, induce tolerance to some antigens, or we can develop an allergy to some antigens later. And by large, this is done by glycans. So, glycans are so-called post-translational modifications, they're added to antibodies after the protein part is defined. And they modulate, they modify, and they change the structure of the so-called FC domain or the fragment crystallizable region. It's called fragment crystallizable because we could crystallise it in a lab because we have the same sequence in all antibodies. Variable regions have different sequences, but it's also called the constant domain because it doesn't change from antibody to antibody. And this constant domain is binding to different receptors, which then activate the immune response. And adding glycans to immunoglobulins can either promote or suppress the inflammatory response to a given antigen. This is why it is very important.

Rina Bogdanovic [06:20] So now, I think some people might be wondering - if antibodies have a role to play in inflammation, why is it negative to have a pro-inflammatory antibody if they would induce inflammation? Shouldn't we want to have the best response possible?

Gordan Lauc [06:37] Yes, but against the dangerous antigens, we do not want to have an inflammatory response to the molecules which are not a threat to us. So, the immune system has a very delicate role to distinguish between antigens and molecules which are dangerous and those which are not dangerous. So yes, we would like to have the most efficient response, for example, antibodies against the virus, we want to eliminate the virus. But at the same time, we do not want these antibodies to bind to some other parts of our body and then cause inflammation in other parts, because then we call this autoimmune disease. So the balance between adequate immunity and destroying the pathogen and autoimmunity is extremely sensitive and dynamic. So we need to optimise our response to an antigen to have maximal benefit for the entire organism. So sometimes, we want antibodies to elicit a full-scale immune response to kill everything around. For example, this happens when the cell is infected with the virus, the cell is producing viruses, and then our immune system will kill the entire cell to stop it from producing more viruses. And this is good. But if our immune system is making a mistake, and it's killing our own cells, we can have very serious diseases. So inflammation is sometimes good, and sometimes it is bad. And in particular, it becomes worse as we get older. Because one thing we should always keep in mind is that our genome is optimised for a lifespan of maybe 35 years. Because this was the period when humans were getting offsprings until maybe 100-150 years ago. So nothing in our genome is optimised to keep us alive after the age of 35. And then the damages start to accumulate. And one of these long-term damages is low-grade chronic inflammation. So inflammation gets out of control. Instead of doing the very important task of destroying pathogens, inflammation starts to cause small little damages all around our body, which then needs to be repaired, which costs a huge amount of energy. And ultimately, it's involved in the development of most chronic diseases we have today. So inflammation is underlying cancer, metabolic diseases, and inflammatory diseases. So too much inflammation is actually what is making us age faster and eventually die.

Biological Age as a Predictor of COVID-19 Severity 

Rina Bogdanovic [09:48] Excellent. Thank you for introducing the idea of chronic inflammation. In one of your studies, you stated that people with severe COVID-19 had an older IgG glycan composition What is meant by this?

Gordan Lauc [10:01] So this is something actually, David Sinclair and I speculated on in March, and April 2020, when there was initial data showing that COVID is primarily dangerous for the older population. While young people mostly do not have any serious consequences, we said - Yes, but age is not the number of times the Earth circled around the Sun. This is how we measure age because we count it in years. But on a biological level, at the level of the molecules, this does not have to be so, these two ages, biological and neurological do not have to go in parallel. And we know that some people age much faster. And some people will be old in their 50s, while other people will be young in their 70s. And there are even some diseases, where people would age rapidly and they will be old at the age of 15, or something like that. So then we speculated that molecules which measure biological age, and one of these molecules is glycans, could be better biomarkers for people at high risk of severe COVID, than just a chronological age. And this was published as an Editorial in Ageing, I think, in April 2020. At that time, this was speculation. But later, half a year later, we managed to analyse a number of cohorts of patients all around Europe, which had either severe or mild disease. And we did indeed see that people who had a higher GlycanAge or the more proinflammatory IgG glycan composition, were more likely to develop severe disease than the people with a younger IgG glycome, and this was on top of chronological age. So when you correct for chronological age, people at age 60, chronological, if they would have an older glycome, they have a higher probability to get severe COVID than people who had a younger IgG glycome.

Behind the Scenes of Study Design: Stratifying COVID-19 Patients

Rina Bogdanovic [12:17] Now we are going to focus on disease severity and COVID. And I think a good idea would be just to define what we mean by asymptomatic, mild to moderate levels of severity. So if you don't mind, I have taken these from one of your studies and I can read them out so that our listeners know what we mean when we refer to them. So by asymptomatic, we mean individuals who are seropositive for COVID-19, but have no symptoms, seropositive meaning they have COVID-specific antibodies. Mild are individuals with no evidence of pneumonia, but who have typical clinical manifestations such as coughing, fever, loss of taste, and smell, and so on. Moderate are individuals with pneumonia, and severe are individuals with needed hospital intensive care and need intensive invasive mechanical ventilation. And critical are individuals with need of immediate invasive mechanical ventilation, and admission to the hospital intensive care unit or those who have deceased during the hospitalisation. Now, I imagine a great priority when designing the studies, is identifying patients in whom COVID-19 was the main disease. So the severity of their symptoms could not be attributed to any other pre-existing illness. How was this distinction made?

Gordan Lauc [13:36] So this was actually one of the most difficult things we had to do in doing that study. Because, unfortunately, on a global level, we still have problems in distinguishing people who are in the hospital because of an infection with the SARS-CoV-2 virus, and people who are in the hospital because of some other diseases, but just got positive for SARS-CoV-2 virus and globally, there is no solution for that. So what we did in our study, we went in an extremely conservative way. So we collected blood samples for 1000s of patients because, you know, all around the world, there were so many people infected. But then we went very deeply into their clinical conditions, and we eliminated all people from the study with cancers, with active cardiometabolic diseases, so everybody who would be hospitalised because of their other conditions, we just eliminated them from the study. So we really tried to focus only on people where COVID was the reason for hospitalisation. And I think this was very important because, especially now I think, over 80% of hospitalised patients would be hospitalised because of other diseases, they would just randomly have a SARS-CoV-2 virus. So we had clinician specialists, who actually worked in an intensive care unit, going into individual documentation of every patient to see, when was that patient hospitalised and when was the patient infected, because many patients were actually infected during hospitalisation. So if they were already in hospital, and they got COVID later, it's really hard to know whether it's the virus or the disease, which is causing problems. So we only looked at the people who were more or less healthy. It's hard to define health when someone is 80 or 75, but who did not have a severe condition, which would require hospitalisation before. And then after infection with the virus, they ended up in hospital. And then either they had a moderate trajectory, severe or terminal outcome. And then we compared how glycans look and what happens with the glycans in these different disease scenarios.

The Role of Proinflammatory Glycans in COVID-19 Severity 

Rina Bogdanovic [16:24] And what did you find when comparing patients with mild and severe COVID?

Gordan Lauc [16:31] So additionally, we first saw this predisposition element. So people who were more pro-inflammatory at the beginning, they did have a higher disease risk of getting a more severe disease. But also we noticed that the IgG glycan composition was changing during the disease because one of the roles of IgG glycans is to modulate inflammation. So it's kind of a signalling mechanism, which we don't fully understand. But for example, we know if you take immunoglobulins from a young person and give it to an old person it generally suppresses inflammation. This is the so-called IVIg therapy. So we looked longitudinally, so we are collecting samples every few days in hospitalised patients. And then we realised that people with the worst outcome had very rapid changes towards the proinflammatory IgG glycome. So people who made a mistake of making all their immunoglobulins proinflammatory most frequently died. So obviously, the decision of the immune system to make all immunoglobulins proinflammatory somehow was the risk factor, which is logical because most of the people who died of COVID, didn't die because of viral activity. They died because of the response of the immune system, which then caused lung inflammation, and the lungs were filled with the fluid and they were not functioning, and people eventually died because of that. So the role of immunoglobulins to suppress inflammation seems to be very important for a good outcome.

Rina Bogdanovic [18:33] A term that's commonly heard when talking about severe COVID is cytokine storm. Could you explain what it means and how proinflammatory antibodies might impact it? 

Gordan Lauc [18:43] So the cytokines are signalling molecules that are released by the cells of the immune system, they activate other cells of the immune system, and there is this pro-inflammatory cascade, which is activating the immune system to its full extent. To understand it, we have to think about what our immune system normally does. So the normal function of the immune system is, for example, we have some kind of cut in our skin. Bacteria come in, they start to multiply, and they treat us as food. So these bacteria think we are food and they multiply like crazy. And then, what we do is we send all our arsenal of different weapons, the neutrophils to the antibodies and innate immune system there. And many of these weapons we have are not smart weapons. They're dumb weapons, they destroy everything they see. This is what kept us alive for a million years. So if you have a cut and then you have some kind of swelling around and there's more going on, you'll kill some of your cells. You will have new ones, and everything's fine. So the immune system is always overreacting. So when there is a threat, it wants to kill everything. But it also has to be controlled. So we have a control mechanism, which suppresses this inflammation. So the cytokine storm is the mechanism, which is activating the immune response. So when there is a cytokine storm, if it's local, you can have very rapid local swelling, you know, sometimes your hand will be twice the size of normal. But then in a few days, this calms down. The problem is if something like that happens in your lungs because if your lungs get fully inflamed, they cannot perform the function and then you cannot live. We do not fully understand all aspects of the glycans in the suppression of the immune system, we still need to do a lot of research. But there is a lot of evidence suggesting that IgG glycans are one of the signalling mechanisms used to suppress inflammation. So, normally, young people have this very efficiently. So they can have a very rapid inflammatory response, we know that children react like crazy to some kind of infections or even minor inflammatory events, but then they suppress this inflammation very rapidly. So there is a burst of inflammation and then shutting down inflammation. And older people both react slowly, but also suppress inflammation slowly, and this is very individual. So this IgG glycome can be, there are people who are forty-something with the IgG glycome, which is similar to people of nearly 80 years old, and vice versa. So this is an important aspect of the immune system, which is still underappreciated by many immunologists, and we still have to learn everything. So it would be very dangerous to speculate too much. But I think so far we can say it's very important. We know it is important, but it has to be studied more. 

Impact of Lifestyle Choices on Disease Risk

Rina Bogdanovic [22:22] And I think it's very important also for our listeners, who might be panicking now about their pro-inflammatory antibodies to mention that glycan composition is not set in stone, but rather it can be very highly impacted by our environment and our behaviour. So do you think it is safe to speculate that individuals who do have a higher proinflammatory action of the antibodies could potentially reduce it and reduce their risk of severe COVID through lifestyle and behaviour?

Gordan Lauc [22:52] We know that approximately 40% of this IgG glycan composition would be heritable. Heritable means it is something we got from our parents, we cannot change it. 60% is changeable. It's affected either by epigenetics or direct environment. So epigenetics is a kind of memory during most of our lifetime, including prenatal life, where information from the environment from our mother is telling our immune system how to behave, and this can be maintained for decades. And then there are environmental factors, meaning if we are overweight, the fat tissue, especially the old fat tissue, does not have maintenance mechanisms. Because until 50 years ago, nearly no one, not only humans, but also animals would maintain the fat tissue for several seasons, be able to get fat in the autumn, and then get very skinny by the spring. So there is no evolutionary pressure to develop maintenance mechanisms to preserve the old fat tissue healthy. What's happened with the modern diet, is that people kept accumulating fat tissue without losing it in the winter. So that fat tissue starts to accumulate damage, oxidative damage, DNA damage, all types of damage, which promote inflammation, because when there is damage, the immune system comes and kills the damaged tissue, which promotes inflammation. So if somebody is obese, he's always very pro-inflammatory. Also, we are all very diverse, so evolutionarily people evolved to use different types of foods. Some are more adapted to carbohydrates, some are more adapted to fat, and some are more adapted to proteins. And there are no standard humans. And I think the best example, of how different we are, is the pace at which dietary recommendations actually change. Until a few years ago, carbohydrates were the best, you know, you have to eat healthy carbohydrates every morning. Now, carbohydrates are considered to be the worst. And for decades, fat was labelled as bad. Now, we think, again, fat is good, but I think it's very individual. So some people can tolerate carbohydrates. Some people cannot tolerate some fats, and so on. So we cannot make general conclusions. But we can know that if we are eating a diet, which doesn't fit as well, it can also be pro-inflammatory. There is an extremely important element of the microbiome, which we were also ignoring for decades because all bacteria are considered to be bad, we have to kill all bacteria, and we have to live in a sterile environment. But now we know that we cannot live in a sterile environment, we are actually in symbiosis with our bacteria and without our bacteria, we cannot survive. And now we learn even more about the viruses and the millions of viruses, which live in us, which are also symbiotic and help us control the bacteria. So if you mess up our microbiome, ultra-processed food is really messing up our microbiome, because if you think about food, which can stay on a shelf for months, without bacteria growing there. And if we keep eating that food, then the same preservatives, which are killing bacteria in the food, are killing bacteria in us. So we mess up our microbiome, we eat the wrong diet, we do not move, and we don't use our muscles, which then again, can get inflamed. And we can really increase the inflammatory levels a lot. So I think we can do a huge amount of damage to our immune system by doing bad things. But then again, if we stop doing these bad things, then our immune system recovers. So we have clear evidence that losing weight is beneficial. Changing your diet can be beneficial, but there is no magic diet. So there is no one diet, which works for everybody. Physical activity is beneficial, but not too much physical activity, because we were kind of, so media propaganda was claiming, it's not a bad diet, it's just that you're lazy. That's the problem. So we were all taught, you know, you just have to strip out the bad diet, and then you can buy all the junk food, you can buy all the sugary drinks and processed food, just you have to go to the gym. But now we know this is not true. So you cannot set out on a bad diet. And if you exercise too much, you're actually doing damage to yourself. And I think it's very clear when you think about the professional athletes and professional athletes, they will be old in their 30s. Other people are considered very young in their 30s. But a 34-year-old football player is considered to be very old because if you use your body too much, you spend it. You can't use it forever. So too much exercise is not good. Too much food is not good. We need to do everything in moderation and then our inflammatory levels go down. And also our glycome improves.

Glycan Biomarkers in Disease Prediction

Rina Bogdanovic [28:58] Now we have all, during COVID heard who the people with the most predispositions for severe COVID are - obese people, whether it be older people or people with comorbidities, does the same hold true when you're looking at glycan composition? 

Gordan Lauc [29:13] It's highly correlated. So what we see is that yes, older people, obese people, hypertension, and diabetes, all change glycome in this prime inflammatory direction. We are not fully confident about what is the cause and what is the consequence. So obesity is driving pro-inflammatory conditions, but also pro-inflammatory conditions may generate dissatisfaction which then drives kind of urges to eat to make yourself happy because you don't feel happy. So these things are directional, but definitely what we have done in this pandemic has made people more obese. So the BMI increased especially in children, which is horrible. We put people under more stress, which is also horrible. And we made people unhappy. So, all these things are affecting our health. And we are seeing the consequences, we are seeing the mortality rates going up, which we cannot explain. We are seeing drug abuse, violence, and traffic accidents going up, which are all consequences of our decisions to fight the virus, not with our immune system, which would be the best way, but with some kind of restrictions, which actually then didn't do much. But they caused a lot of damage.

Rina Bogdanovic [30:46] Arguably, what we could improve on from a previous pandemic, is developing a better patient stratification method, basically finding a way of distinguishing between patients who are likely to develop severe COVID or a severe version of the disease, and those who will most likely be asymptomatic or have mild symptoms. Do you think that the implementation of biomarkers such as glycans, has the potential of changing and prioritising treatment, as well as maybe amending some of the restrictions?

Gordan Lauc [31:23] In principle, they could. But we cannot use at the moment, the global capacity to analyse glycans prevents them from being used as a global biomarker, but they could be used as a personal navigator. Because imagine in spring 2020, there was a global recommendation, to lose extra weight, eat healthily, not be under stress, and moderate exercise, then we will actually reduce the number of people at high risk. So we will not only stratify people, but we will decrease the total number of people who can have severe disease. And the problem with motivating people to live healthily is that usually, the reward comes after years or decades of making hard decisions. So I have to decide today, to skip the desert to do a little bit more exercise, to try to relax, these are all difficult things to do. And if I will see the benefit only after decades, then I don't have to do it today, I can do it tomorrow, and I can do it next week. So psychologically, these decisions are difficult. But if there is an objective evaluator, which will show you in a few months, whether your hard decisions have actually paid back already, whether you have already decreased your disease risk, and not only for a single disease, for multiple other diseases, then people get more motivated. And the other problem is that you know, whenever we look for advice, we get advice for a standard human. Standard human does not exist, there is no standard human. So at the moment, there are some attempts to do things like nutrigenomics, meaning we will look at your genes and tell you what to eat. These things still don't work, one day, maybe. But today, we do not have enough knowledge to say which genetic polymorphism will make a specific diet good for you. The only thing we can do is try it and see whether something works for us. And we cannot see it by looking in the mirror. Because we cannot tell the difference between how we look now and tomorrow. So these biomarkers could actually help motivate people. And it works. So we are doing it already. So the glycans are being used as a personal navigator for longevity by I think over 15,000 people so far globally. And we see that people, when they get the feedback, respond. So if something works, they keep doing it. If it doesn't work, they try something else, and eventually, they find something which works. So, at the moment I see glycans more as this personal navigator. One day they will become a routine blood test like HbA1c or CRP or such. This will come, the problem is that the technology to analyse the glycans is still not available in the routine labs. So the lab simply cannot do it and then the small number of labs which can analyse glycans definitely cannot analyse millions of samples which are being analysed every day in routine labs. But in maybe a decade, a little bit more than a decade, this will become a routine test. And then what you said could be, right so people could actually, we check glucose, we check blood pressure, to see the risk for cardiovascular diseases for diabetes, we will be checking glycans to see the risk of inflammatory problems.

Rina Bogdanovic [35:34] Now, just to reiterate, what is it that makes glycans so suitable to be prognostic biomarkers? Could you maybe also define the term glycoforms, and how that makes glycans so suitable as biomarkers?

Gordan Lauc [35:52] Glycans are chemical structures, which are added to a specific site on a protein which we'll call the glycosylation site. But different glycans can be added to a given glycosylation site. If we talk about IgG. If glycans have sialic acid on their top, they will become anti-inflammatory. So antibodies carrying these glycans will suppress inflammation. If glycans are made, without sialic acid, and without galactose, they will become more pro-inflammatory. So the same molecule will activate inflammation in this specific case by the lectin pathway, activating the complement and then killing the target, that's very detailed and molecular. So, glycans decide the role of immunoglobulins. And the decision of how a glycan will look is a very complicated decision. So our studies have identified over 40 different genes, which work together to make this decision. And these genes are not genes which make glycans, they're not the assembly line for glycans. These are the genes which regulate our immune system. And then depending on what these glycans have to do, they will make a different glycan. For example, we have studied in three seasons patients with influenza. So patients who were hospitalised because of severe pneumonia caused by the influenza virus. And at the same time, we were looking at patients who were hospitalised with pneumonia, but caused by a bacteria. So the symptoms are the same. We have lung inflammation, it's pneumonia. But in one group of patients, this was caused by a virus, and in the other group of patients this was caused by bacteria. So this is still unpublished, you weren’t able to read this paper. But what we have shown is that glycosylation is different in these two pneumonias. So if a patient goes to the hospital, sometimes it's not so easy to know whether the inflammation is caused by bacteria, or by the virus, you have to do some blood tests. And then often physicians are just guessing whether it's bacteria or virus, but our immune system knows the difference. Our immune system somehow knows that the antigen, which is dangerous, is bacterial or is a viral and then it's making antibodies to be optimised for fighting against viruses, and fight against bacteria. Because we fight viruses and bacteria in a different way. Bacteria, we will attack bacteria directly. And then we will mostly eat that bacteria. So we'll just engulf it and destroy it. When it is a virus, we actually have to kill the cell which is infected, which is dangerous because you know you're killing your own cell. So, you have to be very careful not to kill the wrong cell. And immune system is optimising antibodies by putting different glycans, and different glycoforms of this structure on the immunoglobulins. So, this is also called alternative glycosylation. So, putting different glycans at the same glycosylation site to generate a different molecule, which will do a different work. And also we also did the COVID. We looked at the glycans in COVID, and they also changed but were slightly different than in influenza. So in addition to telling the difference between the bacteria and the virus, our immune system can say - look, this is an influenza virus, look this is a Coronavirus. So these viruses are different. So we are fighting them in a little bit different way.

Rina Bogdanovic [40:03] That was going to be my next question. I was wondering if the glycan patterns which predict severe COVID are similar to those which might predict severe influenza. Or are they completely different?

Gordan Lauc [40:14] We do not have a study predicting severe influenza. So I cannot tell you that. I know that the changes, which happen in severe COVID, are very similar to those which predict severe COVID, but not exactly the same. There are some other aspects. So, you know, we have to be open and say that we still know very little about glycosylation, in general, and also glycosylation in immunity. And we also have to be frank and say that we know very little about our immune system. So, most of the textbook knowledge is overly simplified. So, we present it in a way that we can understand it. But the immune system is actually one of the most complex systems we have. Because, you know, it kept us alive for millions of years against all the pathogens, and pathogens mutate like crazy, they multiply like crazy, and they would really like to eat us. But then eventually, we do manage to defeat them in most of the cases. And this is what our immune system does. And I think we still have to study it for decades before we properly understand all the aspects of the immune system.

Biobanking: A Vital Tool in Pandemic Preparedness

Rina Bogdanovic [41:39] In the review you mentioned, with David Sinclair, you also talked about the importance of biobanking and preparing samples to be used in the future. Have biobanks of COVID samples been made during this pandemic? And are they already being used today to be studied further?

Gordan Lauc [41:54] So there are many biobanks of COVID patients, even in our lab, we have a couple of 1000 COVID patients with different outcomes. And yes, it's very important to study it in the future. One of the problems is that we are neglecting all other diseases because of this single one, which is actually not even so dangerous anymore. But I think it's a good example of how we can learn a lot if we focus, if the entire scientific community focuses on one problem. But there were also problems in focusing, because hundreds of 1000s of papers were published in COVID. And I believe over 90% of them are total junk, they're simply not true. And I think what we have to learn from this pandemic is how to do better science. And even more importantly, how to use scientific information to make decisions because many things were done in the name of science, which had nothing to do with science. So the word science was misused by politicians, by companies to get their personal power or to get profits. And this is very dangerous because people are losing their trust in science. Because when you see science being misused, and you don't understand science, then you can't tell the difference between good and bad science and you just say science is bad. And I think what is happening now in a large part of the world, is that scientists are not trusted anymore. And this is not good.

COVID-19 Regulations and Responses: A Croatian Perspective

Rina Bogdanovic [43:48] Yeah, I think it's a really difficult problem for especially individuals who might not have a good background in science to distinguish what is true and what is, as you said, propaganda. But I think you are quite a unique guest having had experience both as having sat in the advisory panel during the lockdown in Croatia, as well as then also researching COVID. So you've seen it from both perspectives. Now Croatia has had one of the strictest lockdowns at the beginning of the pandemic, and now is one of the more liberal countries. So what was it that led to this change in policy?

Gordan Lauc [44:28] Spring 2020. We're all scared. So, especially for those who work on viruses for a longer time, we know how viruses can be dangerous and how deadly they can be. And then there was a novel virus with a lot of propaganda. Now we know it was propaganda coming out from China that it is dangerous and most of the world shut down. And Croatia had one of the strictest lockdowns in March 2020. But then our government established the advisory panel, which was relatively large. And we started looking at the data. And very soon it was clear. It's mostly older people who are at risk. And the second important element came from New York in April, showing that this virus is not that dangerous, but it is spreading extremely quickly. So we learned that over a third of the population of New York was infected in the first few weeks of the pandemic, meaning that it cannot be much worse than what already happened. And then, we also did a large study to look for the seasonality of the virus because we knew that respiratory viruses are generally seasonal. Nobody knew for COVID, but we did a study, and we showed that actually, hospitalised patients were recovering much faster when the spring came. So already in late April or early May, we made the decision to open the country. So by large because of this study, which we coordinated for the seasonality, we managed to persuade our government that the summer will be safe, and that opening and summer will not cause any damage. And then Croatia fully opened in May 2020. And we were one of the few countries in Europe, which had a normal summer in 2020. And during that summer, the research came from other parts of the world, which indicated that all these restrictive measures which were introduced, were not really very efficient. So that even the shutting down of schools, closing the public transportation, and state home orders would decrease this speed of transmission by 15-10-20%. So you would not save anybody, you would just extend the period when they will get infected by a few days or a few weeks. So we were really actively opposing the pressure from outside and there was huge pressure from the European Union, that all member countries should go into lockdown. And we managed to kind of sideline these requests. And Croatia never had a full-on lockdown, we only had one unfortunate decision to close restaurants and cafes. But this was some complex politics. But for most of the winter, we were still able to live partly normally. And when we look at the final outcomes, especially the first wave, so winter 2020, we were one of the most successful countries in the world, partly because we didn't have a summer lockdown. So a big part of the population got some immunity from the small amounts of virus that was spreading during the summer, then we were hit a little bit more by the delta wave because obviously, this immunity was waning a bit. So then the delta wave was not that good in Croatia. But in the end now, when we look at a couple of years back, none of the countries that were imposing very strict measures really benefited. For example, Slovakia is a similar country to Croatia, they had very strict lockdowns. They were testing everybody with antigen tests very early, and actually, they had more people who died of COVID than Croatia. And while we had a similar problem with viruses, in other countries, Croatia did not cause so much damage as some other countries and when we look at excess mortality now, we are actually better in Croatia today than some other countries that had more strict measures because you know, when you shut down the hospitals, when you scare your people, when everybody's afraid when everybody goes home, you are not diagnosing cancers, you're not diagnosing diabetes, you're increasing the stress level, you're increasing the obesity level and then that’s driving morbidity and mortality for years to come. So we will be paying the price of lockdowns for years. So I think Croatia made good decisions. I think it would be even better if we had less restrictions. So I think that Sweden did the best job. So when we look now, at Sweden, they did the best job and nobody really benefited from the restrictions and the damage was horrible. 

Vaccine Mandates and Universal Masking: Is It Too Much?

Rina Bogdanovic [50:13] With all of the information which we now have available about COVID-19, what are your thoughts about continuing vaccine mandates or limitations to enter countries based on vaccination status, or universal masking?

Gordan Lauc [50:27] Mandating a vaccine is a very radical decision. And we have to be very sure that there is a huge benefit and very little risk. So the problem with this mRNA technology is that we still do not know all the risks. So it's not good to mandate when you don't know the risks. And the second aspect is, we have to, you know until the COVID, you would never vaccinate somebody who had the disease. Because it's, it's just absurd. So if you had the disease, you develop immunity, why would you vaccinate? And we were mandating vaccination of people who were previously infected without any evidence of benefit, and with known potential harm. And I think these were the wrong decisions. And universal masking can be beneficial in a short period of time, and if used properly, of course. I was one of the first people who were actively promoting and lobbying for the use of masks. But they're not efficient in the long term. So for example, masks in schools are completely inefficient, with no benefit. And there is harm. Masking, even younger children, no benefit, and there is harm. So I think it's very important to balance benefit and harm. And we still don't know what is actually the harm of a long-term decrease in exposure to different environmental antigens. So we know that all organ systems in our body have to be active, to develop. So if we don't exercise our muscles deteriorate, if we don't use our brain we're losing cognition, so if we don't use our immune system, what happens with our immune system? And it's very, very risky to experiment on a population level. So what will happen for example, in the US states, which had universal masking compared to states, which didn't have it? It will take years to see the consequences. So if somebody is mandating something, masks or vaccines or any other drug or anything, that person or organisation have to be very certain of the consequences. And now, we don't have that because we don't have sufficient science to say what is going on. And the decisions are made mainly based on lobbying. And the problem with lobbying is that the one who has more money has more lobbying power, and this is not the way medical decisions should be made.

Lessons for Future Pandemics

Rina Bogdanovic [53:51] I agree. I think we are only now beginning to realise the damage that was potentially done, especially to children, both in their education as well as the development of the immune system and just normal physical development. So yeah, hopefully not very severe. We'll see in the coming years. When it comes to research, about COVID, especially research in your lab, what is next, what are the next open questions?

Gordan Lauc [54:18] I think we need to use this situation of so many people being infected, vaccinated, and treated with different therapies to try to understand how the immune system works. So we will definitely use these large cohorts of people which we have who were either infected or vaccinated or vaccinated and then infected and so on, to try to understand the basic functions of the immune system, so that we know more when something like this happens again. Because viruses are evolving. So just a few days ago there was a paper suggesting that the Omicron variant actually evolved in the mice. So not in some kind of South African human population, but in the mouse population. And we will always meet new viruses. And a new virus can be a small threat or can be a large threat because we should not forget the so-called Spain flu. And the pandemic in the 20th century killed many people and killed many young people. For example, in my family, my grandfather lost I think, two brothers and a sister in a week. And that was really horrible. So we have to be aware that viruses will evolve, that there will be new pandemics. And that we have to find a way how to use our immune system, how to help our immune system, to fight viruses, and not destroy society, because we are afraid of a virus. Because if we do more damage with our response, then what is the benefit? We shouldn't be doing it. And I think, now we have to look back and really decide what was good, and what was bad, and what we should be and what we shouldn't be doing in the future. And this is not an easy discussion or easy decision because people invested lots of their authority in specific decisions, and it won't be easy for them to change their minds. But the good thing is that we have different countries, which have different responses. Also within the US, we have different states with very different responses. So we can easily compare, and actually make a good scientific conclusion. What was good and what was not good.

Rina Bogdanovic [57:03] Excellent. Thank you. I think this is a perfect place to finish our conversation today.

Gordan Lauc [57:09] It was a pleasure chatting with you.

Rina’s Outro

Rina Bogdanovic [57:10] Thank you very much for joining. Now speaking to our listeners, I hope this conversation provided clarity for some lingering questions surrounding the COVID-19 pandemic. If there is one thing I would like for you to take away from this conversation it is that daily lifestyle and health decisions do matter and have a huge potential to reduce your susceptibility to infectious and chronic diseases alike. If you would like to access more information about this conversation and Gordan’s previous work, follow the link in the description to the show notes for this episode. Equally, if you want to find out more about GlycanAge, head on to glycanage.com where you can access a whole list of our scientific publications, blog posts, testimonials and of course this is where you can order your GlycanAge kit. Watch out for our next episode where I will be joined by Louise Newson, a renowned menopause specialist, who is aiming to increase knowledge about menopause and perimenopause, she also campaigns for better menopause care for all women. We will be unravelling the wider implications of menopause on health and its role as a female hormone deficiency. Please don't forget to leave ratings and reviews for this episode and engage with us on social media. Thank you for listening and have a great day.

 

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Disclaimer

Please be advised that this show is for information only and should not be considered as a replacement or equal to medical advice.