Why I Do What I Do: Spotlight on Tyler Wellman, Patient Family Supporter December 4, 2017 by Lauren Eva Tyler is the younger brother to Will, who was diagnosed with Minimal Change Disease at 25 years old. His disease quickly progressed to FSGS and then kidney failure. Will received a kidney from his mother, but the FSGS began attacking his new kidney soon after transplant. We sat down with Tyler to hear about his recollections of that time and how Will’s experience with kidney disease changed his outlook and influenced his life decisions. NKI: How old were you when Will first started having health issues due to his kidneys? (L-R) Brothers Will, Tyler, and Grant at the 2015 Tampa Pig Jig. Tyler: I think that was spring of my sophomore year of college; I would have been 20 or 21. I can vividly remember the day that Will started feeling rough. Will, my other brother Grant, and my cousin and I went to go see my grandma, and Will was already feeling pretty bad. We went into a Publix supermarket on our way, and Publix has these huge scales that you can weigh yourself on. We were walking out and all weighed ourselves, and Will was 15 lbs. overweight. He got on it and said, “What the heck is going on? Will you guys get on this and see if your weight is accurate?” We all got on it and said, “Yeah, it’s normal for me…” He said, “I’ve gained 15 lbs. That’s so weird.” And he just felt terrible. When we were at my grandma’s, he took a nap pretty much the whole time we were there. After that, a few doctors’ appointments later, he finally got diagnosed with Minimal Change Disease. It was almost a full year before they did a second biopsy and he got diagnosed with FSGS. NKI: When did you realize how serious it was going to be? Tyler: When he first got diagnosed, it was kind of well-controlled, and we had the understanding that MCD goes into remission with steroids. I had gone to Indonesia for two months that first summer that he was diagnosed with MCD, and he wasn’t really that sick at that time. But by the time I came back, he was starting to retain a lot of water weight. The steroids weren’t doing what they usually do, he was still putting on a lot of water weight, and it was hard for them to keep it off. I can vividly remember how puffy he was with all the edema. When they couldn’t figure out how to get it under control, it was really scary. He would just lay in bed all day, because if he stood up, all the water weight would go down to his legs. He had to lay flat. It got so bad that at one point he had stretch marks, and there was fluid coming out of the stretch marks because he had so much fluid. He was kind of kept prisoner by that. He just laid in bed all day. We felt so helpless because there was nothing we could do for him, and everything the doctors were trying wasn’t working. It was really frustrating and sad to see somebody you love suffering like that. NKI: Were you guys close growing up? What kind of impact did this have on you as a family? Christmas with the Wellman brothers Tyler: We’d always been really close; we were really close growing up. Both of my brothers and I would hang out and do a lot of stuff together. I had gotten really active with my faith and my religious life when I was in college, and at that time Will was in Kentucky in graduate school—this was before he got sick—and he was kind of trying to figure that stuff out too. So we got even closer talking about it. Then after he got sick, he became even more interested in trying to figure things out and make sense of his suffering. Having those kinds of conversations definitely brought us even closer together. NKI: It seems like both your and Will’s later life decisions were in some ways influenced by Will’s experience with kidney disease. Could you talk a little bit about your decision to become a doctor? Tyler: When I graduated from college, I went to Micronesia and taught high school for two years. My plan was to maybe go to graduate school or to seminary when I got back. But then, after I was there for a little bit, I realized that I didn’t want to go to seminary. I wanted to do something more hands on, I wanted to have a skill set that I could offer a community. At the time, I was teaching biology in Micronesia and getting updates with what was going on with Will and the treatments that they were trying. I was trying to understand why Will was taking chemotherapy drugs, why they couldn’t figure out what was wrong with his kidneys, and why this was all happening so fast. I remember reading on Wikipedia all the time about these things and trying to understand it. This was all while I was teaching biology and getting really interested in the biological sciences. That got me into thinking about medicine. Then, after being in Micronesia for about a year, Will had his kidneys removed because he was in kidney failure. I went home in December of my second year there for a few weeks for Will’s kidney transplant. I pretty much stayed in the hospital the whole time I was home because Will was there. I would go home to sleep and shower and then go hang out with him all day in the hospital. Tyler and Will with Chris Whitney (center), a close family friend, at NephCure’s Washington, DC Advocacy Day this year. When I was there with him, it all started to click for me: that medicine would be a good fit for everything that I was interested in. Seeing Will’s interactions with the doctors and seeing how much of it for Will was more than just a medical thing, that there was also this spiritual and psychiatric component of dealing with illness—that really appealed to me. After that, I was sure I wanted to go into medicine, and from there the idea of medical school took on a clearer form. NKI: What was your reaction when you found out that the transplant wasn’t going to end up working out for Will? Tyler: That’s another vivid memory. After Will had the transplant and the surgery was done, he had to go to the ICU because his blood pressure was out of whack and hard to control. My cousin and my brother and I were hanging out in the ICU a lot. I remember being in there when they told us that there was protein in his urine, which was a sign that the disease was already starting to damage his new kidney. And you could see on Will’s face, it was just the worst news you could imagine. It was heartbreaking. My mom was still in the hospital recovering from the surgery when Will found out that the surgery was not… that nothing would come of it. He hadn’t even had the kidney for a full month before they took it out. He had had all these ideas in his head about what life after transplant was going to be like. You could see on his face, all of that had just gotten taken away from him. There was so much buildup going into it, for all of us, all of these expectations—that Will was going to get this transplant and everything was going to be better, that he was going to be able to travel all the time. My mom was a perfect match. Everything seemed so good going into it. Then just like that, it was all taken away. It was pretty devastating. After that, I had to go back to Micronesia. When I was back there, Will had his third surgery where they took out my mom’s kidney. NKI: I know Will has mentioned that he wouldn’t want another transplant until there’s a cure. Tyler: Yeah, we talk about that every now and then, because having two brothers, Grant and I obviously wouldn’t think twice about giving our kidneys to him. But I think it was just so emotionally traumatic for him to go through that, that the thought of doing it again is overwhelming. He doesn’t want to ever have to experience that again. NKI: When you think about the future, your hopes for yourself or your hopes for Will, is there anything in particular you focus on? Tyler: I think about Will’s capacity to understand human suffering and to connect with it and make sense of it. I think about his ability to retain faith and hope, while also being able to help people get through their own suffering and help them make sense of it, too… I think he has the capacity to do that where few other people do, because of what he’s been through. His faith has become so important to him. Most people that have changed the world or have gone on to do huge things, most of them either grew up under oppression or they had a traumatic experience when they were young that was a turning point and filled them with a sense of purpose and drive. I think that’s the redeeming part of all the suffering that Will’s dealt with. It’s given him this very clear sense of purpose and knowledge of what he wants to do with his life and how he wants to contribute to the world, in a way that other people who haven’t had to go through a negative and dark experience like that don’t necessarily have. I think it’s impacted me in the same way, just obviously to a much lesser degree than it has him. But I think our capacity to confront suffering head-on and to try and make sense of it has been very much impacted by that. It definitely plays into how I envision myself taking care of patients. So much of my own personal drive and sense of mission and purpose comes from the conviction that Will has of, to use religious language, of redeeming suffering. Of taking this negative thing and redeeming it to make it positive and to bring something productive out of it. I think that’s his whole understanding of suffering: that it’s not meaningless, and it’s not all negative. There’s so much good that can come out of it. It puts you in touch with other people in a way that life without suffering might not necessarily do. (L-R) Will, Grant, and Tyler and two of the newest members of their family at the 2017 Tampa Pig Jig. We were delighted to sit down with Tyler and so moved by his thoughts and memories of his brother’s diagnosis, transplant, and continuing ordeal with chronic kidney disease. We’re so grateful to have such a committed family be part of our NephCure community. You can meet Will, his family, and a community of NephCure supporters at the Tampa Pig Jig, which is held yearly in late October. Check back at the Tampa Pig Jig website to stay updated on the list of performers, schedule, and tickets.
Genetic Research into FSGS and Nephrotic Syndrome: an Update from the Pollak Lab December 3, 2017 by Kylie Karley An Update from the Pollak Lab By Andrea Knob We first checked in with the Pollak Lab and Andrea Knob—a genetic counselor and clinical research coordinator—about a year ago. Below is an update of their work, which receives funding from NephCure to study genetic causes of kidney diseases like FSGS and Nephrotic Syndrome. Patients and family members affected by FSGS and Nephrotic Syndrome are invited to participate in the Pollak Lab’s research. Please contact Andrea for more information. Andrea: As the holiday season approaches, we want to express our gratitude for the support of all of our patients and families, nephrology providers, and support networks including NephCure in the challenge to fight kidney disease. In the Pollak lab, we are working hard to identify and understand the genetic factors that may be contributing to the cause of kidney diseases such as FSGS (focal segmental glomerulosclerosis), Nephrotic Syndrome, unexplained proteinuria, and unexplained kidney failure in individuals and in families. We hope that by learning more about what causes these conditions, we can eventually help scientists discover better treatments with less side effects in the future. Researchers in the Pollak Lab Technology has been significantly improving over the years, and so has access to these technologies. We are able to look at genes and different variations of genes and study them in ways that were unimaginable decades ago. Genes (which we can think of as the “words” within DNA) are the instructions for the body to carry out its functions and give rise to traits. We look at genes related to the kidney in order to see if the instructions are what we expect or if there is variation. From there, we want to know whether a genetic variant is a normal part of the diversity from person to person or whether the genetic variant might be giving incorrect instructions for the kidney to function as it should. The Pollak Lab is looking for patients and healthy family members to participate in their ongoing study. You can participate from anywhere in the world! Here at the Pollak lab, we have identified genetic variants (mutations) that we know are associated with kidney diseases such as FSGS, Nephrotic Syndrome, and related conditions. We have done a lot of work with genes such as ACTN4, NPHS2, TRPC6, INF2, and APOL1, for example. We want to know more about these genes and how they work, but we also think that there are other genetic mutations to be discovered. Current genetic technologies allow us to study the actual genes, but we know that the stories from patients and families experiencing kidney disease is truly at the heart of the answers that we are seeking. If someone has a particular gene variant, what does that mean for that person? What are their exact symptoms? Do other people with the same gene variant have similar symptoms? What treatments have worked or have not worked? What additional factors (genetic, environmental, lifestyle) may be accounting for the differences from person to person and/or family to family? To answer those questions, we have to rely on the generous contributions of time, information, and personal stories from patients, families, and providers which helps us to understand kidney disease in new ways and helps us to develop new ideas and strategies aimed at prevention, diagnosis, and treatment. We are truly indebted to all who have participated in our research this year and in the past, for without your generosity, we would not be able to do the work we do. Andrea Knob—Genetic Counselor and Study Coordinator for Dr. Pollak’s study We also invite anyone to participate in our ongoing research, and we hope to team up with providers who care for individuals and/or families with FSGS, Nephrotic Syndrome, unexplained proteinuria, and/or kidney failure. We hope to continue our collaborative efforts and reach out to communities nationwide. We invite you to contact us at any time whether you are a patient, family member, or friend looking to learn more about our research, a previous research participant following up with updated medical, family history, and/or contact information, or a nephrology provider interested in referring a patient(s) and/or collaborating. Our study is very simple and can be completed from home. To learn more about us, you can contact us by phone at 617-667-0467, by email at aknob@bidmc.harvard.edu, or visit our website by clicking here.
NephCure Funded Research: Dr. Anant Madabhushi December 2, 2017 by Lauren Eva Dr. Anant Madabhushi is developing deep-learning software that could predict how diseases develop. In October, NephCure awarded Dr. Anant Madabhushi a NEPTUNE Ancillary Studies Grant for his work on computational imaging of kidney pathology slides. The Nephrotic Syndrome Study Network, or NEPTUNE, is a long-term observational study that has gathered health data and biological samples from close to 2,000 glomerular disease patients nationwide. Researchers can apply for grants to conduct research on this de-identified patient data. Besides having helped fund the creation of NEPTUNE, NephCure also now helps provide the funding that make a number of the ancillary studies possible. We recently spoke with Dr. Madabhushi to learn more about what he and his team will use the NEPTUNE data to study, and how he sees his work contributing to the future of precision medicine in the kidney field. NKI: Could you give us a brief synopsis of your work and what you’ll be using this award to study? Dr. Anant Madabhushi Dr. Madabhushi: Over the last 12-13 years, my group has been developing the technology and algorithms for analysis and computational characterization of tissue images. When someone gets a biopsy, their tissue slide has historically been read by a pathologist. But now with improved technology, we can scan these slides and create digital images. We can then start to train a computer to create a predictive model that is able to look at the digital images and identify patterns. Doing this could tell us about disease presence and aggressiveness and potentially about response to therapies, which is a big deal. Being able to use a computer to figure out, from a routinely acquired tissue slide alone, if there are patterns which may tell us which patients may or may not respond to a particular therapy is of immense value to a clinician. It allows for potentially better therapeutic management for the patient, potentially obviating the need for more aggressive therapies in patients who may not receive added benefit from them. So that’s been a large part of our work over the last 12 years. Most of our work has been focused in the cancer domain. I’m really excited about the NephCure award because it represents our first foray into the non-oncology space: we’re looking at kidney disease, which is somewhat novel to me. The project that we are pursuing with the NephCure award is to develop a set of tools and algorithms—software—that will start to analyze tissue images of kidney biopsies. With these tools, the computer has the potential to start to recognize patterns of aggressive disease. The ability to do that in the context of kidney disease is huge, because there’s still so much that we don’t know about kidney disease. We still don’t know so many things about response to therapy and outcome and prognosis in the kidney disease space. The long-term vision is that these tools will allow a clinician to be able to prognosticate, based on kidney biopsies, how a patient is going to do and what treatment might be appropriate for them. I need to qualify that we have one year. So the question is: what are we going to be able to do in one year, and how does that set the stage for the long-term vision and realization of the bigger picture of kidney precision medicine? The goal of this specific project is to develop a set of tools that will allow end-users, that is, nephrologists, pathologists, to use this software to create very deeply annotated mark-ups and portraits of the different structures in kidney pathology images. For instance, in kidney pathology images, we know there are different individual substructures, like glomeruli, proximal tubules, capillaries, and so on. The goal is to train the computer so that it can go in and start to identify all of these structures on its own. Once we’ve created a deeply annotated data set of images with all these structures identified, now one can start to ask specific hypotheses. For instance, once the computer has identified where all the glomeruli are, can I figure out whether there is an association with treatment response or recurrence of disease, just based on the number or location of glomeruli? So what we have is essentially a sort of a pattern-detection pilot project. Hopefully by the end of it, we’ll have these patterns mapped out by the computer, and then the nephrology and nephropathology communities can start to look at those patterns and say yes, these patterns seem to be important in transplant rejection, these patterns seem to be critical in chronic kidney disease or nephrotic syndrome. The goal is to create the enabling technology that allows clinicians and pathologists to go in and start asking those prognostic and predictive questions. NKI: Is this software that your team is developing something that, down the line, will get smarter with more data? Dr. Madabhushi: That’s absolutely right: the more you give it, the smarter it becomes. The problem is, it’s not just about giving it any data, you have to give specific data to the computer. In other words, if you want the computer to recognize what a glomerulus and a capillary are, you have to have an expert, a pathologist, sit down and map out these specific structures and then feed the image to the computer. The computer then looks at a large number of these and starts to learn and recognize these structures and then starts to provide the output. Let’s think about that for a second. Who are the people that are going to provide these annotations? They would be expert pathologists, nephrologists, and nephropathologists. These are not people with a lot of time. I’ll give you an example: we published a paper in Nature Scientific Reports looking at how to train a computer to recognize patterns of invasive breast cancer on tissue slide images. That work took four years, because we had 600 slides. On each of the 600 slides, we had to have a pathologist sit down and manually mark up where the cancer was. Those annotated slides were then used to train the computer. A lot of these algorithms are very dependent, not just on images and data, but on manual annotations of the data to become better and better. The pathologists and clinicians who are going to be able to do these annotations just don’t have the time. They don’t have the bandwidth to be able to sit and spend hours doing the markups and the annotation. What is the alternative? You need to be able to make the computer quick and efficient in the way it learns. One of the critical attributes of what we’re developing is a very lightweight version of this learning infrastructure. In other words, what if we could train the computer with just four or five examples? If you could, in 20-25 seconds, mark up what you want the computer to find on four or five slides, and then the computer rapidly uses just those four or five examples to create a network and a prediction and give you the results. An example of the way a computer can use deep learning, aided by manual annotations from a pathologist, to learn to identify the substructures of the kidney. Now, because the computer learned with just four or five examples, it’s probably not going to do a great job. But that’s okay, because what the end-user can now do is edit the results from the computer. Let’s say the computer found the majority of the glomeruli, if that’s what we’re going after, but it missed a few. Now the user can go in and say, “I see that the computer missed it here and here, so I will mark those up. I also see that in these few places, it seemed to identify something as a glomerulus when it wasn’t. So I will erase that because that result isn’t right.” So now with another 20-30 seconds of interaction, we’ve cleaned up the results from the computer. The computer then takes that cleaned up result and re-learns. What we’ve done is created a very efficient way for the computer to learn that is not taxing on the end-user. The initial result is not great, but with a few iterations back and forth, the computer can very quickly start to become very efficient and accurate. The other advantage of this model is that it makes it very generalizable. I won’t need to spend three or four years creating a dedicated glomerulus detector. In one day, I could have the software learn what a glomerulus looks like. This is a big deal, because what would have previously taken years, we can maybe do in a few weeks. That is really what is exciting about this. The computer is able to do the bulk of its own self-learning: We’re teaching the computer to be more effective in learning rapidly. NKI: You mentioned that you hadn’t really worked with the kidney before. How did you get involved with kidney pathology and get connected with NEPTUNE? Dr. Madabhushi: Three people: Laura Barisoni, John Sedor, and Michael Feldman. They got me into thinking about kidney pathology. Michael Feldman is a pathologist at the University of Pennsylvania. I’ve been working with him for a long time on a number of different cancers. He called me up one day and said, “We’ve got to start thinking about the kidney.” Before I knew it, I was connected to Laura Barisoni, who is one of the world’s leading nephropathologists at the University of Miami. And then, Dr. John Sedor, a nephrologist literally down the road at the Cleveland Clinic who I had not met before, stopped by my office one afternoon, and we started talking about the kidney and kidney pathology. So this conversation started about a year ago. It’s actually quite unbelievable. I met John and we started to brainstorm about opportunities in the kidney space. This work is the culmination of those conversations and the frequent meetings that we have. It’s been their persistence, resilience and passion that got me excited about kidney pathology. I’d been very happy working in the oncology space. This was them appreciating the utility of the tools that we’ve been developing in the oncology space and realizing that these tools could be transformative in the kidney pathology space. I really credit these three folks for bringing me over to the kidney side of things. I will say, this award is a real shot in the arm. It really energizes us. We’ve been doing this work off and on using cobbled resources. Andrew Janowczyk, Yu Zhou, and Jeff Nirschl from my group have done an outstanding job in creating the initial software infrastructure to get us where we are currently. Now, given the fact that we have this award, it really allows us to increase the tempo and rev things up. We can use this as a basis to launch potentially even bigger projects and create a bigger operation in the kidney pathology space. We had a great time chatting with Dr. Madabhushi about his work and are very much looking forward to seeing his team’s advances in kidney pathology imaging. Stay tuned to www.NephCure.org for updates on their research and other news from the field. Dr. Anant Madabhushi is the F. Alex Nason Professor II of Biomedical Engineering and the Director of the Center for Computational Imaging and Personalized Diagnostics at Case Western Reserve University.