Sylvie Breton, PhD, MSc: The Power of Discovery

Ever since she joined the Mass General Research Institute in 1994, biophysicist Dr. Sylvie Breton has been driven by the promise and potential of discovery. She has devoted her career to research to better understand the inner workings of the human body at the cellular level. More specifically she has focused on developing tools to help doctors prevent and treat acute kidney injury, a common medical complication that affects more than four million people each year and is often called the silent killer for its lack of symptoms.

In fact, her discoveries have led her to make unexpected connections and her research has moved toward the male reproductive system and men’s health. Today she serves as the Inaugural Richard Moerschner Endowed Chair in Men’s Health and she continues this quest for discovery and encouraging the same for others. So welcome, Sylvie.

A: Thank you for having me.

Q: to start out with can you talk a little bit about the work you’ve done with acute kidney injury and how you got to where you are?

A: Sure. So, first acute kidney injury is a very complicated or often deadly complications of hospitalized patients. It affects one in five adults at the hospital. And doctors have very limited tools to diagnosis and also treat AKI.

So, AKI actually happens when your kidneys stop working. It’s almost like having a kidney attack. It doesn’t cause any symptoms, so the patients do not know they are in a AKI crisis, and the doctors don’t have good tools to actually diagnose it really early. It’s a very deadly complication for that reason. So, it will happen often secondary to different causes of hospitalization.

It could be a major surgery. It could be a major car accident, sepsis, name it. It’s something that will often affect a lot of people at the hospital. In my lab we have been studying kidney biology for a number of years and we like to think outside of the box, so we are actually comparing the kidney with a smaller organ that is located in the male reproductive tract called the epididymis.

And we set out to really understand how cells communicate with each other and how cells sense the environment so that they adjust the function. And one role of both the kidney and the epididymis is really to control the pH of the environment. We wanted to understand how these cells can actually sense pH and how can they adjust their function accordingly.

So, we looked at the genomic profiling. We identified the genome signature and we found a very surprising result in the so-called kidney intercalated cells. They express very, very high level of a specific receptor that we didn’t anticipate, and we found that receptor actually senses a danger signal that our body creates when it’s under stress.

These patients are often at risk of developing a kidney attack. So, how do the heart communicate damage to the kidneys? And it’s via the release of this damp molecule which is called a danger molecule that circulates in our body and doesn’t create so much damage.

The problem for the kidneys is that it’s their role to excrete this molecule while it will get amplified in the pre-urine as it is being formed in the kidney. This molecule then binds the receptor that we just found was so highly expressed in these cells, and this receptor now starts initiating an inflammatory response. So, renal inflammation or kidney inflammation will then lead to kidney damage, and that is what happens when people have an AKI or Acute Kidney Injury.

We were pretty excited by this discovery because not only did we have a way for doctors to diagnose the kidney injury, even sometimes predict it, because we could detect this danger molecule in the urine of these patients, but also we knew how to block the receptor. We had in our hands a potential strategy to offer doctors and patients for both a diagnostic and a therapeutic combination.

Q: So, basically, because you can see the danger molecule you can predict and stop what would have happened. Is that--

A: Exactly.

Q: -- Accurate?

A: Exactly. So, this danger molecule we actually tested that in a short, a small study in cardiac surgery patients. We can actually detect this molecule in the urine before the diagnosis markers that doctors use, and we can predict therefore that these patients will have acute kidney injury in a day or two.

Q: So, when you started out on your search looking for these indicators did you know what you were looking for or were you just searching?

A: It was a total surprise, honestly. So, we were looking for other receptors of the same family, because they were pH sensors. This one is not a pH sensor; it’s a danger sensor. We were really surprised to see it, but we couldn’t fail by looking at it, because it was so much more expressed than the other receptors, so that triggered our curiosity and we said, “Okay, what is it doing?”

Q: When you start doing research do you usually have an end in sight, or is it usually sort of we know we’re going to go in this direction? How do you approach a problem like that?

A: Often we make hypothesis and we follow this hypothesis and we get results. Often these hypotheses are okay, but we can’t, by looking at a pathway A we will find B, we find something that is unexpected. And I think often the breakthrough in medicine or the major discoveries we make are often those discoveries that we did not predict we would make. It’s almost like we need to listen to our results and really explore what they are telling us and adjust our way of thinking according to what we get in the lab.

And in this case I think it’s the power of basic research. Basic research is what’s the driving force for any breakthrough in medicine.

Q: Can you talk a little bit, I hear people talk a lot about basic research, but I’ve never been totally clear what it refers to?

A: Basic research or fundamental research in biology is really understanding very well what happens within an organ. So, the function of this organ, the function of the cells that build up this organ. And people will say, “Why don’t we know already what kidneys do?” We say, “We know what they do, but we don’t necessarily know how they do it and how they adjust their function.

We eat a lot of meat or we do a lot of exercise, we’re creating acid. How do the kidneys know they have to dump more acid in the urine all of a sudden? This is the mechanisms underlying cellular function that are still not completely understood. And that’s why we need to still do a lot of basic research we call it. It’s the understanding of the really the function of these cells.

Q: So, I think as a layperson you think our science is so advanced, and to hear that there are these other things that we don’t understand is surprising.

A: Well, I’ve been studying these so-called intercalated cells for 24 years and the similar cells in the male reproductive tract, they are called clear cells, and still we are discovering new things.

We discover new, new small organelles in these cells often. We discover how they communicate, what is the code they use to talk to each other. So, they work often in a concerted manner and they adjust the function relative to the other. So, there is a lot we still need to learn.

Q: And is that, is it common to most of the organs of the body that we still have this sort of basic understanding that we need?

A: Sure, and I would say perhaps the two more complicated organs in the body are the brain and the kidneys. So it’s surprising that I say kidney, right?

Q: Yeah.

A: But the kidneys have a lot of different cell types--at least 25 different cell types. They are one million cell units per kidney. There is one million small filtering units and tubular units in kidney, per kidney. So, just to understand how they organize with each other and how they, again they respond to what we do to modulate our homeostasis in our body, we have still things we need to learn.

Q: I was surprised to hear how many people have these acute kidney problems and there was so little we knew about it.

A: It’s actually, as you mentioned earlier, it’s called a silent killer, because it kills four million people every year, it kills more people than prostate cancer, breast cancer, heart failure, and diabetes all combined, and yet it’s not something that people are aware of, but we all know of people who have a medical complication. I know my granddad had a medical complication after his sepsis. I then learned it’s actually AKI he died from.

Q: It seems like it’s hidden as an issue. Do you have a sense of why that is?

A: And I think it’s because it doesn’t hurt. The patients don’t suffer. It’s not something that hurts you.

Any other organ but the pancreas maybe or the brain, when they are injured they, all of the other organs we know, if we don’t, the stomach doesn’t feel well we know immediately, the heart we know. The kidneys don’t hurt when they, when they hurt. So people are not aware of it, so therefore it’s not something they think about. Doctors do think about it, but they won’t necessarily say your kidneys have failed or we are worried for your kidneys. They will say, “You have a complication. We’re looking at it.”

Q: Yeah.

A: And also because there is no treatment at the moment, because again the kidneys are so complicated. In this case actually we’re looking at organ-organ crosstalk so we’re looking at how a distant organ to the kidney communicates damage to the kidney.

So in this way it’s important to actually look at the patient as a whole and in more holistic manner and understand there are messages that circulate in the body that the one organ can use to transmit damage to the other.

Q: Yeah, and it’s funny to hear you say that, because I think, as you said, you think about your organs as being these separate entities and you have specialized doctors for each one of them, but on the other side it makes a lot of sense that they’re all part of this one system within your body and so there are those connections.

A: And especially for the kidneys, because the kidneys are often at the center of the storm, because they are trying to really release and then and excrete all these danger molecules floating around, and by doing that, and again they’re concentrating those, so they become then the new target for these molecules. They’re sacrificing themselves to save us, basically.

Q: Thank you, kidneys.

A: Right, exactly.

Q: I’m wondering, now, so you’ve made this discovery about what causes this acute kidney injury. You’ve come up with some diagnostics and some treatments for it. It seems to me it has the potential to shift medicine and the practice of medicine. So, what does it feel like to be in those shoes?

A: It’s amazing. I mean it’s almost humbling in one way, because you, when you realize this, when we have this eureka moment in the lab and you say, “Oh my god, I’ve got something that can change patients’ life” it’s very exciting, but then you don’t want to miss, you don’t want to miss it. You want to make sure that it will reach the patients, because in our labs we work in the bubble, so we now need to get this discovery out and known and developed so that it is a real drug, basically, a real medication, or a real diagnostic for patients.

So, it’s our ultimate goal. The basic researchers or scientists, when we work in labs, ultimately, we all dream of it somewhat. We don’t necessarily think we will make a discovery that will have this amplitude, but when we get there it’s really exciting.

Q: It’s exciting to even read about it, to think that all of these thousands of people could, who maybe would have been affected will now have a totally different trajectory.

A: Absolutely. And the kidney field has been a field where there was, I would say, less progress made compared to the cardiology or even oncology, for example. Yet it’s a very serious problem. Having a kidney problem can be very deadly, and I think kidney patients, when I actually meet with them they are looking for solutions and they need, they need hope in front of them.

Q: Yeah, absolutely. So, you’ve made this discovery and I’m wondering when you think about taking it out of the lab and into patient care how do you think about that?

A: So, this is something we are, honestly we are not trained to do as a basic researcher. We are trained to make discoveries, but first we need to learn to protect this discovery before we actually make it public, and that is something I realized relatively late in my career.

So, the first thing I would say is that make sure you are protecting it through patent application. You are in possession of this amazing discovery that now you have to make it public and known. People who are going to be able to provide the funding for us to actually develop it, and now it’s more like outside of the traditional research funding that I’ve been used to do.

So, we actually decided to jump and then see whether we would fall off the cliff or we would fly off. So I decided to become cofounder of a startup company, and assembling a team that can do what I am not trained to do.

So, very often what happens that you build up your business case and then your value proposition and you go around and then you talk as many people as you can, and we did get some success in doing that. So, right now I have a very good team with me who are involved in developing this new molecule into a real medication and some angels who were really deep into this, because some of this had seen it firsthand.

One of them was the father of a young boy who needed cardiac surgery and the surgeon told him, “I am pretty confident that his heart will be fixed after the surgery, but I’m worried about his kidneys.” And he said, “What are you talking about?” And he said, “Well, I need to talk to you about AKI.” So, they knew AKI.

So, this is the type of people you see initially who believe in you and will believe in your story, and then you move it to the next level. And now we have, we have made success, we completed our seed round, and we’re getting into IND, so Investigational New Drug application at, for the FDA approval for eventually be allowed to try it in patients. So this is where we are. Lots of things to learn on the road.

Q: I love hearing you talk about it. What was it like to go from being in the lab to now leading a company?

A: It had, I had to think a lot about how to reformulate how I explain things to people, because the way scientists think, we are building a story and it’s all evidence-based.

So, I would start being very boring, and everybody would fall asleep, and so I would test what I would tell to people, to people near me, and they would say, “No, no, no, no, it’s boring, Sylvie, so change your way.” So, now I start with “what is AKI?” more than what are the cells I am looking at. So, it’s like a more global way of looking at things and how it may make an impact on patients, because ultimately that is what we’re looking at.

Q: Have there been other challenges beyond the communication piece in this pivot that you’ve made?

A: Well, the challenge is because I still want to be in charge of my own lab, and as you mentioned discovery before, so it’s not because I made that discovery that I stopped making discoveries, so I still want to remain in my lab full-time.

So, it’s the striking the balance between how much time I will use to build this startup company versus how much time I still want to run my lab. And that’s why it’s so important to build a team around me, so the team I assembled now is doing most of the work on the company side. So I can stay in my lab and continue to make discoveries.

And making these connections between the kidney and the epididymis I think we can not only help patients with kidney problems but also couples who go to the fertility clinic. Half of the cases of male infertility are still called idiopathic, meaning we don’t know the cause.

So why is that? Half of the men, they are infertile, but we don’t know why. Still to these days. So, that’s why I want to study this little organ called the epididymis, which is very important, in my opinion, for the spermatozoa cells to mature well.

Q: Can you talk some more about that? When I read what you did I was so surprised that it was kidneys and male reproductive system.

A: Yeah, they do sound like they’re completely different organs, right? So, the kidneys are there to maintain the blood, the pH of our blood very stable, to make sure we get enough water, if we drink too much we can dump more water in the urine, the salt balance. There is a lot of things the kidneys do.

The epididymis also does pretty much the same thing. And it is all very important for pH adjustment, sperm cells, they need a very specific pH at which they will mature well and they will be stored. The testes can make millions of spermatozoa all the time, but these sperm cells are baby cells, they are not mature. Now they will not be able to find the egg and fertilize the egg.

So they have to go through this long tubule that is seven meters long in men, that is called the epididymis. It takes them about one week to do so. And as they move along this little tube they get new proteins, they shed new proteins, and they mature. And that is when they will really acquire the ability to fertilize the egg.

So it’s a functional thing. So, when a man goes to a fertility clinic they will look at sperm count, the sperm numbers will be fine very often in half of those men, but the function is not there. It’s an organ that is very understudied. Very few labs in the world actually study this organ. And I think, my opinion, that is why we have so many cases of male infertility that we still do not understand.

Q: It’s kind of incredible there are these, so many little nooks and crannies of the body that we didn’t even know, I didn’t know were there.

A: And in my lab I think it’s one of the hallmarks of my lab is that we try to think outside of the box.

So, I was trained as a biophysicist and I’m a cell biologist, so I look at things a lot in mechanistic ways. It’s more how they work. And then by looking at the epididymis and the kidneys, by the way they have the same embryological origin, so it’s not so surprising that they have cell types that have similar function.
And the epididymis is a simple, more simple organ. I mentioned the one million tubes per kidney. The epididymis is one tube per organ, so it simplifies it right away. So then I can look at what happens in the epididymis and I can translate that to what we think may also happen in the kidney. And so far all these comparisons have worked. What happens in one organ also happens in the other.

Q: You talked a little bit before about making this initial discovery. Does that propel you to the next discovery or do you take some time to feel satisfied?

A: Oh you never take time to feel satisfied, never. So, it’s nice and now we want to explore it more, so we have animal models to explore. The AKI model, for example.

So, we can treat the mice and actually the molecule I was talking about treats them very well. So, our little patients do much better with that molecule. That’s why we’re so compelled to now look at the developing it into a medication.

One thing I would like to explore right now, is to see whether the epididymitis, which is the inflammation of the epididymis that affects a lot of men thousands of men have pain, undiagnosed pain that is most likely due to an inflammatory response, we would love to explore our new molecule, whether it could also help these men.

Q: And I’m wondering do you have a creative process for research that you follow or does it, is it different every time?

A: Well, the creative mind is a complicated thing, right? So, for me especially, and I think for everybody around me, to be in our creative mindset, we need to be away, we need to have protected time that is away from the administrative burden that we face. So, my ideas are very rarely I will have them in my office. It’s the least convenient place to get ideas. I will have my ideas when I hike, when I am on the beach looking at the sunset, when I do activities outside.

I love to be near nature, so very often it’s when I go for a long walk with my dog and all of a sudden my mind gets ideas. I don’t even ask for my mind to get ideas. It’s like they’re there and they come, they come up.

I always love to talk with my colleagues. We have lab meetings when we sit down around a table and we brainstorm and we test our hypotheses. I have been fortunate to have extremely good postdoctoral fellows, for example, and technicians. And the one thing I tell them is that when you come to my office the first day I said, “I am the happiest person in the world, when you tell me I’m wrong.” And they go, “What?” I say, “Yeah, I mean that means my ideas may not always be the right one. And when you tell me that I feel like I’m not, no longer lonely in this, we’re together in this. So we can exchange ideas. Challenge me.” And that frees up their mind as well.

Q: I love that idea of empowering your colleagues and your trainees to challenge you. How do you encourage them to do that?

A: Yeah, my office door is always open and the fact we have these lab meetings where I listen to them and I say, “Well, this is my idea. This is what I think the results are telling me. But again I may be wrong. You are closer to your results than I am. You’re the one who is generating them.” They have the instinct sometimes to say, “Hmm, this doesn’t feel right” I say, “Okay, if you think this doesn’t feel right there is something. Let’s explore that more.”

They know that they don’t have to fulfill my ideas. I am fine with the results that don’t fit our hypothesis. Actually, as I said earlier, that is how we make the best, the next discovery.

Q: Is there a memorable time when one of your trainees or your colleagues challenged you and you got to one of those discoveries that you maybe wouldn’t have?

A: Well, this happens pretty much all the time, honestly, so it’s okay. I think there are different little ways like that where I say, “Oh, this is, I think this is what it’s telling us.” And they will say, “No.” I say, “Alright, okay. I’m listening.” And then there is something I didn’t think about, and I say, “Oh you are absolutely correct. How can we test that?” So, this is how it goes. You need to be able to follow your nose and the nose of your colleague.

And I think that is what makes scientists, that is what makes it such a fascinating and exciting job. It’s the best job in the world, basically.

Q: Why do you say that?

A: Because the power of discovery, it’s like, almost like addictive. It’s like a drug. In our case for example we do cell biology, so that is why I came to the hospital here is to be able to learn the advanced microscopy techniques that will allow me to see with my own eyes what I’ve been measuring with electrodes when I was a biophysicist, when I was measuring currents and voltages in cells, but I wanted to see what it looked like.

And every time I go in the microscope I feel like I am diving into an ocean of new discoveries. It’s beautiful and it’s much more beautiful than what you see on the computer, actually, in looking at these molecules that have been lightened up by fluorescent probes. It’s gorgeous. So, just doing that every day, for me it’s a blessing.

Q: The idea that sticks out to me that I love is that idea of you find these questions you didn’t even know you should be asking and it shifts you in this totally new direction.

A: Yeah, and that is what, that is what NIH has a hard time understanding. The National Institute of Health, what do you do, you write a proposal for the next five years, you make a hypothesis, and you’re supposed to stick to the plan.

What if all of a sudden the hypothesis I made is okay, but I just made, like in this AKI story, I was looking for a receptor that responds to pH, and that is what my NIH grant is allowing me to do. I will still do it, but saving lives is much more important to me, so it’s hard, because now you need to turn around, write another application, get it reviewed, and making sure the NIH people, the next experts will be excited.

It’s a year down the road before I can even start doing anything. And that is why the philanthropy money we get here at Mass General is so crucial is that we don’t waste the time that it takes to review these grant proposals. We can get onboard right away and that is what the chair is going to allow me to do.

Q: So, it sounds like you can be a little more nimble with what you’re doing.

A: Much more, yeah. Yeah, much more flexible and then pursuing these new exciting avenues that we didn’t even know existed six months ago.

Q: And I guess that you mentioned six months. What is the pace of new discoveries?

A: Well, it can be very long. It can be short. There is a little bit of luck in it, I must say, and I think one of the best, the essential quality of a scientist is be perseverant and patient. And you will have new data for sure, the techniques you’re using may not work first time, the model you’re using may not be the right one, you may hit a wall sometimes, and at some point it’s good to stop and rethink completely.

What kept me going is as long as I have ideas and how I can move forward I’m fine. And then it’s the challenge, but it’s also what makes it exciting.

Q: That’s what I always think of is the-- I am not a person with that focus. I’m so in awe of the perseverance, as you said, to follow these small but meaningful, impactful questions from just the kernel of an idea through some discovery.

A: And that’s why I think people, people in the lab are very hard worker, but they have to be smart in the way they work. You have to be passionate about it. If you don’t like the bench work that is not the place for you, but also the team working environment, which I love, so to be part of a team, to exchange ideas, and I mean this is extremely valuable.

Q: And I’m wondering have there been points where you have gotten discouraged? Have you gotten into a research funk that you have to get out of?

A: I always try to have more than one research going on. And that is also what I try to give to my fellows. So, I don’t want to put all of our eggs in one basket, for example. So, when fellows come in my lab I will give them a challenging, more risky project together with another project I know they will get solid results.

So, and it’s by trying to combine the two, the risky research versus the more solid ones we keep going basically.

Q: When you think about your younger self, is there advice you would give yourself?

A: Well, what advice do I give my daughters?

Q: Exactly, yeah.

A: So, one of them is in academia as well in different field, but still in academia, and what I tell both of them, basically, is that the career, a career path is not a straight line. You cannot anticipate where you are going to be in 10 years. I didn’t even know I was going to work on the kidney when I was doing biophysics. So, it’s not that. It’s not that important.

But as long as you keep moving, if you keep moving forward the forward may be left or right, pivot if you need to, and adjust with your expectations and your aspirations. And as a woman it will take longer time if you have kids, but don’t worry about it. Life is very long, so if it takes you a little bit more number of years more than others it’s okay, you’ll get there eventually. Don’t be in such a hurry. So, that is just keep moving.

Q: I’m curious, you mentioned having kids, and did that shift your career, your path, your perspective?

A: Yes, it tainted my life all my life. I-- When having kids, wanting kids, and balancing kids and career, I made a few choices that I got out of, because they didn’t fit me. So, I did make a lot of adjustment in my career. I paused for six years. Before I did my PhD, for example, I was a research assistant for six years, because I wanted to build a family.

Eventually I realized I am going to go for a PhD, so I did it, it took me a long time to get where I am, but in retrospect I was thinking I was wasting my time doing these six years, but I didn’t. I learned so much. And it prepared me so much more for my PhD. I did my PhD very quickly.

So, in the end you feel like you, sometimes you feel like you are not progressing, but you are in one way, and just I call it my bulldozer approach, slowly but surely.

Q: Just keep pushing.

A: Keep pushing, keep pushing. It’s okay. You’ll get there.

Q: Yeah. I mean as a younger person I think sometimes it’s so intimidating, because you have this feeling that you need, you need to know your direction, you need to know where you’re going, and everything you do should be moving in that direction. And then if you have any questions it shakes things up and it’s hard to rebalance.

A: And it’s okay and you need to be flexible. It’s fine. Maybe in the end this direction is not what you like or you would like to change. That’s fine.

Q: Yeah.

A: So, it’s not something-- Let’s not put ourselves in boxes and making sure we fit the box. If it’s not a square box we want, it’s a round box, okay, let’s make the box round. Be flexible, basically, and listen to what you want. That’s what I tell both of my daughters and my young, my young fellows too.

Q: You’re at a point in your career where you’ve been appointed to this endowed chair. What do you hope to accomplish as you look forward?

A: It’s a great honor first, and it’s humbling, and then at the same time you feel exhilarated, because it’s freeing up my brain. If I have an idea I don’t have to necessarily think about writing a proposal, convincing an expert. I have these funds that I can test these new ideas very quickly and get new ones. It’s really, really freeing up my ability to think clearly about what I want to do.

Q: Alright. Well, thank you so much, Sylvie. It’s been a pleasure talking with you. Before we wrap up though I have my final five questions. What is the best advice you have ever gotten?

A: I had, that was about doing my PhD when I was, when after my six years of being a research assistant, and my supervisor said, “Sylvie, you will never lose in doing it. Just do it.”

Q: I like it. Just do it.

A: Just do it.

Q: So the name of this podcast is “Charged”. What does that word mean to you?

A: Charged. I think it’s excitement. It describes about discoveries. This almost like a drug addiction. I’m addicted to the discoveries. I’m charged by being in my lab.

Q: How do you recharge?

A: Hiking, walking with my dogs, sunbathing, things like that.

Q: Do you have a favorite hike?

A: Well, we hike in the White Mountains very much, so it’s great.

Q: When and where are you happiest?

A: Surrounded by my family and in nature.

Q: And lastly, what rituals help you have a successful day?

A: Having a good night of sleep is essential for me, so if I wake up charged by having a full night of sleep I’m good. Yeah, and I always look forward to coming to work every day, so I am never sad because tomorrow is Monday. I say, “Alright, tomorrow is Monday. Good.”

Q: That’s beautiful. Alright, well that concludes our time together. Thank you so much for talking with us, and really enjoyed it.

A: Thank you for having me. It was a great pleasure.