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Should You Stop Eating Red Meat? Glycans, Inflammation, and Cancer with Prof. Vered Padler-Karavani

Podcast published on 8/8/2023

Evolution had never been able to invent a cell, whether it's a virus, bacteria, yeast or mammalian cells, that would not be covered with sugar. - Prof. Vered Padler-Karavani

32 minutes reading time
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Episode summary

Could your steak dinner be tricking your immune system? In this episode we shed light on the connection between specific foods and colorectal cancer. Explore xeno-autoantigens, grasp the nuances of immunotherapy, and question the reliability of animal-derived heart valves. Vered Padler-Karavani is the principal investigator in the Department of Cell Research and Immunology at Tel Aviv University. Her research combines glycobiology, immunology, bio-nanotechnology, cancer research and xenotransplantation. Tune in to uncover the hidden connections between glycans, our diet, and the potential health repercussions.

 

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Conversation timestamps

We discuss: 

  • Why study Glycobiology [01:35]
  • Xeno-autoantigens & Xenosialitis [03:16]
  • Where Does Neu5Gc Accumulate? [06:33]
  • Red Meat & Colorectal Cancer [10:28]
  • Tumor-associated Carbohydrate Antigens [11:54]
  • Immunotherapy: Potential & Limitations [13:22]
  • Animal-derived Heart Valves: Safety & Efficacy [20:02]
  • Navigating Safety Regulations for Biologic Therapies [31:27] 
  • Neu5Gc in Foods: The Gcemic Index [34:14]
  • Does Prof. Vered Padler-Karavani Still Eat Red Meat? [37:23]
  • Neu5Gc as Biomarkers [38:08]

 

About the guest

Vered Padler-Karavani

Vered Padler-Karavani

Prof. Vered Padler-Karavani is a distinguished biochemist with a PhD from Tel Aviv University. After gaining valuable experience in her postdoctoral training with Prof. Ajit Varki at The University of California, San Diego, she founded The Laboratory for Glycoimmunology at Tel Aviv University. The crux of her research blends glycobiology, immunology, bio-nanotechnology, cancer research, and xenotransplantation, leveraging the latest technologies in these fields. With several esteemed grants from the European Commission under her belt, Prof. Padler-Karavani has led comprehensive investigations into the immunology of carbohydrates. Notably, she was part of the TRANSLINK health consortium, probing into the risk factors of animal-derived heart valve implants in around 5,000 patients. Currently, her research centers around understanding the mechanisms of glycan immune recognition and responses in both animal models and humans. She is particularly interested in the immunological foundation of anti-carbohydrate antibodies, their effects on cancer and heart diseases, and the development of innovative diagnostics and treatments for these diseases.

Follow Vered on social media:

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Twitter 

 

Articles, books, and other media discussed in the show

Prof. Vered Padler-Karavani Lab: News & updates 

Video: Association between Neu5Gc carbohydrate and serum antibodies against it provides the molecular link 

The role of antibody responses against glycans in bioprosthetic heart valve calcification and deterioration | Nature Medicine (2022)

The role of antibody responses against glycans in bioprosthetic heart valve calcification and deterioration | Nature Medicine (2022)

Association between Neu5Gc carbohydrate and serum antibodies against it provides the molecular link to cancer: French NutriNet-Santé study | BMC Medicine (2020)

Directed Evolution of Therapeutic Antibodies Targeting Glycosylation in Cancer | Cancers (2020)

 

Conversation highlights

"So in fact I invented this term [xeno-autoantigens] when I was in Ajit Varki’s lab. We investigated the sialic acids called Neu5Gc where Ajit at the time, wanted to investigate the differences between men and chimps. And one of the key things that he found is that while chimpanzees and other mammals can synthesise these non-human sialic acids, humans miss them or are genetically deficient in the gene that is synthesising Neu5Gc. So, besides that genetic difference, there were a lot of implications. And one of the big things that even only recently we could really prove is that when we consume mammalian-derived foods, we get Neu5Gc into our bodies, and that affects our immune system, we find Neu5Gc. Although we cannot synthesise it in our body, we can still find Neu5Gc accumulating mostly in cancer tissues. And the only source for that would be the diet. But our cells are self and the Neu5Gc is presented on self glycans, but it's actually a non-self, a moiety. So the term Xenoauto means that Xeno is different from a different organism, auto means self. So it’s presentation of non-self sugar in the context of self glycans. And that's why we get auto xeno antigens that can be recognised by xeno-autoantibodies that bind to these non-human sugars." 

"We know that all cells are covered with a thick layer of glycans. And these glycans are really sugar chains, and these sugar chains can be conjugated to proteins and lipids. And in fact, evolution had never been able to invent a cell, whether it's a virus, bacteria, yeast or mammalian cells, that would not be covered with sugar. So this is really, really important. But what we know is that in cancer, the sugar coating is different. So the sugar coating of cancer cells is different than that of normal human cells. And it's not simple because you don't have one gene that will determine the sugar coating, actually it relies on a complex metabolic pathway which have a collection of enzymes each taking one sugar unit at a time to assemble these long sugar chains and in cancer, there are specific mutations or changes to these metabolic pathways that lead eventually to a differential sugar coating on cancer cells. And that could be used for diagnostics and therapy for cancer."

"If the patient had the first surgery [transplantation of animal-derived heart valves] at 65, then 10 years later, it will function which means he would be 75 and at 75 to go through another surgery that must be devastating. And what you ask is something that all the physicians and the cardiologist that actually run the surgery asked me - How do you know that you still have Neu5Gc, the tissue may come from the pigs, but it's in the body for 10 years, maybe that had been removed. And actually, to address that we took the explanted valves in patients that had to have that valve removed. In order to replace it again, because it malfunctioned. And there we quantified the Neu5Gc, we found that at least 20% of the original amount of the sugar is still there, even after 10 years or 12 years within the body, it's still there. And the antibodies are also found within those tissues in the explanted valves."

 

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. Is your diet tricking your immune systems? Today, we will be talking about xeno-autoantigens. Now, you might already know that antigens are molecules, or substances that our antibodies can recognise. Very often, they are foreign, which allows our immune system to defend the body. But let's go back to the term xeno-auto, xeno meaning foreign and auto meaning self. So how can something be both foreign and originate in our own body at the same time? You might be surprised that the answer to this paradoxical question lies in the consumption of red meat. This discussion on xeno-auto antigens will take us far beyond diet, from colorectal cancer, innovative immunotherapies, all the way to animal-derived heart valves. My guest today is the principal investigator in the Department of Cell Research and Immunology at Tel Aviv University. Her research combines glycobiology, immunology, bio-nanotechnology, cancer research and xenotransplantation. A warm welcome to Vered Padler-Karavani.

Vered Padler-Karavani [01:35] Thank you.

 Why study Glycobiology

Rina Bogdanovic [01:37] So before we get into our discussion, I want to know how you first got involved in glycobiology research. And how come you decided to stay in this field?

Vered Padler-Karavani [01:42] So actually, when I graduated, with my PhD from Tel Aviv University, I was thinking about what would be my next thing. And at the same time, there was a big publication in science talking about glycoscience. And I was truly amazed. I didn't know anything about it, I started reading. And then I started reading more. And I found that in San Diego, there was a big hub for glycobiology. One of the key players there was Ajit Varki. And I went to an interview in his lab and I really, really liked it. So I decided that this would be my next big thing. And at the same time, I also knew that in Israel, there will not be many glycobiologists, and this field would benefit from having that expertise brought back to Israel. So that was the key.

Rina Bogdanovic [02:34] And how is the situation right now with glycobiology research in Israel? Besides your lab, of course.

Vered Padler-Karavani [02:40] There are a few labs, but we still miss a national effort to leverage the glycobiology, as we see in other countries, like in the United States and England, or, you know, in other countries where you have national resources and facilities, we don't have it here. But people that try to or stumble upon glycobiology know to contact me, and then I can deliver the message or refer them to other people in the field. And, yeah, so it's great to be one of the leaders in Israel with that.

Xeno-autoantigens & Xenosialitis

Rina Bogdanovic [03:16] Amazing. We have a pretty interesting discussion today. It's a very interesting topic. So I thought a good place to start is by defining some of the key terminology. So could you define what we mean by xeno-autoantigens and Xenosialitis?

Vered Padler-Karavani [03:29] So in fact I invented this term [xeno-autoantigens] when I was in Ajit Varki’s lab. We investigated the sialic acids called Neu5Gc where Ajit at the time, wanted to investigate the differences between men and chimps. And one of the key things that he found is that while chimpanzees and other mammals can synthesise these non-human sialic acids, humans miss them or are genetically deficient in the gene that is synthesising Neu5Gc. So, besides that genetic difference, there were a lot of implications. And one of the big things that even only recently we could really prove is that when we consume mammalian-derived foods, we get Neu5Gc into our bodies, and that affects our immune system, we find Neu5Gc. Although we cannot synthesise it in our body, we can still find Neu5Gc accumulating mostly in cancer tissues. And the only source for that would be the diet. But our cells are self and the Neu5Gc is presented on self glycans, but it's actually a non-self, a moiety. So the term Xenoauto means that Xeno is different from a different organism, auto means self. So it’s presentation of non-self sugar in the context of self glycans. And that's why we get auto xeno antigens that can be recognised by xeno-autoantibodies that bind to these non-human sugars. 

Rina Bogdanovic [05:17] Sounds like a very confusing situation for our immune system.

Vered Padler-Karavani [05:21] Very. And in fact, there have been a lot of studies, especially in mice, but then later on in my lab, we did a lot of work in humans actually to show that condition, this ongoing war between our immune system and our cells. So the cells take up Neu5Gc, as a Trojan horse and presented in the context of nonself. Our antibodies try to recognise something that is different from pathogens or invaders. So Neu5Gc in that respect is an invader. And therefore when we develop antibodies, these antibodies try to bind and attack tissues that are expressing Neu5Gc, and that's where we discovered, Ajit actually took the lead in that and defined the term Xenosialitis. That's an inflammation against this xeno glycan that is presented in the context of self. So our bodies tried to attack this invader Neu5Gc, and it resulted in a puzzling situation.

Where Does Neu5Gc Accumulate?

Rina Bogdanovic [06:33] I'm curious about which human tissues are most affected by the accumulation of Neu5Gc, and how does that correlate with the diseases which are associated with red meat consumption?

Vered Padler-Karavani [06:43] it appears to accumulate in cells that divide rapidly. So of course, the common cells would be cancer that they lost control over division. And we also know that in cancer, there is overexpression of this sialic acid transporter, SiaT, that then incorporates the Neu5Gc even faster, although cells can also take up this sialic acid by macropinocytosis. Basically, they drink the media, where they can take up the glycans or glycoproteins or glycolipids. And yeah, so cancerous cells mostly, but the other cell types would be endothelial cells or cells that divide rapidly.

Rina Bogdanovic [07:27] Now, you said it is a pretty confusing situation, as it says, xeno-autoantigen. So, is autoreactive inflammation, autoimmunity, commonly associated with Neu5Gc? 

Vered Padler-Karavani [07:41] See, I can say that many years ago, Neu5Gc was defined by Hanganutziu-Deicher a moiety. And based on the discovery, of these investigators, that's the names of the investigators. And at the time, although they didn't know exactly what was the antigen, they thought maybe it would be only the glycolipids that contain Neu5Gc, now we know that it's much more broad. Then they discovered this HD antigen in many different types of diseases, the antigen and the antibodies, in autoimmune diseases in many chronic inflammation diseases and later on, it was also shown in more sophisticated tools that these antibodies really play a role in cardiovascular diseases in other types of autoimmune diseases, some in diabetes as well. And in cancer, of course, so whenever you have the antibodies, it basically mediates chronic inflammation that could support cancer growth. But on the other side, it can also be used as a therapeutics if you use it as a good and high amount of levels, high-affinity antibodies, then this could be turned into a supportive treatment rather than a devastating disease.

Rina Bogdanovic [09:15] Could you please comment on what are some of the other theories for red meat associated with disease risk?

Vered Padler-Karavani [09:21] There are many explanations in terms of red meat and disease. The most common one we know is cholesterol which is associated with heart disease but of course, there are many others like TMAO and different compounds when you grill the meat. There are many theories but what I can say is none of these theories was specific for red meat. But then recently we found that the level of the antibodies that we can find within humans is associated with a level of red meat and that could explain the association between cancer risk and red meat consumption and that would be specific for red meat or mammalian-derived foods in general. So the level of Neu5Gc that is consumed could be linked to the level of antibodies that were key to understanding where you have one explanation that would basically summarise many different types of diseases, including cancer.

Red Meat & Colorectal Cancer

Rina Bogdanovic [10:28] I think it would be interesting if you could tell us a bit about global trends in statistically looking at the correlation between colorectal cancer in particular, and red meat consumption.

Vered Padler-Karavani [10:40] Thank you. That's a very good question. Because when we started to investigate that, we actually looked at databases for red meat - national red meat consumption across the world, in over 120 countries, including the United States, Australia, all of Europe, Africa, and Asia. And then at the same time, we also had access to another database that tracked colorectal cancer risk. And we found a direct correlation between higher consumption of red meat and higher risk of colorectal cancer. So in countries that consume high levels of red meat, like the United States, Australia, and South America, then you would have a high risk of colorectal cancer. And it's the opposite in countries that consume low levels, like India or Africa, except for South Africa, where they have annual barbecues. So we know that actually in South Africa, people consume a lot of red meat, but not in most other parts of Africa.

Tumor-associated Carbohydrate Antigens

Rina Bogdanovic [11:54] Now we're looking specifically at cancer. What are tumour-associated carbohydrate antigens? And what is the benefit of characterising them?

Vered Padler-Karavani [12:03] We know that all cells are covered with a thick layer of glycans. And these glycans are really sugar chains, and these sugar chains can be conjugated to proteins and lipids. And in fact, evolution had never been able to invent a cell, whether it's a virus, bacteria, yeast or mammalian cells, that would not be covered with sugar. So this is really, really important. But what we know is that in cancer, the sugar coating is different. So the sugar coating of cancer cells is different than that of normal human cells. And it's not simple because you don't have one gene that will determine the sugar coating, actually it relies on a complex metabolic pathway which have a collection of enzymes each taking one sugar unit at a time to assemble these long sugar chains and in cancer, there are specific mutations or changes to these metabolic pathways that lead eventually to a differential sugar coating on cancer cells. And that could be used for diagnostics and therapy for cancer.

Immunotherapy: Potential & Limitations

Rina Bogdanovic [13:22] Speaking of therapy, what are some of the common types of immunotherapy and what are their limitations?

Vered Padler-Karavani [13:29] You can divide at-large immunotherapy into active or passive immunotherapy. Active immunotherapy is when you teach the immune system to attack cancer while in passive you just give them the therapy from outside like antibodies or different cytokines that you can give from the outside. When we look at active immunotherapy, also here you have many different things and for example, cancer vaccines, or a CAR-T immunotherapy, or checkpoint inhibitions, where you can actually teach the immune system to react to the disease condition. And with sugars of course, that is a very hot topic that people are trying to now leverage the changes in the sugar coating of cancer versus normal cells to design novel immunotherapy approaches to treat cancer specifically.

Rina Bogdanovic [14:35] Could you maybe talk a bit about your work with carbohydrate-based vaccines?

Vered Padler-Karavani [14:39] Looking at the Neu5Gc, we knew that Neu5Gc accumulates mostly on cancer cells and therefore generating an active cancer vaccine that would use or even exploit the already common Neu5Gc response that would be leveraging the efficacy of the immunotherapy. So to do that we actually generated nanoghosts that are covered with multiple presentations of Neu5Gc. And then we also optimise the immunisation regime and conditions in a way that once we inject the cancer vaccine, the immune system will be high, robust and long-lasting. And that is key. Because if you have a low anti-Neu5Gc response or at least a high but low affinity, then you would not only not kill cancer but actually would promote it. So there is a risk. So with the novel design of our nanoghost vaccine, we could show that with the regime that we have developed, we can generate a robust and sustained response over time, which basically teaches the immune system to attack the cells that already have the Neu5Gc.

Rina Bogdanovic [16:03] And would this be used in addition to traditional therapies? or would this be a novel, unique treatment that could be applied?

Vered Padler-Karavani [16:15] It could be on its own. And of course, it can be combined with many types of either passive or active, other active, immunotherapies. And it has room for both. And of course, looking at the diet is key to understanding which people would benefit from such a vaccine. Of course, people because we already showed based on studies from a very large cohort of 20,000 individuals, we showed that people who consume high levels of red meat are those that would have high levels of these antibodies that in fact could be associated with a cancer risk. Those people would benefit from a high antibody response but have high-affinity antibodies from the vaccine because we know that they already have Neu5Gc in their bodies. But on the other side, people who consume low levels, they wouldn't be at risk for cancer. And for them, actually, perhaps different types of immunotherapy would be better.

Rina Bogdanovic [17:26] Yeah, I'm just thinking of people who are vegan or who don't consume any meat. This would not be a very effective approach, perhaps if they developed cancer.

Vered Padler-Karavani [17:34] Not for Neu5Gc and that's still a question that we are investigating. Because in the study, we didn't have particular vegans or vegetarians. And of course, that's under investigation. But we did show that people who consume low levels of red meat have low levels of antibodies. And we actually even developed a Gcemic index where we took all the foods and compared them to steak and then we define that if you take one or two steaks per week, 250 grams per steak, so half a kilo, having a meat per week, that's on the safe side. But if you eat four or five steaks per week, then you would already have a high risk of developing high levels of the antibodies that in another study we showed are associated with a higher risk of colorectal cancer. So we know what are the highs and lows. And we also developed a method even without needing to question the people if they consume or not, based on their antibody characteristics, we can say if they are high consumers or low consumers, so we have a kind of a diagnostic test to really tell if you're a high red meat eater or not. And that could support fitting the right therapy for the right people.

Rina Bogdanovic [19:02] And could this therapy potentially be used as a preventative measure for cancer? Could it inadvertently then support further inflammation?

Vered Padler-Karavani [19:11] The active cancer vaccine you're asking? Well, in another study, we showed that if you take antibodies that are purified from humans, that were developed from the diet versus antibodies that were developed from a vaccine, in this case, a different type of vaccine. These antibodies have differential effects on cells. We don't know exactly what it means, but we definitely know that the gene networks that were activated in dietary antibodies versus active cancer vaccines are completely different, and in fact, a mirror image. So there is a very good chance that actually, the vaccine would be beneficial rather than having high levels of antibodies from the diet. We know for sure that they are different, but they're not the same.

Animal-derived Heart Valves: Safety & Efficacy 

Rina Bogdanovic [20:02] Now going into focusing more on cardiovascular illness, which is also very commonly associated disease with red meat intake, we're going to talk about xenotransplants. So could you define what we mean by those first?

Vered Padler-Karavani [20:17] So in xenotransplantation, we know that many people that have a diseased heart or diseased kidney, have to get a donor transplant. And that of course, we know for many years that there are many different proteins and people that get a full organ have to be immunosuppressed. But even smaller items like a biological heart valve, can also carry animal-derived tissues. So in the case of aortic valve stenosis, for example, in heart valve disease, we know that the heart pumps the blood to the whole body, and then from the lungs, also to the heart and then from the heart to the whole body. And the unidirectional flow is mediated by heart valves. These heart valves tend to deteriorate in some individuals, more commonly over 60 or 65. And they malfunction because there is sedimentation of calcium in those tissues. And the calcium sedimentation then limits the opening and closing of the valve. And in that case, when that happens, you cannot remove the calcium anymore, the only thing you can do is to remove the valve and put inside a different valve. And then the patients have two options either to take a mechanical valve that doesn't have any animal-derived tissue, but then they would have to take anticoagulants for life with the risk that comes with that of bleeding. And the second option is to have a bioprosthetic heart valve that is made of animal tissues. These animal tissues are like cows or pigs or horses. And we knew when we started this study looking at these animals, like chimps, have Neu5Gc. They also have another immunogenic glycan that is associated commonly with xenotransplantation. It's alpha-Gal. So these two immunogenic sugars are found in the tissues. And we found that based on a very long study that took almost 10 years, we actually tracked patients before surgery and up to 15 years after the surgery to see what happens if those individuals get the bio-prosthetic heart valves that contain tissues from these animals. And what we found is that indeed, at least, even immediately, one month after the valve transplantation to remove the diseased calcified valve, these antibodies developed higher levels of anti-Neu5Gc and anti-alpha-Gal antibodies. We also showed that eventually, these antibodies mediate the calcification of the valve that then doesn't allow it to function. The Neu5Gc from the diet was also found in the original native valve from the patients that actually caused them to need the surgery, to begin with. Does that cause the disease we don't know? But we know that the antibodies and the sugars were there when the valve was calcified. And that caused them to require this surgery. We also know that people that receive bioprosthetic heart valves many of them tend to deteriorate again after 10 years, once they are in the body. And when we started the study, we hypothesised that the antibodies that we already have in the blood anti-Neu5Gc and Anti-Gal could possibly attack the new mechanical bioprosthetic heart valve. And this is exactly what we found, that the antibodies that we have or the patients have attacked the bioprosthetic heart valve and they mediate calcification and that process even starts very early. Two years after the transplantation we could already see the calcification. Although it will function over 10 years. This process starts very early. Importantly, what we found is that if we generate genetically more modified animals like pigs and cows that do not express these immunogenic sugars when we try to use these tissues in an animal model, we see that even if you have very high levels of the antibodies, they would not mediate calcification. So you need both, you need the xenoautoantibodies and you need the xeno-auto-antigen. So you need both the sugar antigens and the antibodies to mediate calcification. If you remove the glycans, you know that it would generate probably safer valves that would not tend to get calcified in patients.

Rina Bogdanovic [25:31] So a lot to unpack there. And what you just said, one place I want to start with was that you said that patients who have had to have their heart valves removed could find Neu5Gc, even on their native heart valves. So could you maybe explain how inflammation caused by new Neu5Gc might contribute to the calcification of these heart valves?

Vered Padler-Karavani [25:57] I can say that we don't know exactly what mediates this inflammation, but we know for sure, also in this native and in the calcified native valves, and in the calcified bioprosthetic heart valve, we know that we found the sugar we found the antibodies, and we found to complement the position. And we also found TNF-alpha deposition in the native calcified valves. So we know that there is a process of inflammation, which are the cells that mediate that is still under investigation. And of course, once we know that perhaps we can design therapeutics in vivo, to maybe limit that inflammation.

Rina Bogdanovic [26:45] Now, you said that these bio-prosthetic heart valves do tend to fail within the 10 years of implantation. And so I'm wondering, and I'm guessing many of our listeners might be thinking that after this very long period, could you still find these original Neu5Gc antigens present on these heart valves, which were explanted?

Vered Padler-Karavani [27:11] So actually, if the patient had the first surgery at 65, then 10 years later, it will function which means he would be 75 and at 75 to go through another surgery that must be devastating. And what you ask is something that all the physicians and the cardiologist that actually run the surgery asked me - How do you know that you still have Neu5Gc, the tissue may come from the pigs, but it's in the body for 10 years, maybe that had been removed. And actually, to address that we took the explanted valves in patients that had to have that valve removed. In order to replace it again, because it malfunctioned. And there we quantified the Neu5Gc, we found that at least 20% of the original amount of the sugar is still there, even after 10 years or 12 years within the body, it's still there. And the antibodies are also found within those tissues in the explanted valves.

Rina Bogdanovic [28:15] Now, you did mention something that's very interesting, which is using animals, which usually donate these valves, and suppressing the gene for Neu5Gc, could you maybe explain what the logistics would have to be of incorporating this at a larger scale in clinical practice?

Vered Padler-Karavani [28:33] So it's very complicated. Basically, many of the valves, or I would say the common valve, there are many different manufacturers, but the common practice is to use the pericardium that's a very thin tissue that lines the heart, in order to generate the tissues of the valve. We have a frame and then the tissues, you generate flasks like tissues that would then open and close to allow the unidirectional blood flow. And in order to generate one such valve, you would need around four or five animals to generate one valve. So naturally, that is very complex because you need to generate a very large herd of animals and facilities to allow that when we did the study, we had just a few cuffs of bovine and just a few small pigs that we could just use that not in order to generate the complete valve but rather to generate to just use the tissue to do the studies. But really to have it large scale we need some companies that would help pop in and take on the effort to manufacture such valves.

Rina Bogdanovic [29:55] Did you find similar issues with other xenotransplants? You mentioned kidneys as well.

Vered Padler-Karavani [30:02] I personally did not do this investigation. But we did look at anti-Neu5Gc response in patients that received transplantation or have other organs. But the question was different. What we asked was - What is the outcome in these patients that are immunosuppressed by receiving anti-thymocyte globulin, patients that go through transplantation have to have immune suppression. And one of the ways to do that is to use an antibody against T cells. These antibodies against T cells are produced in rabbits most commonly. Rabbits are non-human mammals, they have Neu5Gc. So these drugs actually contain Neu5Gc. So when these patients received the drugs, we actually showed that these patients, although they were immunosuppressed, had higher levels of anti-Neu5Gc antibodies, and maybe explaining why in some individuals, the transplant does not last longer. And perhaps limiting red meat consumption could also help in that respect.

Navigating Safety Regulations for Biologic Therapies 

Rina Bogdanovic [31:27] I'm curious in terms of other biologic therapies where antibodies might be generated in other mammals. So what would be the implications for people who might take these medications long term and also for autoimmune conditions for instance?

Vered Padler-Karavani [31:43] Well, I was part of a study that looked at antibody therapeutics that are of course, we looked at Neu5Gc presentation, and we did find that actually, it was in Ajit Varki’s lab it was published in Nature Medicine, that some of the common drugs that are used in the clinics do contain Neu5Gc and that depends on the production system. So if you use mouse cells, like hybridomas, of course, it would have Neu5Gc on those drugs. And as we did with, we showed for anti-thymocyte globulin, that you have an increased antibody response in many different contexts, we see that there is an increase in the antibody responses. And in that particular study, where we looked at other drugs, common drugs that contain Neu5Gc, we showed that in mice, when you have at the same time, anti-Neu5Gc antibodies and the Neu5Gc-containing drugs that had mediated rapid clearance of the drug. And that could explain why in some individuals, those drugs don't work. Or maybe they just find an escape during therapy. And we don't know that for sure. But perhaps this could be also associated with a diet.

Rina Bogdanovic [33:13] Do you think that this is very well recognised in the medical field, the presence of Neu5Gc, and the impact that it might play on patients?

Vered Padler-Karavani [33:24] I know that in academia, it's not very well recognised, but in the industry, Yes, it's very well recognised. And I think that even the FDA requires really to look at the glycosylation pattern of antibodies as a part of the regulatory package. But there are no specific guidelines. That means, you have to have a profile, but they don't know exactly what to ask. And I hope that with other studies, of course, we will be able to define what is good and bad, what is a threshold from which it would be devastating or not, or maybe doesn't matter for every disease, nor for every drug, maybe there are certain drugs that are susceptible, where others are not. So there are a lot of unknowns in this system.

Neu5Gc in Foods: The Gcemic Index

Rina Bogdanovic [34:14] I'm curious, you mentioned you developed an index for assessing how potentially harmful different foods are. So just to reiterate, is there a safe dose of red meat that can be eaten without the risk of Neu5Gc Associated Diseases?

Vered Padler-Karavani [34:32] The index was not really showing the disease risk. The Gcemic index, as the name maybe implies is just the amount of Neu5Gc in different foods. We know from many mouse studies that high levels of Neu5Gc could be associated with diseases in mice. In humans, we showed that if you consume high levels of Neu5Gc, you would have high levels of antibodies and in very limited human studies, we showed that high levels of Neu5Gc antibodies are associated with diseases. So, this is a triangle that is not complete. But there are hints that if you consume high levels of Neu5Gc, you would be at risk of many different types of diseases. So, the index really reflects the amount of Neu5Gc in different foods. And intuitively, one can think about it as a glycemic index where you can say how fast a food item is metabolised. So in that respect, the glycemic index refers to the amount of Neu5Gc in different food items. And if we compare it to steak, we thought that this would be most intuitive. We gave the score of one, or two steaks, and then divided everything compared to that. And what we found, for example, is that goat cheese has three times the amounts of Neu5Gc than steak, which means that you would need to add to eat 1/3 the amount of steak to reach the same amount of Neu5Gc, but I can say that or milk, for example, had 1/10 the amount of steak, which means that you would need to drink 10 litres of milk per day, in order to get to this one amount of steak. So then it kind of puts things in perspective in terms of the possible risks or possible amounts of Neu5Gc that you have in the different food items. And then a person can judge on, you know, for himself if that's good or bad. And I'm not saying red meat is bad, red meat has very good advantages, like, you know, iron and different vitamins. So it could be good. But my conclusion from the study was that, like everything in life, you should have it in balance. So too much of a good thing also is not good. And just limiting the amount will be, I think better. So one or two steaks is fine, four or five, six per week is not fine.

Does Prof. Vered Padler-Karavani Still Eat Red Meat? 

Rina Bogdanovic [37:23] If I may ask, I’m curious, has doing this research impacted your personal dietary habits?

Vered Padler-Karavani [37:30] That's funny you're asking because I really limited the amount of red meat many years ago when I started to work on Neu5Gc. And then, I eliminated it so much that I really had to take iron infusions because it was too low. So I'm saying from a personal perspective that iron and red meat could have some beneficial you know, items in the food. So as I said, balance is good. And if you stop eating red meat like vegetarians and vegans, then you have to supplement your diet with something else just to be on the safe side.

Neu5Gc as Biomarkers

Rina Bogdanovic [38:08] And I think a very good place to leave this discussion is by asking you if you think there is a potential to use anti-Neu5Gc antibodies as biomarkers of red meat-associated diseases?

Vered Padler-Karavani [38:22] Well, that's very complicated. I know that people are trying to do that, but because it's so related to the diet, then it could be limited to people that perhaps eat some higher levels of red meat. And we don't know yet, what would be that marker, what would be that biomarker. And it's still under study. But we did come up with a ratio of the different glycans and linkages of the set, which we didn't discuss at all, it's a bit more complicated to look at the linkage of the sialic acid to the underlying glycans. So we have a way to see who are the people that have high levels of antibodies, but connecting that to the disease is still yet to be investigated.

Rina Bogdanovic [39:18] Definitely sounds very exciting either way. Thank you very much for joining me for this conversation. It was really a pleasure.

Vered Padler-Karavani [39:27] Thank you very much. Rina. It was a pleasure as well.

Rina’s Outro

Rina Bogdanovic [39:30] Now speaking to our listeners, I hope this conversation has deepened your understanding of the interplay between diet and immune response and the transformative potential of research focusing on Xenoauto-antigens. If you would like to access more information about this conversation, and Vered’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 over 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. 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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