881: Dedicated to Discovering the Causes and Treatments for Hearing Deficits - Dr. Christopher Cederroth

Studying hearing loss and tinnitus

0:00Hi, and thanks for joining me today for episode 881 of People Behind the Science. I'm your host, Dr. Marie McNeely, and this week I am happy to revisit our interview with our guest, Dr. Chris Sederoth. Listeners, Chris's research examines hearing loss and tinnitus, or ringing in the ears. Over 300 million people in the world have hearing problems, and Chris is dedicated to understanding the causes and developing treatments. In our conversation, Chris gives us an inside look at his life and science.

0:30So get ready to meet another one of our magnificent people behind the science. Every day, discoveries are made that will change our understanding of the world around us. Dr. Marie McNeely is here to bring you the brilliant minds who are making these discoveries so they can share their incredible stories and take you on an amazing journey. Welcome to People Behind the Science.

Family life in the Swedish countryside

0:55Hello, everyone, and welcome to People Behind the Science. Today, our wonderful guest is Dr. Chris Sederoth. So, Chris, welcome to the show. How are you? Fine. Very fine. Thank you. Wonderful. We are excited to chat with you today about your experiences, but first, I want to take a moment to introduce you to our listeners. So, listeners, Chris is an assistant professor within the Laboratory of Experimental Audiology working on tinnitus within the Department of Physiology and Pharmacology at the Karolinska Institute in Sweden. He received his PhD from

1:29the University of Geneva, and he was awarded the Denver Penard Prize for his PhD work from the University of Geneva. And during that time, he also contributed to the launch of the startup company Amazentis. And before joining the faculty where he is today at the Karolinska Institute, he was awarded a Swiss National Foundation Advanced Fellowship for his postdoctoral work conducted at Rockefeller University, as well as the Wenner-Grenn Foundation and Nicholson Postdoctoral Fellowship to support his research at the Karolinska Institute. And Chris is here with us today, listeners, to talk about his research, but also to tell us about his experiences in life and science. So,

2:01Chris, today, we want to get to know you both as a person as well as a scientist. So, can you start by telling us how you spend your time when you're not in the lab? Thanks, Marie, for the introduction. I'm very happy to be here. And your question is hard to answer because most of the time I'm doing science. So, maybe I would say that apart from my scientific passion, I'm dedicated to my three kids, Sirianne, Torgal, and Arisia, who are age seven, five, and three years and a half now. And I can say that outside of the lab, my hands are full and me and my wife are clearly missing an extra pair of hands.

2:32Of course. I'm still looking for the one that told me that having three kids is the same as having two. Yeah. So, what are some of the favorite activities that you're doing with your kids these days? At the time we were in Stockholm, in the city, we were visiting a lot of the museums, like the Vasa Museum. There's Unibaken, which is the museum of Astrid Lindgren. The Natural History Museum, which I like to spend time with the kids. But now we've moved to the countryside. That's 60 kilometers north of Stockholm in a city called Nortelje. And then there's a lot of outdoors activities that we do. And typically, Swedes say, you know, there is no bad weather. There's only bad

3:04clothing. So, whether it rains or whether there's snow or ice or even sun, which happens sometimes, it does here. We're outside biking, going all around. We're having a very good time. We're pretty close to the archipelago. So, it's a very nice environment to be. Well, I love that. I've never heard that before. There's no bad weather, only bad clothing. I'm going to have to steal that one. So, fantastic to hear more about your life outside the lab. But I do want to hear a little bit more about your research as we go through this

The public health burden of tinnitus

3:29interview as well. So, can you start by giving us the high-level view of what you tell people when they ask, what do you do? Well, I first tell them that I'm working on hearing loss and tinnitus. And most often, they say, what? I have to repeat it again. And obviously, they have hearing problems. So, the reasons why I'm working on hearing disorders is because it's first the fascination of that organ. It's a complex architecture that serves the purpose of hearing, but also because it's an increasing problem in society. Today, it's about 300 million people in the world that have hearing

3:59problems. And there's been some predictions that in 2025, it would raise to 900 million. And this is huge. It's much more than diabetes. But everybody talks about diabetes because it's a pandemic and nobody talks about hearing problems, which are so frequent. And the problem is that there isn't much attention towards auditory disorders. And maybe that's because unlike diabetes, no one dies because of being deaf, but it severely affects life quality. To give you an example, hearing loss is ranked second by the WHO right after depression, before schizophrenia, as the cause of viewers lived

4:32without disability. And unfortunately, hearing disorders have been underestimated and neglected by public awareness and funding authorities. So, I developed also interest in investigating tinnitus. That's the ringing in the ears, this phenomenon of phantom sensation of sounds that affects about 15% of the population. It's quite broad. And since it's a phenomenon that accompanies aging and age-related hearing disorders, it's quite frequent. And even when you look at people around 60 years of age, that's near 40% of people that have tinnitus. It happens that

5:04myself, I also have it. So, I'm very well-placed to understand what people can endure. I've had now tinnitus for 16 years because of a blast injury. So, it happened when I was in Spain for New Year's Eve. And people in Spain are celebrating with a lot of firecrackers. And it happened when a young man came in the crowd and threw out a dynamite stick that just exploded next to my ear. Oh, my gosh. I barely had the time to protect my ears. But in fact, I've been choosing to protect the ones of my girlfriend instead, which I regret because the next day she left me.

5:34Oh, no. I was going to say, what a romantic story, but it does not have a happy ending. I mean, in any case, I'm quite lucky in that phenomenon because I don't have an obvious hearing damage. I don't have a severe form of tinnitus. But there are very severe cases happening in the world. And that varies between country to country. So, on average, it's maybe 10% of the tinnitus cases are delimitating. It prevents people from sleeping, from being productive at work, and they seek help. And often, they want disability pension. And if you think of terms of financial costs to society, hearing loss is quite high. That's around €220 billion

6:08in Europe for hearing loss. That's around €150 billion in the US. And there are very few studies that have been focusing on tinnitus because it's quite new as a problem. And so, the problem is that not all countries take care of tinnitus intensively as the Netherlands or Germany, which they have tinnitus centers like the Charité in Berlin. And this is somewhat disappointing to say that there is little governmental interest for tinnitus management. So, you go to doctor physicians, understand very little about it and its burden. Most often, they leave patients out of their office and tell them, you have to live with it. There's nothing we can do to help you

6:41out, which is wrong because trying to understand what's the cause is the first step in the management process. Certainly. Well, it sounds like your own experiences as well as the public health importance of hearing loss that you study really motivates you to do your research. But do you have a favorite motivational quote or a saying or another force that really keeps you going every day? Because I know things can get really busy as a scientist and maybe disheartening as you're starting to see that not many people are maybe as excited about this field as you are. I would say that one is maybe more related to science because even at times when I've had that

7:12upbringing or lacking concentration, I couldn't make mistakes. But in fact, in these times, that's the moment where I would understand my experiments best. Einstein mentioned that a person who never made a mistake never tried anything new. And that is motivating in the sense that science is a risk-taking moment. And if you don't give it a try, then you will never get new things popping out. Definitely. Well, I think that is a fantastic quote. And I think as scientists, we make a lot of mistakes. We have a lot of challenges and the path isn't always smooth. So we'll chat more about your path as we go through. But I want to start by talking about some of the

Early mentors and marine mammal conservation

7:43people who you've encountered along your journey. So Chris, is there a particular person that stands out to you as someone who was a really strong role model for you or maybe a mentor as you went through your career? I have a few. When I left high school in Geneva, I was heading towards the university to follow courses in biology. And at that time, I was convinced to devote my energy to protecting the environment and in particular marine mammals. And I was completely fascinated by the work of Camelon Cousteau, who was a French scientist, studied many forms of life in the sea. And unfortunately, living in Geneva, next to the Lake Le Mans, there was not much to see and for sure,

8:18no large marine mammals. Sure, sure. That's when I met the Swiss Citation Society, which is a non-governmental organization devoted for the protection of marine mammals. So even if Switzerland didn't have, they were pretty active. And the CEO, the president of that society was Max Olivier Bourque. So he created that society because Switzerland was part of the International Whaling Commission. So it was important to have a lot of sensitizing events for the public to understand why Switzerland was an important member. And I had to give a voice and opinions on the conditions of whalings around the world. At that time, I joined the

8:50society. I was pretty active and mostly particularly contributing to sensing missions that we had in the Mediterranean Sea to evaluate the impact of human activities on populations of Finwell accumulated in the Ligurian Sea. That's between Corsica, France and Italy during the summer I was there. And Max Olivier was a key role model because he had a unique way of gathering a large number of volunteers to serve the purpose of the society. He had an organization that was completely opposite to pyramidal structures, which I always thought was the common way of having an organization.

9:21His society was more like a constellation with him in the middle, very flat with a myriad of passionate people and students, retired people working for free all around and having specific tasks that they completed willingly. So that was a very nice lesson on how successful the system could be in a flat hierarchy with highly motivated people. And I was fortunate to meet someone like him that had a very big natural aura to bring people together. The second and third role models were my PhD supervisors. So Professor Serge Neff and Jean-Dominique Vassali. Jean-Dominique Vassali was at that time

9:54director of the university, meaning I've seldom met him, but the very few interactions I had with him were the most constructive and motivating ever. So he has always been present in lab meetings and he had a very natural way of thinking outside of the box. He always pointed out at what you would have never thought about. And on top of this, he was a man of great integrity. And at that time, Professor Neff had arrived from UT Southwestern and he created his lab in Geneva on sexual development. He had received funding from the Swiss National Foundation to do research on endocrine disruptors and how

10:28environmental compounds can affect sexual development. And although I was his very first student, he had a lot of trust in me. And I guess he understood that it was better to keep me unleashed, which turned into a very productive period. So even without myself having the expertise, I brought metabolism as a research topic in the lab. And thanks to multiple collaborations, I initiated that five years of PhD resulted in 20 publications. So it was a very nice moment out there. Finally, the last role model was Jim Hutzpah, who's now a professor at the Rockefeller

10:59University. And I joined his lab, as you mentioned, thanks to a fellowship. And because I came in with my own money, he allowed me to initiate whatever project I wanted. And that's where the idea of bringing tinnitus research to mice came as a big question. And that's an area for which he had no expertise. But he took a big risk by having someone who had a completely different background in science. Sexual development is quite far from the ear and the brain. So it was quite unique to have this opportunity. And having the interactions with him was very rich. Definitely. And I know we've had actually Jim Hutzpah on our show before, and I can attest to

11:32the fact that he is just a wonderful human being. So a great mentor. And wonderful to hear about all of these different mentors that you've had throughout different phases of your career and starting quite early. So you mentioned you had this interest in biology and marine mammals specifically. Was this kind of your first love in science? Or is there a memory that even precedes this, that sort of hinted at this interest in pursuing a career? No, I think the love for the sea environment came very, very early. I was raised in a family that was business oriented, something I never had a sense for. I was quite a type of daydreamer and always

12:03observing and contemplating the environment. But when I became a teenager, maybe that's when I was confronted to all these movies from Cousteau, that was really intriguing. It was all the aspects of my surrounding life that I could not access. So I wanted to go under the water and see what was going on there. And it's quite funny because I was far from it being in Geneva. So I had to do a lot of little jobs here and there to get money. I didn't have the sources to go abroad and to get an appropriate education outside of Switzerland. So I stayed there. And that's when I met the Suicitation Society. And that was a very big step into going into the scientific environment.

12:39But what was striking being there and starting working on marine mammals is that I started teaching people about our missions, coaching them on the importance of the ecosystem and what we're doing. And it was exactly the type of field studies I envisaged. But after a number of years of dedication, I found that all my efforts had little impact. And it was a bit frustrating. And the scientists from were collecting data and never published a scientific article or never disseminated their reports to the governmental agencies. So I wanted something more concrete

13:10of my endeavors. And especially because I was putting so much energy into what I believe was an honest cause. So after that moment, I was doing my bachelor's degree in Geneva and I decided to find a lab where I could learn more of what the bench was, which was pretty uncommon to find a student begging for hands-on at this stage of the education. So I was knocking on doors and trying to find out who could just teach me. But PIs wouldn't spend so much time in coaching someone on delicate procedures if there wasn't at least some small type of guarantee of seeing the student for a longer type of period.

13:43So I got rejected by a number of labs. But that's when I met Professor Serge Neff. And this was a key moment in my career for science because he opened the door. He got surprised about my CV and all the little jobs I had done during my studies. I've been a security agent, a limousine chauffeur, a housekeeper. Really? Wow. I've been taking garbage out of all the restaurants. But he saw that I had experienced what was the rigor of a job. And when I came there the first day, then he told me, I'm leaving for a meeting for a week. So then I thought, holy gosh, is that the good idea? Is it the good place to be? So he then

14:18presented me his lab assistant. And then the cupboard with all the chemicals introduced me to PubMed and all the literature research, which I was not familiar with. And then he told me, Chris, we're going to try to isolate with a cell sorter, fluorescent expressing cells from the mouse gonads during the differentiation to either ovary or testes in order to find what their RNA transcriptome and find out the genetic programs responsible for gonadal differentiation. So, wow, that's great. Fascinating. And then he said, well, I want you to prepare a functional protocol for when I come back.

14:48Oh, wow. Was he the one who was nuts or was it me? Right. It was crazier. How could he trust me? I've never done bench before. And then he left. And I think it was the most stressful time in my whole life. And I worked day and night to underdivide all the protocols, which wasn't easy because tissue cell sorting at that time wasn't routine. Anyway, in one week, I managed to present him something which took a whole day to make it functional, but it worked. It wasn't perfect. But it showed him that it was doable and he was very happy about it. And he gave a lot of return in terms of mentorship. And that's how I got

15:22offered an opportunity to do a PhD in this time. Well, that is quite impressive, I must say. And you mentioned previously this being unleashed experience happened later on in your PhD work as well. So can you tell us a little bit about your next stages along your scientific career?

Building a mouse model for tinnitus

15:36Yeah. So after I finished the PhD with Serge and Jean-Dominique Vassali, I wanted to go back to hearing science. It's something that I didn't mention before. At the moment, I was in the bachelor and I was trying to find out if I wanted to stay in the ecology environment or make a transfer to more bench work. I didn't know really what to do. I didn't have a big fascination for all the RNA molecules, which I found very abstract, which is things I'm doing now, in fact. But the thing that made me change was that there was a course from a biochemist

16:08and he presented an image of sensory hair cells along the cochlea that were shining green because of calcium influx. And it was so beautiful to see that snail ship that made me think about the auditory system immediately. So I had done a master's trainee in France for a year and it was a very hard experience. It didn't work that well. That's why I also came back to Geneva to continue with Professor Neff. But after the end of the PhD, then that's when I said, all right, I want to go back to auditory research. That's my big gig. I want to have fun in this. That's how I met Jim. And that's how I started

16:40joining his lab. And his attitude was, the lab is open for that aspect of curiosity. So what do you want to do? I wasn't expecting that question. Then I thought, all right, tinnitus, nobody works on it. And there's no cure. There's nothing that has been emerging at that time. So why not doing it? And I've been working with mice as a model. Why not trying to do tinnitus in mice? So I spent three years working there, building up a model, which was recently published in the Frontiers edition. We have a research topic where we're gathering a lot of different knowledge from different people since tinnitus is so multidisciplinary. So people can go there and have a look if they want to, in fact.

17:15So I had that model developed there. It was the logical path to go to the laboratory I'm in now to continue characterizing this mouse model and find people that have more expertise than Jim to understand more the mammalian auditory system, the brain connective networks, and how all of this is generating tinnitus. Well, it sounds like you have had an exciting career journey through science and a lot of opportunities to have this freedom to explore the things that you were excited about, which I think is phenomenal. And we mentioned briefly in the introduction that you got interested in the

17:46startup scene or had a hand in a startup company. So can you tell us what prompted that?

Discovering metabolism effects in natural compounds

17:50So at the moment I joined the lab of Professor Neff, we were having questions about how endocrine disruptors or chemicals that you find in the environment were affecting sexual development. And one of the questions we had, which was an important governmental question, is if you eat soy that contained phytoestrogens, would it affect your reproductive abilities? Would it affect your sexual development? And it happened that it does nothing. So we came up with some results. Yeah, it decreases a little bit sperm production, sperm motility, but it doesn't make you infertile.

18:23That's positive findings for the society, but it was negative findings in terms of impact. That's when we saw that the animals that were fed with soy, they were impressively lean. So the amount of fat was decreased tremendously. It was really visible. And then we started asking the question, what is going on in these animals? So they had improved glucose tolerance, improved insulin sensitivity, and all of these aspects of metabolism that my boss was not familiar with, I had to seek help elsewhere. And we started collaborating with a large number of labs within

18:53University of Geneva that had great competence for that. And at that moment, we had been showing all these beneficial effects of those natural compounds. Came Patrick Ebisher, who is the dean of the EPFL, so the Polytechnical School in Lausanne. And he had been working on other natural compounds found in fruits, like pomegranate that had an effect on Alzheimer's disease. And the company then merged with my boss and Patrick to create amazentis, which aimed at finding natural compounds to prevent

19:25development of diseases or even cure them. That's how amazentis got created. Well, this is very cool. I love this story because it's sort of the unexpected findings that when you dig in a little bit deeper, explore a little bit more, kind of turned out to be the most interesting in a lot of cases. So now we've talked about a lot of wonderful aspects of your career that got you to where you are today, Chris. But I want to hear a little bit more about something that you have going on in the lab right now that you are so excited to be working on. So can you tell us

Circadian rhythms and noise vulnerability in the ear

19:50about a current project? Oh, yes. That's a project that's related to circadian rhythms in the ear. But that's a project that is led by Professor Canlan, in which I'm contributing in the lab now. And I've been involved since I came. So circadian rhythms is a process that enables organisms to adapt their physiology to predictable changes in the environment, such as light, dark cycles, temperature, or humidity variations. So it's pretty conserved from bacterias to mammals. And to do that, the body senses all the environmental cues that tell each organ what to do and when. So in

20:22the same way that metronomes help musicians internalizing the sense of tempo, these cues influence those biological clocks to facilitate their internal representation of time. Among these cues, you have the light, dark cycle, as I mentioned, temperature, but also food consumption, social interactions. And many of these physiological processes are subjected to temporal regulations. That includes the sleep and wake cycles from the brain, feeding behavior, metabolism, energy homeostasis, immune responses, heart rate, blood pressure, and renal activity.

20:56You also have hormonal secretion. And we found recently that auditory functions are also influenced by such mechanisms. So the first experiment was to find that some mice that are subjected to the same level of noise in the day or in the night. So it would be a noise level that is comparable to what people endure when they're going to discotheques. So mice that are exposed to that level during their sleep phase, that means during daytime, because I remind that mice are nocturnal animals. They have their hearing recovering completely, but those that are exposed during their active phase,

21:28that means the night, have permanent hearing damage because they cannot recover as well from the noise trauma. And that's when we found that there was a clock hardware composing the cochlea. So the molecules that regulate rhythmic functions in that organ was present in the ear. And the clearest evidence that we had came from reporter mice that we've used and expressed a luciferase that is coupled to one of the key clock proteins called period two. When we cultured the ear of these mice, we could observe robust oscillations in luciferase activity, which was used as a readout for period two

22:02rhythmicity. And these oscillations were really strikingly clear or robust, and it could last for more than a week in isolations. So a lot of researchers argued that whatever organ one would take, it would oscillate, but that's not true. There are a large number of publications showing that in large screens from brain areas, only half of them would oscillate. In our cells, we've found less easy to reveal period two oscillations in the inferior colliculus, which is an important relay in the auditory pathway. So the clock in the ear appeared very clearly as robust, and we asked ourselves,

22:32the question, if there's a clock in the ear that could regulate vulnerability to noise at different times of the day, what's making mice being vulnerable during their active time? And we questioned the influence of neurotrophins, which have been shown to regulate the neurotic growth in the ear. And we found that when the animals are subjected to noise during their sleep time, the ear is capable of secreting a neurotrophin called BDNF, brain nerve neurotrophic factor, as a response to the noise insult. And this does not happen during the active phase. And there,

23:04the ear had no ability to produce more BDNF. So in absence of that neurotrophic response, the ear was not capable of recovering from the noise damage. And then we came to the idea of testing a pharmacological approach to rescue that condition. So with my background in phytoestrogens and phytochemicals, we used a natural compound called dehydroxyflavone DHF, which is found in many plants. And it mimics BDNF by selectively binding the TREP-B receptor. And when we pre-treated the animals during their

23:35active phase before the noise injury, that means when they're most sensitive, we were able to see that their hearing recovered as well as if it was a daytime. And now we're investigating what are the cues that is orchestrating all the molecular clock in the ear. And I'm very excited about this project because it's linked to ideas I had in my mind already far back in time when I was a graduate student in Geneva. And I followed the courses from Uli Schibler, who was a pioneer in circadian rhythms. At that time, I had visited his lab. That was 14 years ago. And he had generated a triple mutant

24:09mouse of key clock control genes. And he was very puzzled by an unexpected phenotype. He found that these animals died every Monday and Thursdays. Really? And that's where you learn how important it is to keep very good records of any observations. And in fact, they found that these were the days when the animal facility care used a vacuum cleaner to clean the animal rooms. And the mutant animals died of audiogenic seizures. So it's all related to sound sensitivity. Seizures were generated by the noise of the vacuum cleaner. So it's a nice

24:40coincidence to work on a topic that I'd raised my curiosity a long, long time ago. Absolutely. Well, this is fascinating work. And now you mentioned how recovery from damage or trauma has the circadian rhythm. Are there also rhythms in phenomena like tinnitus? That's what we're investigating now. And it's not as straightforward to answer, because all the behavioral tests that we have are sensitive to the degree of hearing loss. And as a consequence, since animals at night have greater damage, we need to compensate for that influence. The other way of approaching this and what we're trying to do now is more epidemiology.

25:14We've recently created a cohort here in Stockholm. We were gathering a lot of tinnitus participants from other cohorts that we identified. And we're asking questions about when tinnitus had emerged. Was it more in the morning or in the afternoon? We have more circadian related questions. So to understand if there is an influence on tinnitus generation, eventually fluctuation, because also some people report that it's more intense at different times of the day. And how is this influencing that symptom? Well, very cool to hear more about what is keeping you excited and busy in the lab these days. And I

25:47think we've talked about a lot of the great aspects of your career and the work that you're able to do. But we haven't yet talked about a lot of the challenges and the struggles. And I think

Overcoming logistical roadblocks with animal shipping

25:54no scientist can escape these frustrations, these failures. So Chris, can you tell us about one of your own experiences of something that really stumped you or a really big challenge that you faced and how you got through it? We could spend a full podcast only on that. But maybe one related to that mouse model that I generated when I was in Jim Hudspeth lab. It's funny how things go because my PhD was a situation without too many problems. There was a lot of publication, it was quite straightforward results. But the postdoc was a challenge because it was the first time that

26:25I was confronted into building my self-hypothesis and testing them. So when we came with a behavioral approach to assess tinnitus, I found also that mice, they were quite resistant to tinnitus induction by either noise or medication. And that's how I came afterwards with the hypothesis that it depletes the ability of buffering glutamate from mice. Then I would exacerbate tinnitus. So I use glass knockout mice. So they're lacking a glutamate aspartate transporter. And that worked very nicely. I could really just looking at the phenotype, I could tell which one was a mutant or

26:58not. The problem came when I had to transfer the project to the Carlin scout. And Jim was very, very generous because he said, this is a project completely yours. This is not my topic, so you can take it under your arm. And I was honored by this. So I prepared everything before I had to leave. I had to ship animals by plane. I had arranged everything with the veterinarians on both sides from Rockefeller and Karolinska. And I prepared the very two last best breeders I had to ship them. And the day before the shipping, the veterinarian from our department calls and say,

27:32you cannot ship them. So there is a fur mite infection in your animal facility in New York, and you cannot ship them over. This is a serious infection. But I said, my animals in my room, they're not affected by it. Yeah. And yes. And the problem is that it takes time to be detected. And that's why you need a 36 month quarantine. I said, well, the animals won't be able to breed anymore. That's how it is. So I was stuck because I was leaving and moving my family and everybody to Sweden. So it was a big, big problem because at the moment we started submitting the paper for

28:02publication and we had questions of reviewers and couldn't start it. I couldn't answer. So we came with the conclusion that I could not send these animals alive. I had to ship cryopreserve embryos. But to get embryos, you need to perform in vitro fertilization. And to do that, you need to collect the sperm and the eggs of the females that you've been super ovulating. So it's all a process that is very costly. I need to find funds first to pay for that, because obviously I wouldn't ask Jim to contribute for something he had no direct interest in. And this took already about six and a half months. At that time, I already had the sperm and the eggs

28:37frozen. And then when I got the money, I could pay for these procedures and I got all the frozen embryos shipped over to Karolinska. And at the moment I wanted to start the procedure of implantation here. Then the facility that was supposed to do it started moving. So I had to wait nine months before the whole facility here was operational again to be able to get the first animals starting breeding. And in the meantime, I had all the questions from the reviewers I couldn't answer. So the paper got rejected several times. This was a big, big problem. Some of the first

29:11comments from the reviewers was, well, you're working in a C57 background. I said, yes. And then they said, that's a problem because they have a point mutation on a catarin 23, which makes their hearing degrade faster with aging. So it's a model of age-related hearing loss. And I wouldn't understand that as a problem because since you're comparing wild about knockouts in an age where they don't have hearing problems, what's the issue with that? But hearing community was not keen in having this like that. So they wanted a genetic background that's clean of all these auditory degradation.

29:42That's the CBA. So I had my first animals generated and I back crossed them into a CBA background. And that's when I found that the behavioral test was not functioning at all. Oh, wow. One thing after another. So then I was stuck again, not being able to answer all these questions. And so I took wild animals, made the test and found out that the test was in fact very influenced by the genetic environment. So there was specific backgrounds that were very responsive to the test, others that would not. And that's important when you want to start applying these methods because that's for

30:14the moment one of the only objective measures for tinnitus. And if it can be applied to humans, this can be great because you can then make comparisons between effects. If you're testing a medication, if you have an effect in animals, you have a direct comparison with humans. But knowing now that the genetic background has an influence, if you try to apply that knowledge to humans, then you can think and plan your experiments better in terms of design and considering the ethnicity in consideration when testing this. In fact, this method that we're using has been tested before by some people from Canada. And it has been rather controversial because there weren't

30:49clear, repeatable results. And probably there's an influence of more factors than we can ever think about. And the work that has now been published tells that you have to think about all these small details. Absolutely. Well, it sounds like Chris, you have had to get creative and be very resourceful throughout this whole situation to really solve this quandary and get through this challenging transition period in your career. And I really liked it. It sounds like you viewed a lot of these hurdles more as a learning opportunity rather than really getting down on yourself. Well, you should have looked at me at the moment. It wasn't easy. I was furious and feeling

31:21important. But indeed, when you look at it afterwards, it's clearly a big learning process. It's been impacting on my funding strategies because obviously I was not publishing in Antinitus. I was claiming I was doing it, but then when I was applying for funds, I said, well, you have no experience in Antinitus' area, so how can we trust you to do things all right? And hopefully now it's out and I can convince all the funding agencies a little better. Absolutely. Well, we don't just want to talk about the challenges that you face, Chris, though. So can you tell us next one of your own success stories? And this can be a big success or

31:53even just a small win that meant a lot to you? Yeah. So that's something that's ongoing now.

Investigating the heritability of bilateral tinnitus

31:58Coming here to Carolyn's Garden and having the mouse model ready from the start, I started contributing with the circadian projects with Barbara. And another aspect that was also trying now to develop a human Tinnitus project. And I joined a Tinnitus consortium called TINNET, which is a European funded network by the cost agency. The cost is the Corporation for Science and Technology. So it supports networking. We have a big question and the question is how to solve the problem of Tinnitus heterogeneity. And the problem with Tinnitus is that there have been

32:31innovative methods generated, but the tests in the clinical trials haven't been successful. And the thought behind that is that it's because Tinnitus is so different from one person to another, that this is what could have been creating all of these negative outcomes in the clinical trials recently. So Tinnitus can be pulsatile, it can be constant, it can be occasional, it can be intermittent, it can be in one ear, in two ears, it can be generated because of an noise damage or medications that can be created, some people think by stress and emotions. So there is

33:01a big complexity behind there. And one can think there's not a single drug or treatment that will be applicable to everybody. So how can you break down people into groups? So I joined the Tinnitus Consortium having in mind to do more of genetic studies. And that's because we found one of the genes that is involved in Tinnitus in mice with this GAST study. And obviously, the question is, can we find SNPs or proformisms in humans and vice versa? If you find genes in humans, can you use animal models to validate what's going on and understand more about the mechanisms behind

33:33that? So one of the first questions that we had with this Tinnitus Consortium was, is there any evidence that Tinnitus is irritable? And a very, very few studies have been talking about that. And those that have addressed the problem said that there was no genetic influence. And we wanted to break a little bit that preconceived idea and go to the very beginning, that means twin studies. And the advantage with twins is that you have the monozygotic twins, that's the true twins, and the dezygotic twins, which are the non-similar twins.

34:06Mm-hmm. Fraternal twins. Yeah. Yeah. Yeah. And if you see that the occurrence of tinnitus is more frequent than those that are monozygotic, that means that there is a genetic influence. So this has been a standard method for evaluating the heritability of a large number of diseases. And when we started doing that, we used the Swedish Twin Registry, which is based here at Karolinska. It's a national registry. It has more than 150,000 people in there. So we had a huge dataset. And within there, 70,000 had answered

34:37questions regarding tinnitus. And we had about 7,000 that had tinnitus. And from that, we could break down into groups and we could distinguish that there were people that had tinnitus on one side only, and people that had tinnitus on the two sides, on the two ears. And with this, we started looking at the concordance. So what's the likelihood that one of the twin has it if the other has it? And we could see that unilateral tinnitus is rather purely environmental. There's very little genetic influence on it. But if you look at bilateral, then something happens there.

35:08And that's what the interesting thing is. You start breaking it out into genders and age groups, and you can see that the younger you go, and the less you get noisy effects from the environment. It would grow old with age. You have factors like stress and work. You have diseases that happen naturally with aging that start becoming the source of a potential tinnitus effect. But if you go in younger groups where you have less of those environmental impacts, then we could see that in young women, there is a high heritability where the genetic environment supersedes that of the

35:42environment. So that's very exciting. We have it now submitted for publication. It's in review. It's not out yet. I hope it will get out so people can then appreciate that. Some forms of tinnitus are influenced differently by different factors. So bilateral tinnitus can be influenced by genetics. The unilateral is purely environmental in a way. So we can start considering things differently. And I think this is the first step also in all of these approaches is that if there is a genetic influence to tinnitus development, maybe there are also some forms of tinnitus that are simply diseases.

36:17There are young people below 18 years of age, teenagers, even younger ones that have tinnitus. Is it simply due to a disease phenomenon rather than it's symptomatic of another disease? And if people can improve the readouts, the methodologies to assess tinnitus, to manage tinnitus and the different clinics, then it will lead to better knowledge and also better care for these people. Congratulations on this success. I love this idea of you really starting to deeply investigate something that people have just been accepting as true. And I think

36:49there are a lot of these things in science that everyone just says, oh, well, that is the case because that's always been the case. But until you actually start to dig into the data and what's actually going on, I think you're missing a lot of the big picture. So wonderful success story there. And it's great to hear about all these different successes because there's a lot of challenges in science. And it's so nice to take a moment to celebrate. So how did you celebrate the submission of this influential paper? Well, I would say that submitting it was not that much of a success when we found that those differences, that was already a striking result because it was really obvious. I guess once it's

37:23published, that will be when the celebration will be really happening. How do we do that? We have a gathering with all the people from the lab. Hopefully if it's beautiful outside, we were out and then have a glass of champagne and celebrate this. And if it's not beautiful out, you just have to put the appropriate clothes on for the weather, right? Exactly, you guys.

37:41Well, great to hear again about these successes. And I know you can keep quite busy keeping up on all the papers that you have to read for your field, but it's kind of fun to escape the literature for a little while. So I love getting book recommendations from everyone that we have on our show. So Chris, can you give us a recommendation of a book that you've really enjoyed that you think me and the listeners should check out?

Scientific fraud reports and institutional lessons

37:58Well, I need to go back in time because since I had the kids, I haven't had the opportunity to read. It can be a children's book. That's acceptable. That's okay. In fact, recently, I got a book that was suggested by the president of the department here. And that's something rather actual. And that's the Macchiarini case report that has been generated. And probably you've heard about the problems and the scientific frauds that happened here at Karolinska recently. Sure. So now I have the reports that has been generated by an independent committee that had a close look

38:29on what happened here. And I think that that's a nice way of understanding what's the structure of the university, how it's working, what have been the weaknesses, what have been the recommendations, and how the university is going to reflect on that and move forward. I'm pretty confident that Karolinska is going to be taking lessons and feedback and get the system well done. When I came here for my postdoc, and at the time I had problems having the glass knockout been shipped, here's an example of how Karolinska can take the feedback and make progress on that. I just missed the course for the education to be accepted and going down to the animal facility and doing all the

39:03animal care and the experiments. And although I had seven years of experience, the fact that I didn't know what was happening under the Swedish law and regulation didn't allow me to go down. So I just had missed the course. I had to wait six months before I could go down and do some experiments. And during that time, I started writing a complaint about the lack of funding and intent, which in fact worked well because it got published in Nature Biotechnology. It was a good moment to have a gap in experiments. But then I complained to Karolinska and rapidly, they mounted a online system so that people could jump in as soon as they came and could be efficient

39:39and proactive just one week after coming to work. So all of these implementations happened very, very nicely. In this case about Macchiarini, which is a sad happening, I'm reading on it because when I started in Geneva, there was still some talking about an event that happened. A big case, quite similar in a way, whereby one of my professors, so he was doing a PhD in Geneva, my supervisor was Carl Immensee. I don't know if you remember about that event. No, I don't remember that one. So that was in 79. He pretended to be the first one having cloned mammals,

40:11so three mice generated by nuclear transplantation. Gotcha. And there was a paper published in Cell and there was a lot of controversy with this one because nobody was able to recapitulate his findings, no one. And suddenly when he was keeping secret all these methods and sharing nothing with anybody, his PhD student found out that all the pipettes that he pretended having used over the weekend were still broken on his bench, so nothing had happened. And all the problems started to emerge and there was an investigation happening and Carl Immensee had to leave the University of Geneva. So that happened in 79 and

40:45five years later was shown that, in fact, mice from nuclear transplantation cannot develop to term. So it was a completely fake story. And other people have found that, in fact, the coating of the fur of the animals that had been published could not have been generated from what he pretended to have been cloned. Gotcha. So once you start lying, things appear and you cannot escape, but that's a bit of the lesson there. And in Geneva, that was a big problem because it was mediatically very important that the person that pretended that the first mammals had been cloned was him. And in fact,

41:16Dolly came only 15 years after or something like that. So at that time, it was a very big, important claim. And it had, as a consequence, created a lot of problems in people trusting what was all these genetic manipulations. And then people were becoming very precautious about all of these approaches, which is a negative impact of all of that. But there were other cases that happened in Switzerland during that time. So all universities are not free of these problems. And what happens to Karolinska now is mediatic because first, Karolinska is housing of the Nobel Committee. And it's also an important personality,

41:50like MacGirini had published a paper in a big journal that has been a controversy. And that can be a lesson for any researcher, any university to take a look on the management processes and to improve the transparency and recruitment processes in the publication, the records of the lab. Now, most of the lab that we are in, Karolinska are using electronic lab books, which is very nice to store things somewhere safe, and nobody can escape that. So Karolinska has a lot to do, but it has been tremendously improving in the last years. And I think that's going to be

42:25okay for them. Absolutely. Well, I'm glad you brought this topic up. I think in the wake of one of these big challenges, there are doubts about the integrity of scientists, there are doubts about the institution that start to be raised. And I think though that you're right, there is this silver lining because it does force an institution or really the whole scientific community to pause, to stop, to reflect and to review the practices and try and make things better. So I think that is really important. So I'm glad we chatted about this. We do want to talk a little bit about some of the opportunities for travel that you get as a scientist. And I know we chatted about some of the different places that you have gone throughout your career to train at different institutions,

42:57but I want to hear about your favorite travel experience. Can you tell us about a place that you have been that was just the most memorable and where you were and why you were there? I would talk about Santiago de Compostela. So that's in Spain, north, west, next to the coast of the Atlantic. I was there in 2002, I did an Erasmus exchange. So that's a European program of mobility, an agreement between the different universities. So you ship one student in one country and then the university ships another one back. And I went there because I wanted to know more about all the marine courses and Santiago was a good spot for that. And the second

43:32reason was for the language. And finally, it's been a very rich experience to be there, challenging because of the language. Then in that region of Galicia, that area in Spain, very few people talk English. So I was forced to learn Spanish. And on top of that, it's a local dialect, which is a mix of Portuguese and Spanish. Don't tell that to them because they get offended. Right. It's pure Spanish there. Yep. But everybody was very nice. The food was excellent. I had really a very nice time. The environment was great. There was a lot of nice beaches to go in. And maybe the most shocking

44:04experience was that it was raining all the time. So, you know, when you talk about Sweden being, you know, having clothing to adapt yourself to any type of condition in Santiago, they built up, the first floor was going over the sidewalks so that people wouldn't need to buy umbrellas because it was so windy. The umbrellas were breaking anyhow. They've adapted. I like it. Yeah, they've adapted. I counted the number of days I had with sun over a year and I had seven marks over my wall. Really? That's it? Wow. But despite that, the people was amazingly nice. And I really recommend that place for visit.

44:36The old town is a magnificent place to be. The church is one of the most ancient in Spain and the food is great. So if people can go there, it's the city that all the pilgrims take for a trip, starting in the middle of France and then walking down. So Santiago is the last step for pilgrims to be. And that's where you get a seal stamp that you've done the whole walk. Well, listeners, it sounds like we are going to invest in some good raincoats and trying to make a trip over there. It sounds lovely. So now we've talked about some of your experiences, not only with traveling and some of the people that you get to meet on these journeys,

45:07but some of the wonderful people you've had an opportunity to work with over the course of your career. And I think the people are part of what makes science so wonderful. And I know there are stereotypes out there about what scientists are like, but we try and break them on our show to show people all the different faces of scientists, the different things that you do together, the fun and quirky traditions that you develop in different labs. And I love sharing those stories with our listeners. So Chris, is there a story that you can share of your own that showcases one of these quirky traditions or funny memories?

Lab mishaps and fermentation experiments

45:31Yeah, there are a few too. Maybe the one that comes to my mind was when I was at the University of Geneva. So with Serge Nepp, we were a bunch of PhD students starting with him. And it was quite a routine to go to all of the PhD defenses because you had nice cocktail parties afterwards. And then it was a moment of gathering all together, eating something as well. And we noticed that it was also networking. We were there so frequently that the people that prepared the buffet, they spotted us. And of course, after some time, we could take some of these leftovers with us.

46:05And it happened that once I came and I took back a pack of mozzarella that I brought back into my office because I had something to do some experiments over the night. So I left it over my friend's shelf and I forgot it. Oh no. And I forgot it. And that's how I discovered the process of fermentation. Because two weeks after, when I came back in the lab on a Monday morning, I felt that little smell of puke and vomit. Right, right. And I thought, all right, that's my colleague that just had a big party. And then I shouldn't worry about it. I went down to the animal facility, started working without even really taking a look

46:37of what happened. I came back four hours later, the whole floor was in a big trauma. It was. And in fact, I came in and who did this? Who left that bag of mozzarella up there? The thing had exploded. Oh my gosh. People were trying to clean it and scrubbing everywhere and went through the books. I was hated. And then I made the second mistake and that's where I discovered the other aspect of fermentation is one thing, but the drifts of air is another one. I took the mozzarella back, put it in the trash and put it in the corridor so we could just focus in the room. And then all the smelly thing went

47:13over the entire floor in the building. And then everybody from the whole floor went out of the lab screaming like there was an infection somewhere. And that's how I got my name known from the whole building, which is a good thing. You know, you cross people afterwards in the quarters. Oh, Christopher, that's you. Yes, that's me. Great way to meet everybody. No one will forget you. Well, I'm glad to hear you didn't blame it on your friend having put it on their shelf. So I took responsibility for that. Well, that is a fantastic story. And I'm sure you'll never make that same mistake again now. Never again. I love it. Well, I think this is a great story. And I think it shows that scientists are

47:49human. Like we make the craziest, silliest mistakes too, just like everybody else. So I love it. And now in addition to talking about some of these wonderful stories and sharing some of these fond memories with your colleagues, I think it's fun to talk about the big questions in science that remain unanswered. And I think every scientist has a few questions that are just burning in their minds, but there's something standing in their way, whether it's funding, staff, technology, feasibility, there's always a barrier. So can you tell us, Chris, if we took all of the barriers away, what is the one question that you would want to answer first? Chris That's the one I'm trying to tackle now is to cure tinnitus. And for that,

48:22you would need to understand more deeply all the molecular mechanisms. And to understand the mechanisms, you need the mouse models, but you also need humans. And that's what we started now, creating a database of severe cases of tinnitus and collecting DNA and try to sort things out. But if you want to do it really nicely, you would need a very, very large population. And with what we have enhanced, this is not the case. So what we would need is that every NT clinic starts collecting blood and standardize their measures for assessing tinnitus. And based on that, you would start to be able to

48:58identify severe cases, cases where you have also multiple occurrences in families. So some evidence that there is some internal distribution of genetic spread within the family. And then if all the clinics start gathering their efforts together and you have a large amount of information, you can start doing either GWAS or some sequencing or genome sequencing and start identifying genes that are responsible for each of the different forms of tinnitus. So should it be the pulsatile? If you talk about noise,

49:28trauma, maybe it's what is making you more resilient to noise-induced tinnitus or more vulnerable to noise-induced tinnitus. And maybe pulsatile tinnitus, is it something that's more directed by angiogenesis phenomenons or hypertension, or is it something that happens in the ear? And this, once you start having a list of different compounds, you can go back to the animal models, validate it, understand better how it's acting. Is it influencing the neuronal connectivity, either in the ear or in the brain? And once you have these correlations happening, you can start having more serious targets that

50:02you can start developing drugs that can modulate their activity in a more broad population. And that is the aim of it. And obviously it would require the largest funding ever and the larger amount of resources it could have. Absolutely. Well, it sounds like you've got quite a nice plan laid out there, Chris. We just need to get the funders lined up, right?

50:23Well, that is fantastic and great to hear that you are able to work on one of these questions that you are the most passionate about answering. I think that is one of the perks of the careers in science. So throughout your career in science, though, you've received a lot of advice from mentors. You've worked with a lot of wonderful people. Is there one piece of advice that stands out in your mind that was just the best advice that you'd like to pass on to our listeners today? Yes, clearly. When I was a PhD student, and this was just a little bit before I presented my thesis and defended it, I met two people. One was Jean-Dominique Barcelli, the other one was Denis Duboule. And Denis Duboule, I met him personally. We were in a

50:56Congress for Scientific Excellence in Switzerland. It was kind of a funny situation. I ended up with him in a sauna and that's the one where all barriers are broken. We'd start talking about everything. And I asked him, I'm going now to be searching for a postdoc position. What's your recommendation? And he said, the competition is very tough. It's a lot of hard work. If you want to come back eventually, you will need to secure your funding to secure funding in publications, but of excellent quality. So his recommendation was go in a lab that produces a mass of cell papers, science papers, nature papers, and work like a man man. And then you

51:30can have your luggage ready and your portfolio ready to convince people to support you. And I was there. Well, that's not what my first idea of science was, but why not? Right, right. Then I met Jean Dominique and he was a very busy man. As I said, I knocked at his door, directorate office, and he said, well, Chris, my approach would be different. I would say, engage yourself in something that you like most and what you will do, you will do it nicely and you will do it very well. So whatever happens, at least you will have the motivation and the passion to endure all of these hurdles that you will face. And you shouldn't worry about financing

52:05problems. If it doesn't come as that, it shouldn't have been coming. But if it comes because you have the passion and you have the driving force to make things happen, then you will have the greatest life ever. And I think that's the best advice I've gotten. And in fact, when I started visiting the labs, I had several options and the very big labs in which they were producing a lot of papers, I didn't get the feel. And then I met Jim. And when I found this environment, I said, this is exactly where I want to be, because that's where you do the science you want. So I decided to go with Jim. Well, I love the dichotomy of these two very different approaches or recommendations for

52:38how to pursue your career in science. And I think this sort of highlights the fact that everyone does it a little bit differently. And there's no one right way to find that perfect place for you in science. No, totally. So is there any other last piece of advice or any last note of inspiration that you want to leave our listeners with today, Chris? Well, I would say that the work is really hard. It's a lot of challenge. It's working hours that you never count. On top of that, if you're doing work, because that means you have to work at night as well. We have nice beds at Karolinska for night work. Oh, I like it.

53:09But the message is never let it go. And if you find something that is really your passion, and you have that drive to make it happen, be motivated and test yourself, go and find your limits. When I was a PhD student, I think I had maybe three burnouts because I was working so much. At that time, I was also single. So that was not really a problem. I didn't have the kids to take care of and so on. So I was spending day and night in the lab. That was very productive. And at the end, also, I was able to see my own limits. And I think that as long as you haven't

53:41found your limits, you don't know how strong you can be in one area, one domain, how far you can reach the knowledge. And once you've touched that limit there, the typical points, you know then how much you can spend energy on something specific. And then this, you can apply forever. So my advice would be really give it the best you can until you crack, then you know where's your limit. LESLIE KENDRICK Fantastic advice, listeners. Definitely embrace the challenge out there and push yourself. I think that is a wonderful way to put it, Chris. So now, can you tell our listeners how they can reach out if they

54:13want to learn more about you and what you do? LESLIE KENDRICK Yes. So the Karolinska has a very nice web page. You can simply type my name in there and I have a profile page with my email. You can simply contact me through email. Otherwise, I've got a LinkedIn page. That's also another way of reaching me. Or ResearchGate, I have a profile page there. Recently, because we had this Frontiers research topic launched, we started into medias. We have a Twitter account, which is Tin Research. Or I have a personal one also that I use to bounce back on what we tweet. And we have a Facebook page

54:45on the Swedish Tinnitus Outreach Project, which is then the Human Tinnitus Project we started here, trying to understand more about the genetics of tinnitus. LESLIE KENDRICK Excellent. Well, listeners, definitely check out those resources. Get in touch with Chris if you have any questions. And Chris, thank you so much for your time today. It's been a pleasure. LESLIE KENDRICK Many thanks to you, LESLIE KENDRICK And listeners, thank you for joining us as well. We'll see you next time on another episode of People Behind the Science. Your voyage to explore the lives of today's exceptional scientists has just begun.

55:16You can find everything we talked about today, including our guests' favorite books, biographies, photos, and more, when you visit us at www.peoplebehindthescience.com. I look forward to chatting with you next time on People Behind the Science.

55:40CREDIOS