Stacey Dove (00:03):
Welcome back to Until It's Fixed, where we look at pressing topics in the healthcare industry, new approaches to care, and how to make the health system work better for all of us. I'm Stacey Dove.
Callie Chamberlain (00:13):
And I'm Callie Chamberlain. Today we're going to be talking about the human genome. The human genome is defined as genetic information needed to make a living organism. The entire sequence was mapped for the first time in 2003, and genomic research has made exponential leaps since then. Stacey, have you ever done one of those DNA tests where you send in a sample and you find out about your genetic background?
Stacey Dove (00:35):
I have. I've done ancestry.com and I actually had all of my kids do it too because their dad is adopted, and so it's been really interesting to find out what their ethnicity is because we had never known that before. How about you? Have you done one?
Callie Chamberlain (00:51):
Yeah, I actually did something very similar. I am also adopted and sent in my information to 23andMe to find out my ethnic background. And then more recently I did a different DNA test, which was to confirm a genetic biological family member. So that was a hair sample, but it was really helpful to learn more about my background and like you're talking about, and I'm saying as well, these tests can tell us a lot more than just our ancestry. They can help explain a lot about our health and the conditions that we might be predisposed to, which for people like me and your children's father might be helpful if we don't have access to that information.
Stacey Dove (01:28):
That's exactly right. So what we do know is genes don't actually tell the whole story. So doctors link genetic data with phenotypic information, which are observable characteristics like an individual's height, development and hormone levels, that is called clinical genomics.
Callie Chamberlain (01:46):
The use of genome data for clinical purposes such as understanding disease risk prevalence and to guide diagnosis or treatment is really important.
Stacey Dove (01:54):
What's really interesting is linking genomic and phenotypic data can provide a more holistic picture of your health. It isn't easy, but the key is to use clinical genomics in a practical way. In today's podcast, we will learn how clinical genomics can play a critical role in how we study and treat everything from ultra rare diseases to the most prevalent cancers. Recently we heard Erin Satterwhite, President of Optum Frontier Therapies talk about rare diseases on the United Health Group Weekly Dose podcast. She provided a perspective on rare diseases using a horse and zebra analogy that I think you're going to find fascinating. Let's take a listen.
Erin Satterwhite (02:35):
Rare disease is something that's actually defined by FDA and the current definition is that it's a disease that affects less than 200,000 people in the United States. There's also a classification for ultra rare diseases, which is less than 10,000 per year. And what makes these harder to treat is that they're unusual to most clinicians. And when you hear a clinician talk about their training, one of the mantras is that you look for horses, not zebras. If you hear hooves, and unfortunately people with rare disease are the zebras.
So they oftentimes are misdiagnosed. They get lost in the shuffle, and they go through something called a diagnostic odyssey, which is typically from symptom onset to getting the right diagnosis an average of five years depending on the disease. And that's multiple specialists, lots of different testing, and it's a very frustrating experience for not only the person that's experiencing the disease, but oftentimes they have caregivers that are also supporting them. So it's a really challenging space and one that is really ripe for innovation.
Stacey Dove (03:44):
Since each disease affects so few people, you might think the impact of rare disease on our healthcare system is minimal, but there are an estimated 7,000 rare diseases affecting close to 30 million Americans. And a report from every Life Foundation earlier this year looked at the economic burden of rare disease for about half of that population, the cost for those 15.5 million people totaled nearly 1 trillion in 2019 alone. So the question is how do you get this data and how do you actually put it to use? Callie sat down with two experts with two different perspectives. Dr. Ashley Brenton, a molecular biologist and the VP of clinical genomics at Optum. And Allison Pullins herself, a leader in the field of health technology and mother to James who was diagnosed with Marfan syndrome a little over three years ago when he was just two years old.
Callie Chamberlain (04:45):
Allison Ashley, thank you so much for joining me. I'm really excited to have this conversation. Can you share with us a little bit about who you are and what your backgrounds are? Allison, why don't you start?
Allison Pullins (04:56):
Yeah. I'm happy to share more about myself and my family. So we're recent transplants from California to North Carolina. We live in the research triangle region. Professionally, I've spent the last 15 years in healthcare where I focused on delivering both technology and professional services to provider organizations, specifically hospitals and medical groups. Personally, I'm a wife and a mom. I have a six-year-old son, James, and I have a daughter, Naomi, who is almost four going on like 25. We are truly a very normal American family. We love riding our bikes and going on walks. We have pancakes every Sunday, just the exception being that my son is living with a rare genetic condition.
Callie Chamberlain (05:51):
Thank you. We will get into that. Thank you for that introduction. Ashley, tell us about who you are.
Dr. Ashley Brenton (05:56):
Sure. Hi everybody. My name's Ashley Brenton. I am the vice president of Real World Evidence and Genomics for Optum Life Sciences. I'm a molecular biologist by training, so I've been working in genomics for over 20 years now, which is shocking to say. So I did a bachelor's in public health from Johns Hopkins, a PhD in malaria, immunology and genomics at UC Davis. Followed that up with a viral pathogenesis fellowship at the Scripps Research Institute. And at that point I was done with academia and I entered industry, and I spent a number of years both developing and commercializing precision medicine tools. I've always felt that, one, we should own our own health information, and two, we deserve to be treated like individuals through the healthcare system. And that's why I focused on precision medicine.
Callie Chamberlain (06:47):
Wonderful. Thank you so much for joining us. So Allison, I'd love to come back to the opening you had provided around your son and his genetic condition. Can you tell us more about your family's story and anything you want to share about where he's at and what his experience might have been like?
Allison Pullins (07:05):
Yeah. Callie, I think there's this perception that many people have about what it's like to receive a diagnosis of a genetic condition, and it's something like this. You have these very clear symptoms, you know exactly what specialist you need to go to, and you're seen promptly by that specialist. Then you're very quickly diagnosed, and that's followed by what you can expect from having this condition. And then you are given a drug or maybe multiple therapies to help mitigate the effects of your condition. And there are absolutely genetic conditions where this is more or less the journey. And for my son, it is not so clear cut.
Callie Chamberlain (07:50):
So can you talk a little bit about how you knew to go down the road of genetic testing versus this potentially being a condition that just existed within his own health and health status?
Allison Pullins (08:03):
I think we got supremely lucky, to be honest. We knew something was different about James when he was diagnosed with moderate myopia at only 16 months old, and then that myopia progressed until he was nearly minus eight, minus nine and not even three years old. And at that point, we were deliberating treatment options when we needed to screen him for what exactly was causing his major nearsightedness. And when that test was performed, and instead of the shape of his eyeball causing the myopia, which is the vast majority of cases, it was the irregularity and dislocation of his lenses. And that was what tipped off to our ophthalmologist and to us that this could be an underlying genetic condition.
Callie Chamberlain (08:59):
Wow. What I'm thinking about is just the experience that oftentimes people have with providers where they're dependent on somebody like you're describing to just say, maybe we test for this because this one thing looks like it might be off or might signal to us that something else is going on. What resources, Allison, did you feel like were available as you sought treatment for your son throughout that discovery process? And then Ashley, I'd love to hear from your perspective what your thoughts are on that same question.
Allison Pullins (09:26):
So after we were tipped off that this could in fact be something genetic, we were referred to genetics. However, before we went there, we had to make a stop in the echocardiography lab at UCSF to get an echocardiogram to check for an aortic root aneurysm, which is the hallmark of Marfan syndrome, which is what our ophthalmologist suspected that he had. And unlucky for James, he does have an aortic aneurysm, but lucky for the diagnostic process because if he hadn't have had an aortic root aneurysm and some kids with Marfan do not, he might not have gotten a genetic screening, which is just a shame. It's actually frightening.
Callie Chamberlain (10:14):
So let's step back really quickly. Can you define for us what the condition is that you're referencing that your son experiences?
Allison Pullins (10:21):
Sure. So Marfan syndrome is a connective tissue condition that affects the connective tissues in the body. Most specifically, it affects connective tissue, rich organs and parts of the body such as the heart, the eyes, the vascular system, and the skeletal system.
Callie Chamberlain (10:39):
Got it. So can we define also the genome and the sequencing? And Ashley, I know you're referencing that there's lots of different types of things that can be tested. Let's just ground the audience and what is this? How does this work? If we don't know anything about the field, how do we start to think about what this means and put it into context?
Dr. Ashley Brenton (10:57):
So if we think about DNA, as our starting point, DNA forms the building blocks of life, it's our genetic code. DNA is present in all of our cells. We inherit one copy of those genes from our mother, one copy from our father. The DNA is packaged within these genes, and those genes interact with one another. And that entire collection of genes is called the genome. When we're talking about sequencing, we're reading the DNA sequence within those genes, and that tells us how the cells behave, what proteins they make. So are they making skin cells, are they making the cells in the heart? How are they behaving? And when we talk about a mutation, that is a change in the DNA that is different than what we expect. And it's important to note that we're focusing really on talking about genes and genetic mutations, but we interact with our environment and our behavior can also affect how our genes behave, whether or not they're turned on or they're turned off.
Callie Chamberlain (12:05):
Very helpful. Thank you for describing that for us.
Dr. Ashley Brenton (12:08):
Well, and Allison, let's talk about what a genetic screen really means. There's this idea that, okay, they suspect this genetic disorder, so what happens next? Well, you get a diagnosis and that's not really what happens. There's a lot of luck and there are many steps involved in the process. I know you guys went through some of that.
Allison Pullins (12:29):
We did, and it's when James was clinically dosed with Marfan syndrome, the plan of attack was to test James first for the mutation in FBN1 gene on chromosome 15, which is the Marfan gene. And lucky for us at that very first shot, he did indeed have Marfan syndrome, but it's like shooting fish in a barrel because James could have had Loeys-Dietz syndrome. And that is actually associated with several different genes. So oftentimes people with undiagnosed but suspected connective tissue conditions undergo this frankly traumatic journey to find their specific diagnosis.
Dr. Ashley Brenton (13:15):
It's traumatic and it can take a long time. So if we think about somebody who has a suspected genetic condition, usually you'll start with this just a genetic variant test. If that comes back negative, what do you do next? Well, maybe the doctor says, "Well, it could be these genes. So maybe you sequence a few of those genes or a few parts of those genes," if that comes back negative. And this is taking a while each time. Next, you have what we call either a panel or maybe you get a clinical exome. So that's all the coding regions of the gene.
And that first you have to have that part sequenced, and then you need somebody to analyze it. This takes time. If that's negative, what happens next? Then maybe you get a whole genome sequence. And what I found is that sometimes when that first genetic mutation is found, that's where that diagnostic odyssey stops. Everybody says, okay, that must be it. Except we know that these genes and these mutations interact with one another. So we might actually be missing a lot of what's truly going on in many of these cases.
Callie Chamberlain (14:22):
So when we're talking about doing the genetic testing, this is something that, for example, I've never gone to my provider and they have recommended to me. So how do you even start to enter into this world of possibility?
Dr. Ashley Brenton (14:34):
We've seen a rise in the interest of what we call consumer genomics recently in the last several years. So if you think about something like 23andMe and Ancestry, those are both consumer genomics companies. They're testing people's DNA to give them insights. Now, doctors in the medical community have been doing this for a long time, but it was very focused because we didn't have the technology to do this in a more widespread fashion. If you think back at the history, the human genome project was announced over 20 years ago, and it took years and billions of dollars to come up with the first human genome sequence, a huge effort by many brilliant people.
Now, technology has advanced so quickly that it costs less than a thousand dollars to produce a whole genome sequence, and it can be done in a matter of hours, maybe a day. So we're now at the point where we're able to harness this amazing technology in day-to-day medicine. Genetics can be a great way of determining the types of screening that someone might need.
Callie Chamberlain (15:44):
What do you think about Ashley, how to navigate this system and specifically genomics?
Dr. Ashley Brenton (15:51):
Yeah. So I think it's really important that we remember that this all begins and ends with the patient, and in order to provide good insights, in order to develop the right treatments, in order to make sure that treatments are safe, we need to focus on a holistic patient journey. And we need data to support these analyses, to understand progression of the condition, to understand what causes the different conditions, and then to understand how to treat them.
Allison Pullins (16:19):
Callie, one thing that really surprised me when James was diagnosed with Marfan syndrome was that there were no targeted therapies for my son's condition. And when I started to ask why that was and uncover the history of Marfan syndrome specifically, but all these other thousands of rare genetic conditions that are out there, there are no drugs because there's no data. That's really the very first step in drug discovery is to have these data sets.
Callie Chamberlain (16:53):
Are there any examples of rare genetic conditions where we're further along or they can be an example of where we're trying to go with other conditions like Marfan?
Dr. Ashley Brenton (17:04):
So I think a great example of a condition that has a genetic basis that has made a lot of progress is cystic fibrosis. 20, 30 years ago, a diagnosis of cystic fibrosis was really a death sentence. Many of these individuals did not make it out of childhood, but with advances in sequencing, the mutations that cause cystic fibrosis were discovered, and then companies were able to develop drugs that treat the underlying genetic basis for cystic fibrosis, and now we see individuals living much longer, much healthier lifespans.
Allison Pullins (17:46):
What Ashley said is absolutely correct, but there's a very rich understory as to how that happened for cystic fibrosis. CFF or the Cystic Fibrosis Foundation had the great fortune of having, one, incredibly strong advocates as well as visionary leaders who said, "It is unacceptable for children with CF to die and not live healthy lives." Without that vision, it wouldn't have happened. It's so admirable.
Dr. Ashley Brenton (18:21):
That's an important point, Allison. We have the science, we have the technology that's progressing. We have a lot of brilliant minds working on this. We need the vision too, and we need to connect. It's a whole ecosystem. We need to connect those scientists doing the basic science to understand the conditions with the doctors who are treating these kids. With the families, to make sure that they have the right advocacy, and then working with the regulatory agencies to make sure that these drugs are approved and we have the right safety studies and we're continuing to innovate and to aim big, we should be taking those moonshots.
Callie Chamberlain (19:02):
So where do we start to be able to reach where you're describing the ecosystem is deeply connected and aligned.
Dr. Ashley Brenton (19:10):
So I think that data is at the key of a lot of this because it provides insights into the disease progression, into new focus treatment options and drug discovery, into provider education. So providers can identify people possibly with some of these conditions, order the right genetic testing. So we have a diagnosis sooner, but we have to make sure that we have the right data and that the data are valuable. It's a quality issue and not just a quantity issue.
Callie Chamberlain (19:41):
We're talking about looking at certain types of genes. If we can figure out something about one gene, does it help us potentially accelerate other types of clinical treatments that were not possible before?
Dr. Ashley Brenton (19:52):
So one of the great things about genomics is that all of our genes are interrelated. Where one entire system, all of the genes interact with each other. We're interacting with our environment, our behavior shapes our genes, and so often insights into one condition can lead to insights in other related conditions or even unrelated conditions. So any insights that we glean from any condition can provide insights into a number of other conditions as well, and treatment options.
Allison Pullins (20:25):
Totally. Sometimes there's pushback for people that are not in the rare community and they say, "Why would we be developing drugs for this very small subset of the human population?" And as Ashley said, discovering insights into one particular area of our genome often reveals things that we never even knew that affect far more people. Just because we're looking at a condition that may affect one in 5,000 people, it doesn't mean that that's the only impact that we will have.
Callie Chamberlain (20:57):
What words of comfort or advice do you have, Allison, for other families like you talk about who are out there in navigating what is so complex and full of grief and all of these other things?
Allison Pullins (21:11):
Gosh, I wish I had a playbook to share. I don't. Every journey is so different. When I talk to other families that are just going through the early stages of diagnosis, I empathize with them and tell them that the beginning is really hard and it is a loss, and there is grief that you'll experience even though nobody has died. You no longer can assume your child is healthy and having that taken from you as a parent, it's horrible. I talk about this a lot, and I hate to say that a chronic condition is a marathon. It's like a series of marathons with sprints in between them.
And sometimes patients may undergo acute episodes that are very intense, that are usually accompanied with surgical procedures, hospitalizations, fear of mortality, but then the majority of the time you're simply living with the condition. It may be painful, it may be uncomfortable, it may leave you disabled, but you just live your daily life without much attention from providers or from a support network.
Callie Chamberlain (22:28):
Thank you for sharing that with us. How is James doing today?
Allison Pullins (22:31):
James is six years old, and I'm happy to report he's doing really well. He's in a period of his condition and his health where things are relatively stable, and we are monitoring his vision and his lenses, his aortic aneurysm. We're going to ortho and checking for scoliosis, and he's at this period in his development where he knows he has Marfan syndrome. He's very proud of the fact that he has Marfan syndrome and he knows he has to go to the doctor a lot and that he has to wear glasses, but he doesn't really understand that this is a life-threatening condition that is not going to get any better for him. It will only get worse unless, of course there are breakthroughs in technology and therapies. So for me as a parent, I'm just soaking up every minute of it of his innocence, and we're preparing him to be an accountable and responsible adult later on. But I know that there will be much tougher days for my son ahead.
Callie Chamberlain (23:36):
And he has big goals too, Allison.
Allison Pullins (23:40):
He does. James wants to be President of the United States.
Callie Chamberlain (23:43):
He's got my vote already. Thank you both for being on the podcast today. We are going to wrap with a question, and then I'd love for both of you to answer. So the first question is, what drives your passion for what you do?
Dr. Ashley Brenton (23:54):
I believe that it can make a difference. I 100% believe in science. I believe that we're progressing, and I think that if we remember that it comes down to the patient first, there's a lot that we can accomplish.
Allison Pullins (24:06):
I knew I wanted my life to have impact, and when my son was born, I knew exactly what that impact was.
Callie Chamberlain (24:16):
What is giving you hope right now?
Dr. Ashley Brenton (24:18):
I think making connections like this. So Allison and I met through a former colleague of hers and a current colleague of mine, and we said, "You know what? We have really interesting perspectives here. We are both willing to work at this, and I think we can make something happen." And I think as we see these connections happening outside of our own circles into different spaces, that allows us that vision and that connection to take those moonshots
Allison Pullins (24:45):
Smart people like Ashley give me hope. I mean, the fact that she's working on this problem and won't give up despite the tremendous difficulties and challenges that lay ahead of her, that's so extraordinarily powerful.
Callie Chamberlain (25:00):
Did you have any aha moments or any further clarity during the pandemic or as a result of the pandemic?
Dr. Ashley Brenton (25:06):
I thought the pandemic provided us an amazing opportunity to see how far science has come. All of a sudden there's this new really scary disease, and we immediately sequenced it, identified it. Were able to develop a highly effective vaccine and then roll it out. It was amazing to see science and public health in action.
Allison Pullins (25:31):
For me, it was really fascinating to watch people undergo a traumatic health experience with loss and fear, because that's my everyday life, and I felt like I could connect with people. People understood where I was coming from so much more. Oh my gosh, Allison, like this crippling anxiety that someone in your family could die. That's what you live with every day. So I think it opened up a lot more conversations with people understanding my family's perspective.
Callie Chamberlain (26:01):
Thank you both so much again for joining. It was wonderful to have you.
Stacey Dove (26:05):
As we listen to Allison's story about her family, it was both heartbreaking and yet inspiring and keeping that personal story in mind, we continued the conversation with Dr. Brenton and Dr. Alex Liede, a genetic epidemiologist to look at what goes into studying these life-changing diagnoses and therapies both in the rare disease space and more broadly.
Callie Chamberlain (26:36):
Thanks, Alex for joining us. Thank you, Ashley, for coming back. Alex, can you tell us a little bit about who you are and what you focus on in your organization?
Dr. Alex Liede (26:45):
I'm an epidemiologist working at a drug company called AbbVie, and I focus primarily on real world data and initiatives around innovation related to real world data and building partnerships for access to the right data sources. And partnerships to me it means working with data providers, academics, advocacy groups, registries for access to data, but it also means increasingly working internally within the company with different functions that can leverage real world data. So I've been focusing quite a bit on colleagues on the discovery side and genomics research and precision medicine because increasingly we're seeing more high quality genomic data coming through our real world data such as electronic health records.
Callie Chamberlain (27:43):
Amazing. And can you tell us a little bit about your background as a genetic epidemiologist?
Dr. Alex Liede (27:49):
Sure. So genetic epidemiology really it seems like a newer field, especially when you compare it to epidemiology, which is not really a new scientific discipline. Epidemiology refers to the study of populations or characteristics of populations and diseases within populations. So when we're adding genetic to epidemiology, we're really referring to the influence of genetic factors, their influence on disease incidents and other characteristics for individuals in the population. And importantly, genetic epidemiology really is essentially precision medicine where we can understand subgroups within the population that can benefit most from specific interventions or drug interventions, for example.
Callie Chamberlain (28:45):
Great. And can you share with us a little bit about your background?
Dr. Alex Liede (28:49):
Sure. I did my bachelor's in molecular genetics, and then I completed my master's in genetic counseling and worked as a cancer genetic counselor for several years before embarking on my PhD, which focused on genetic epidemiology, but specifically in breast and ovarian cancer to understand differences in populations. So my focus was primarily in understudied populations that had high rates of breast or ovarian cancer. So I did studies in Pakistan, the Philippines, the Native Canadian population, the Ashkenazi, Jewish and Scotland, where we identified, for example, that there is a common of what is called a founder mutation. So a common ancestor behind the mutation being inherited that predisposes to breast and ovarian cancer in specifically defined populations.
Callie Chamberlain (29:51):
So how do we make sense of genetic or clinical genomic data and how do we use it?
Dr. Ashley Brenton (29:58):
So clinical genomic information can be used in a number of different ways. One is first in understanding disease, what happens, what does the progression look like? What are the risk factors? And another is in how do we develop treatments for individuals with this particular condition? I think that's where my friend Alex comes in.
Dr. Alex Liede (30:19):
Yeah, exactly. I was going to just add that in companies like AbbVie, we really begin with an understanding of the molecular mechanisms of disease that help us understand which targets and how to disrupt that mechanism and really target that area that can interrupt disease progression. So by having access to clinical genomic data, we can understand better the subtypes of the disease as they occur in the population. So that really builds our understanding of what types of patients will benefit most from what types of therapies that we're investigating.
Dr. Ashley Brenton (31:01):
And it's interesting too in this field to see how genetics and clinical genomics differ among different groups of people and also how one's genes interact with their environment. So lots of big differences there, and that's why it's important for us to build these data sets in a way that it's representative, so we have the right information, but we're also looking at the right people.
Callie Chamberlain (31:26):
That's really helpful. To make sure that we're really understanding this concept, can you give me an example of what would be possible from a patient perspective if we were able to have access to all of this data? So from the point of someone being diagnosed, what might this look like?
Dr. Alex Liede (31:43):
For example, historically we've been categorizing disease in the population. We using very broad categories, very big buckets. For example, breast cancer. When we now know that breast cancer comprises a number of different molecular subtypes, we can call it, one of the ones that we understood early on a couple of decades ago was the fact that there were families where breast cancer almost looked like it was being inherited through the generations. So that understanding really led us to identify genetic factors that are important, especially for those families that have a mutation in that gene. And it allowed us to then be able to identify the mutation in an individual who had cancer, and then test an individual in that family that didn't have cancer and better inform on the preventive strategies to reduce their cancer risk with respect to some chemo prevention or drug interventions or surgical interventions to reduce the risk that they will get cancer themselves.
But we can follow a similar logic with drug development where we understand that patients are not responding to therapy 75% of the time once they're diagnosed with cancer. And it's because it's such a big and a heterogeneous group of conditions. So if we have the ability to understand which patient has that molecular driver behind their tumor, we can then understand, well, this particular molecular subtype, we know that they benefit most from this particular intervention. And that's where we're going with precision medicine and personalized medicine is that we are trying to define diseases in a different way than just calling it, for example, breast cancer. And we have even more biomarkers coming to light to understand conditions like breast cancer better.
Callie Chamberlain (33:58):
Wow. That's incredible. Thank you for describing that for us. So when it comes to discovering these kinds of treatments, where do we begin? How do we get to that place that you just described?
Dr. Ashley Brenton (34:09):
So this really comes back to how we build data sets. We need to make sure that we have groups of individuals with particular conditions. We can measure outcomes, and we can look at their genomics to understand which biomarkers or which combination of biomarkers lead to specific outcomes. As we're doing this, we're also trying to understand how diseases progress. So this underlying mechanism of disease, why do some people have it and others don't? Why do some people respond to certain treatments and others don't?
And this gets back to what Alex was saying, with cancer treatment in that for a long time we thought of this as a site-specific disease. And by that I mean somebody has breast cancer, they have colorectal cancer, or they have pancreatic cancer, and now we're thinking about it more at a molecular pathway level. So somebody has a mutation in a specific cell signaling pathway, and that's what allows the cancer to progress. And we're beginning to treat it that way as well and discover treatments for those particular pathways instead of that location in the body.
Callie Chamberlain (35:15):
That makes a lot of sense. So when we think about rare genetic disorders, we know that as many as 25 to 30 million Americans suffer from these. So each disease might be really rare, but of course the total number of people affected is tremendous. So when we think about developing a new therapy for such a small patient population, what are some of the challenges in doing that?
Dr. Ashley Brenton (35:38):
So I think the first challenge is finding the right people. So it's a rare condition, so the data from one individual is incredibly precious, and we need to ask really good questions about what types of data are useful. Just because we have a ton of it doesn't mean that it's able to answer those questions. It's making sure that the genomic data is say whole genome so that you can compare it to other whole genome sequences. I think that allowing patients to be present in their own medical journey and to control, that in many ways is important. So when I build clinical genomic data sets, I make sure that there's a return of results to the patients so that this information can be used by themselves as well as their medical team in the treatment of their condition. So I think putting that patient first and really emphasizing that this is about them is key to making progress.
Dr. Alex Liede (36:35):
It used to be that the challenge was, well, how do we get our hands on deep whole genome sequence data? And we waited for the technology to catch up and it's now caught up. So now the challenge becomes we have so much data from the genome and we need new tools to analyze these data. And then there's also the ethical concern is how do we get the process to make sure that the individual receives the information, is seeking the right advice and healthcare around that? And then it's also very difficult as we get into the rare disease phase, it becomes difficult to conduct a really robust clinical trial. And that's where the value of real world data comes in with respect to having the clinical genomic details contained in there because we can then provide information of how patients would fare under standard of care conditions to help our regulatory agency contextualize the clinical trial, or sometimes we may even be able to perform an analysis that can address the magnitude of effect of the intervention.
Callie Chamberlain (37:49):
Great. What are some of the ways that groups throughout healthcare are trying to address the shortage of information to treat patients?
Dr. Ashley Brenton (37:56):
I think it's important to note here that we actually have a lot of data, but it's not all useful. So if you think about how we're generating data every day, there are wearables. We have the electronic medical records, we have claims records, we have biomarker information. We've seen, I think 23andMe was the most popular Christmas gift a couple of years ago. So we're generating data all the time, but we have to do it thoughtfully and strategically so that we're able to answer the questions that we're asking.
So how do we link biomarker data to clinical information to claims information so that we can see a whole picture. That's important to do. And I think also recognizing that quality can be inconsistent or lacking. So when we're building these data sets, they need to be high quality, they need to be reproducible, we need to be able to compare apples to apples as opposed to comparing apples to oranges like is often the case.
Callie Chamberlain (38:55):
Okay. I think that's really helpful. And I also wanted to ask about the data sets that we were referencing earlier and how those are oftentimes not representative or diverse enough to represent the patient population. Can you tell us a little bit about how we can make sure that that happens?
Dr. Ashley Brenton (39:11):
Definitely. So we know that building clinical genomic data sets is expensive and it takes a long time, and they tend to be very homogeneous. They lack diversity. Most are primarily Caucasians of European descent, so it's key when we're building these clinical genomic data sets that representative, and this means possibly recruiting specific individuals, but really designing the studies. And that means even those early GWAS or genome-wide association studies to be representative and diverse.
For a long time, clinical trials were predominantly Caucasian men, and there were a number of assumptions made. So there were assumptions that women were just little men and that all ethnic groups would respond similarly. So what we saw for a long time was that the number of side effects was greater in women. It's because they weren't represented in those early clinical trials. So in order to make drugs and treatments that are safer and effective for everybody, we need representation on every step along the way.
Callie Chamberlain (40:16):
Is that starting to happen now?
Dr. Ashley Brenton (40:18):
Yes, excitingly. There's a huge emphasis on diversity in data sets right now.
Callie Chamberlain (40:24):
Amazing. Alex, we're going to move into the lightning round. I will ask you some questions and you can just very quickly respond. The first question is, what is giving you hope right now?
Dr. Alex Liede (40:35):
It is giving me hope that companies are more open to developing drugs for rare conditions. We talked about rare disease, and historically large companies have shied away potentially from rare diseases because of the potential for recouping the development costs of these drugs. So I think increasingly, if you look at like oncology where we see a lot of biomarker driven programs, we're talking about rare populations because we're defining them by a rare variant in a specific gene, and so I'm really excited.
Callie Chamberlain (41:15):
Amazing. Did you have any aha moments or any further clarity during the pandemic or as a result of the pandemic?
Dr. Alex Liede (41:21):
Yeah. I think the aha moment was that there is the ability to share data across organizations and across borders, which is really encouraging because that's where we needed to really go and the real time nature of access to data was possible. Historically, a lot of our data providers, when we receive the data, there's a bit of a lag. So what we see in the data once we receive it, the most recent patient encounter may be like six months ago or a year ago sometimes. So by working with some of our data providers, we were able to access data that only had about a three week or a two week lag, which is critical for the pandemic. For us to understand what was happening in the hospitals, in the ICUs and the rates of COVID. So it was really encouraging, really heartwarming as well to see that we can help deliver the right insights in the right time because that's crucial. Is the intent to help change the course of this pandemic with the right data. You need to understand what's happening right now and not what happened six months ago.
Callie Chamberlain (42:35):
Great. Thank you so much for coming.
Wow. Those were such powerful interviews. I feel like I learned so much and it was helpful to take those bigger numbers that we talked about in the introduction and make them really personal with the stories that we heard about today. I think it's really easy to get lost in the economic side or how many people it impacts, but it really helped me understand what it's like for people to live with these rare genetic disorders and how important it is for us to centralize the type of care that people receive. The other thing I'm really thinking about is how complex this system is not just to navigate, but the whole ecosystem of support and advocacy and research and data sets that are required to get us to where we need to be. This really is so interconnected.
Stacey Dove (43:27):
Yes, that's right, Callie. It is an exciting time of taking advantage of human insight and technology to unlock new frontiers in diagnostics and medicine. As we talked about today, clinical genomics have been a game changer when it comes to individual diagnoses and drug development, and our understanding of them is only going to get deeper and more nuanced from here.
Thank you for listening today. Subscribe and tune in next time when we talk about how changes in behavior can have a very big impact on our health. In particular, we'll talk about quitting tobacco and the impact that has. Until then, thank you so much for listening. I'm Stacey Dove.
Callie Chamberlain (44:05):
And I'm Callie Chamberlain. And this is Until It's Fixed, a healthcare innovation podcast from Optum.