Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
Our immune system is designed to respond to danger, to things coming in from the outside. But this is not the case with autoimmune diseases, in which the body turns on itself. Robert Harris is studying inflammatory diseases of the central nervous system. He learns how these diseases arise, how they are perpetuated, and what he can do to stop the process.
Robert: My name is Bob Harris. I am a professor of immunotherapy within neurological diseases at the Karolinska Institute in Stockholm, Sweden.
Nerina: What is your main research topic?
Robert: My main research topic is really to understand inflammatory diseases, we do this in a variety of settings. Primarily it’s been or historically it’s been within the field of autoimmunity where we focus on multiple sclerosis but in recent years we’ve also expanded into Alzheimer disease and brain tumors. So, inflammatory diseases of the central nervous system and what we’re interested in doing is learning how the diseases arise, how they’re perpetuated and what can we do to stop those processes. So they’re designing novel types of therapy to try and reduce the disease burden or hopefully to even stop it.
Nerina: What are actually neuroimmunological diseases?
Robert: Immunological diseases …autoimmune diseases at least are diseases in which the body attacks itself. Usually, your immune system is designed to respond to danger, to things that are coming from outside like infections, but sometimes for reasons we don’t understand why then the body turns on itself and starts to destroy its own tissues and these are called autoimmune diseases.
What happens in chronic inflammatory diseases is that there is disregulation of the regulation and that means that the immune system starts to do things which it shouldn’t do. So, if you have something that goes wrong in your body, then your body should respond and take away whatever it is that is not right. And then that can be either something that happens to your own cells when they become abnormal in the form of cancer or it could be that you get infected by something, a bacteria that comes into your body that shouldn’t be either. So your immune system is there to protect you from these things but sometimes it loses the instructions not to respond to itself and so it starts to attack itself. There are many reasons for this occurring, but really your immune system becomes diseducated and starts behaving in a bad way. And then, when it starts to do that, it starts to attack itself and it can lead to dysfunction in your body and depending on where the damage is done then you can either then develop diseases of your brain, your liver, your pancreas or your joints.
Nerina: What is your approach to try to find a balance again?
Robert: The first thing to try to readjust the balances is to actually prove that there is an imbalance. That’s one of the things that we can do by studying our animal models and by studying our patients’ samples to actually try and work out what’s happening in the blood of these individuals who actually are sick and how do they differ from people who are not sick and that would give us some clues about the immunological processes which are occurring and that would then give us clues about how we can stop them.
Nerina: What is your special approach in your lab or what is your idea?
Robert: We have a number of approaches to try affect immune therapy. The major focus in the last five years has been on novel cell therapy. One of the immune cells which are involved in these chronic inflammatory conditions is the cell called a Macrophage and these are very numerous, they are all over your body in all your tissues and you have a number of them immature called monocytes circulating in your blood ready for action in case something happens. So when you get an infection in your skin, then there will be a recruitment of these monocytes to repair that part of the skin, that go from the blood into the tissue, become macrophages and do what they are supposed to do to kill the infection.
The resident cells which are all over the body have another role and we think that that’s mostly to keep things in check, the homeostatic functions, to keep the balance. So, there’s an interplay between these two cell types.
Then the macrophages themselves can have different properties. They can be nasty ones that chew up the bacteria, these are pro-inflammatory, and then there are others which calm things down and they have anti-inflammatory function and there should be a balance between these two. It’s like Yin and Yang, so when you activate one side, then you should have the other side that comes and regulates it. So, in chronic inflammatory conditions like multiple sclerosis then you have an overactivity of these pro-inflammatory cells that rip your brain tissues apart and that’s why you get the disease. So, our hypothesis is that you have an imbalance in these two populations. People who get these chronic inflammatory conditions are a little bit trigger happy with the pro-inflammatory side and maybe they are actually insufficient in down-regulatorty side, the anti-inflammatory side.
In settings of cancer, for example in brain tumors, then it’s the opposite. The tumor is actually able to survive because it’s anti-inflammatory. So in this case, then it’s the other side that’s actually a little bit too active and you are lacking the pro-inflammatory side. So, in each case, in each scenario then our hypotheses is that if you give back cells of the right sort, so in autoimmune conditions – anti-inflammatory, in cancer setting – pro-inflammatory cells. So, we can take blood from a patient, we can purify these monocytes, make them into macrophages, stimulate them to be pro-inflammatory or anti-inflammatory and inject them right back into the same patient. Hopefully, at the site of where the disease is and that would then restore the balance locally and then it should halt the disease process.
Nerina: What is the peculiarity of your research?
Robert: One of the peculiarities of our research is that not many people work with these cells, these macrophages that we are working with. They are sort of considered to be the garbage collectors in the rest of the body, when you have some damage or you need to get rid of something, you get infections, some bacteria in the skin they get taken care of, the macrophages are the garbage collectors. They come up and get rid of all the dead tissue and make things right again. This is why you have macrophages in every organ in your body as well as theses circulating ones that they can come in high numbers if you really, really need them. They are like soldiers that are pulled onto the battlefield as extra resources, but many people don’t think then that these cells are so smart, but they are very numerous.
So we actually think that they are a little bit underestimated and very few people have been working with macrophages until the last five years and then it’s been sort of a renaissance in the field and the abilities of these cells to be multifunctional more than just the garbage collectors have actually become a little bit more apparent. So now there’s a lot of interest actually in what they do, but people are still not really interested in these being able to use them in immunotherapy the way that we are. It stands to be tested. People have actually started to use our protocol, one of the papers we published where we could show that we could induce anti-inflammatory cells in human cells which we published in the Scandinavian Journal of Immunology. It’s been the most downloaded paper in the last couple of years. So there’s a lot of interest and some people are actually starting to report using our protocol in their systems and in other disease models that we haven’t studied ourselves and it still works as well. So I think it’s coming and it’s not going to become so peculiar but they’re not so many people who think this is the first cell type to study and that’s why we are a little bit strange.
Nerina: Why do you think your approach is better than others?
Robert: It’s not a question whether it’s better, it’s a question of time and money and efficacy. One of the beauties of our theory is that the hypothesis that we will use patient’s own cells. So that there won’t be any problem with any rejection when we try to put these back into the same person. They are their own cells they are just not doing what they should do. So we’re giving them a little bit of help along the way to actually turn into the cells doing the things the right way they should do and put them back in and I think that’s a smart approach.
I think that what we have seen from other immune therapy approaches are that even if they are very successful and if we take an example of Rheumatoid Arthritis where one identified the molecule called TNF which is one of the sickening components which is very highly expressed in Rheumatoid Arthritis patients. So, they found ways to inhibit this molecule by using antibodies or soluble receptors which then can take it away
The immune system has been developed for hundreds of thousands years and suddenly you take a part of it away. It’s a bit like chopping your foot off you would be still able to walk, you would be able to hobble along, but you won’t be able to run and you won’t be able to climb stairs in a good way. It doesn’t really make sense to take something away. So I think that our approach is just giving back something that is really a little bit insufficient is a more natural way to actually reset the balance.
Nerina: What’s next?
Robert: The next thing with this is really to go into patients. One of the challenges with trying to go from experimental systems to humans is me not being a medical doctor is that I’d then have to engage clinicians. So at the moment, I need to try and get funding to fund this and then try to find doctors that are willing to try and that’s really where I want to go. If I can make life better for just one patient then I will feel that I’ve done my job as a researcher.
Nerina: How much do we actually know about ourselves or about our body functions?
Bob: We now know a lot about the body functions, we’ve known a tremendous amount about the immune system, but unfortunately one of the challenges that I see is that we have always been studying disease, we have studied people with allergy, we study people with autoimmune disease, we study people with cancer, but we don’t actually know too much about healthy people. We study aging even as well, but this is when things start to go wrong. But we actually have relatively little experience of healthy people, to actually know what’s going on in healthy people and how does their immune system actually look. Is it always non-activated or is it always on the go a little bit? How’s the regulation done there? So, I think that we need to actually study health in order to get a better handle on what goes wrong when you get a disease. But we know a lot and there are very many therapists that work very well and lots of new therapies being developed so the knowledge that we have it’s actually made tremendous progress.
Nerina: What do you look forward to now?
Robert: What do I look forward to? Summer holiday. No, what I look forward to in research is actually the research community as a global community and a lot of smarter people out there, lots of smarter people than I am and what’s nice is that we then share this knowledge and what I look forward is actually a major breakthrough. It’s been a long time since there has been a major breakthrough in medical research. Maybe the last really major significance was the small pox vaccination and that’s way back in the 60’s. So it’s about time that we actually came with something really revolutionary and we’ve had really good advances in sequencing the genome and so on, but most of the advances have been technological. But I think it would be nice if we actually could really nail one disease and eradicate it from the face of the earth.
Nerina: You got a prize as a great teacher. What is your role, how do you see yourself as a professor?
Robert: You know that some people are good at doing research, some people are good at writing things, some people are good at talking. I seem to have a talent as a teacher. I realized this quite early on and I am heavily involved in all sorts of training and development of training. So it’s something I enjoy doing. It’s fun to be able to inspire other people to be better in what they are doing and that’s the point of a teacher. Whether it’s to students to inspire them in their quest for knowledge or whether I do a lot of leadership training, especially for our Ph.D. supervisors and to inspire them to actually be good in those roles.
Nerina: What is good research?
Robert: That’s a very interesting question. Beauty is in the eye of the beholder and so different people would tell it’s different things. I think good research should be based on sound ethical principles, good critical thinking and should be interesting. So that for me is what good research is all about. Research is all about searching again. That’s where the “re” comes in. So, often good research is nowadays is going over old research but using new methodologies in order to address these questions and that could be just as exciting as finding something completely new.
Nerina: And what is a good researcher?
Robert: Ah…good researcher I am not sure, you need to ask someone else. No, a good researcher should be somebody that is really interested in asking questions. “I need to know” – that’s what drives me. I am inquisitive and I like to be able to think, to be innovative in my thinking and a lot what we do doesn’t work. So a good researcher needs to actually have the stamina to face failure because 90% of the time we fail in what we are doing. We ask questions, we pose a hypothesis, we test them and they show not to be true, so we have to go back to drawing board and start again. So I think a good researcher is actually somebody that doesn’t give up, that actually sees the big picture and for me, it’s the patience. If you see people suffering or if you see people dying from the diseases or the diseases we are interested in studying, there are no cures for them and they are horrible diseases that really affect people. We could have picked up something that would be easier to fix but that’s not so interesting for me. I like the challenge of actually doing something that’s undoable at the moment and really to make efforts to do that and I think that’s also the essence of research, at least in a clinical setting, that want you to actually be trying to do something that’s going to be of use to the patients.
Nerina: Thank you very much, Bob.
Robert: Thank you.
Robert Harris, Professor of Immunotherapy in Neurological Diseases at Karolinska Institutet sent us a short video with some interesting news. Have a watch.