- There are few things harder for a physician to say to a patient than, I don't know what's wrong. Saying that is even harder when you're sitting across from the parent of a child with an undiagnosed condition. As I learned from experience, it's harder still when you work at a national referral center for rare pediatric diseases, since you're often a family's last hope. The physician they're seeing after they've spent months, even years searching for help and exhausting every other option. My heart broke every time I had to say, I'm so sorry but I don't know what's wrong. Pediatrics has reached an inflection point though. One in single-cell biology that can help decipher the origins of many childhood diseases.

- That was Priscilla Chan, a pediatrician and co-founder and co-CEO of the Chan Zuckerberg Initiative, reading from her first opinion essay, use single-cell biology to shed light on pediatric diseases that are currently in the dark. I'll bring you our conversation after a word from our sponsor.

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- Welcome to the First Opinion Podcast.

- I'm Pat Skerrett, editor of First Opinion. STAT's platform for articles written by biotech insiders, healthcare workers, researchers and others with interesting or illuminating or provocative perspectives to share about the life sciences writ large. Welcome to the podcast Priscilla.

- I'm so excited to do this Patrick.

- I learned just before the podcast got rolling that Theresa Gaffney, the producer of the First Opinion podcast, grew up in the same South of Boston region you grew up in and actually played in a high school orchestra with your sister.

- No way.

- Yeah, I actually, I'm from Braintree. I was one year below Michelle at Braintree High.

- Stop it.

- Yeah, do you get back to like Canton or Braintree Quincy area?

- Yeah, so my parents still live in Braintree and I do get back there and it's just, there's some things still really powerful for me for the East Coast. East Coast for me is like so much about academics and truth and sort of building upon what is the great institutions of our country. And then I come back to the West Coast and you sort of, it's just a different vibe. It's about doing things and seeing things differently. So I know that's a gross generalization but I feel it every time I go back home.

- Don't you love this small world stories? All right, so now on to science. Priscilla do you remember the first time you had to tell a patient, I don't know what's wrong.

- There have been many times where as a team, as an institution, we ran out of answers. And oftentimes we could answer something about what was gonna happen next but we couldn't say what was going to happen after the sort of near term that we knew about. And what's another thing that comes with that is sometimes you do know what's happening and there's actually no answer. And we just haven't actually gotten to that moment. And I guess in pediatrics most commonly what happens is you get a very unsatisfying answer. You have a mutation in this particular gene in this location, but it's of unknown significance. And that's sort of the end of the journey that we can often give a family. And then what's next? We don't have more to say or more to tell and it's just a very unsatisfying and devastating answer for a family.

- That's so out of sync with training and ethos of being a physician saying, I don't know.

- Yeah, I mean, we go in, you want to be able to literally heal. You want to be able to go in and write the prescription, do the procedure, be on the journey with a patient. And oftentimes what we learned especially at UCSF where I trained as a pediatrician and we took care of a lot of complex illnesses in kids. Is the best that you can do is to be part of their journey and be comfortable with saying, I don't know but I'm here with you and your family.

- There's a real conundrum with what are called rare and ultra-rare diseases. Each one of them affects a relatively few individuals but collectively there's supposedly 9,000 or more rare or ultra-rare diseases. Does that mean most of them get lost in the shuffle?

- Absolutely, and it's both a hard to diagnose. They don't come top of mind to assess position so they get undiagnosed. But when they do get diagnosed it's often unclear what to do next. But if I put on my science nerd hat, these rare or ultra-rare diseases are actually windows into a human biology. They often present in children because it's really a unique change from the normal human biology that then presents in a specific phenotype. And a very interesting thing is because you often have these specific changes in rare ultra-rare disease, you then have these natural manifestations of what it means for one part of an organ system or a cell type to be not working properly. And if we can actually then plug in scientists to study those questions, you have a beautiful example of how to both learn in depth about how the human body works and you have an opportunity to actually then develop answers. And when I say answers I mean, either treatments, understanding of the pathophysiology or innovative, new treatments that can apply to not just the people with that rare disease, but oftentimes actually generalizes to other people who have more common diseases.

- Well, that's sort of a peek into the future which I'm gonna come back to in just one second. In the old days, but I guess we're still sort of in the old days, how were rare diseases diagnosed if at all?

- You know, in the old days it was, you could only go by a constellation of symptoms. So oftentimes you would have physicians or scientists describe a number of symptoms and it would be called, it would be given a generalized name. Actually autism is a really good example of this. In the past, children with autism were often into the same bucket with kids of all different types of developmental delay. But as we get more sophisticated we're able to tease out the different types of mutations or diseases that cause changes in normal pediatric development that then get more and more nuanced. And today often, it's not unusual for a child with a generic symptom to then be given a whole genome sequence to then be able to pinpoint exactly where in your DNA has there been a change.

- So let's talk single-cell biology then since that's what you wrote about and it's one of the things you sound passionate about. And it's something I think that you and others believe can help get at the root of some of these diseases. Can you explain what single-cell biology is for the English majors listening to the podcast?

- Yes, for sure, I'll try. Single-cell biology is really about understanding what the different cells in your body how they're interpreting the DNA that's the same across your body. And so, you know what I'll use, I love to cook so I'll use a cooking example. Every cell in your body has the same DNA. It has the same basic list of ingredients and maybe some basic instructions for the recipe. Then you go to your lung cell, your kidney cell, your skin cells. They take those ingredients and recipes and put their own flair on it. And they decide to chop up the ingredients a certain way, put it together in a certain way, ignore parts of the original recipe. And so then what you realize is that each cell then has a different interpretation and reading of that original recipe. And when everything goes well, it produces exactly what the recipe wants for the lung cell. But oftentimes, there will be a misreading of the recipe. And then the lung cell will produce an end product that isn't right and sometimes can cause problems in the way the cell or the organ works.

- So sticking with the lung example for a second. So somebody with cystic fibrosis say, may have a problem with the lung but their leg muscles are fine.

- Yes, exactly.

- Even though it's the same DNA.

- Exactly, because there will be a specific part of the recipe that's critical for the way the lung works but is not relevant to the way the leg works. So if we stick with the recipe example for a second, maybe that analogy doesn't quite work but it's different ingredients are more important to some cell types than others. And so in cystic fibrosis there was actually a major breakthrough that was facilitated by single-cell biology. We've known what happens in cystic fibrosis for a long time. You make mucus that's too thick and you're unable to clear that mucus. But we've slowly come to understand that it's the mucus is too thick because of the way the channels in the lung cell balance the electrolytes. So you basically have mucus that's too salty and therefore sort of is too thick. And with single cell biology, we were able to actually read through all the mRNA sequence and say, okay, where in the translation of the original recipe did we go wrong in producing an end product that mucus is too salty? And very recently I would say, I wanna say like year and a half, two years ago, they were able to find the production in effect of a new receptor that hadn't previously been implicated in cystic fibrosis that was involved in this process. And the really cool thing now that we understand that scientists, companies that produce medications, they can start thinking about and attacking that receptor in a specific and different way that it would help address the symptoms in someone with cystic fibrosis.

- So single cell biology is about more than just gene sequencing, gene sequencing is part of it but you're also looking at how the genes are translated, how the protein product might be moved around it. What's the universe of doing single cell biology?

- Doing, like what does it mean? We basically--

- Yep, how do you do it?

- What you do is you is you need to be able to identify cells say, okay this is a alveolar lung cell. And then read out everything that is expressed in RNA which is a copy, the working copy of the DNA that is in every cell.

- There's a lot of RNA and DNA in a cell, that that must be a time consuming and exhaustive process.

- Well, it's one of those things that is hopefully a step change in the way that we can do science. We're only able to do this because the technology and the cost of sequencing has gone down so significantly. And so this wouldn't have been possible 10 years ago but now we're actually being able to do this. There's still a lot of hard work to do to be able to specifically identify a cell and how it relates to others and be able to work through all the data that comes out of the vast amount of mRNA that's expressed in every single cell. But if we can put together these hatlesses of both healthy cells and unhealthy cells, it's a whole new reference set for the scientific and medical community to be able to drive better understanding and better treatments for all of us.

- You wrote that children are being left out of the advances being made in single cell biology. What are some of the barriers or roadblocks to including children in this kind of work?

- You know, children are not tiny adults. And we have to always remember that they have very different and specific biology. The way that a child's body expresses its DNA changes over the course of a child's development. And we need to keep that in mind. Some of the barriers include frankly, engaging and enrolling families and kids in a way that is trustworthy and respectful, but also clear as to this ultimate mission that we're all on together. And I get that. I have two young children, like they're healthy thank God but you know, I have to think about. Do I want to enroll them in a study? Do I want them to, you know, have multiple blood draws? How do I actually explain this to them as healthy kids? But one thing that's been interesting over the course of COVID is, you know, I've also asked myself like, would I enroll them in a COVID study? And I think for me the answer is yes. And there's a lot of ways that I've been able to talk to them about why that would be important. Unfortunately, we don't, we haven't been near a research center but that's something that we spend a lot of time talking about the importance of science. And so one of the silver linings of COVID has been you know, the importance of us all participating in research has come to the forefront.

- How old are your children?

- They're five and three.

- Great ages.

- And I have to say they couldn't be more dissimilar. So very similar genetics, very different phenotypes.

- That will keep you on your toes. So a question, has having children of your own changed how you look at pediatric diseases?

- Before having my own kids, I was able to really keep a academic pathophysiology based lens on my practice. And, you know there are things that are not gonna shorten a kid's life and I'd be able to say like, you know, it's going to be okay. Like, it's just different, not life defining. And as a parent now honestly like, even as a pediatrician I get devastated by a rash or a scar because they're your little people in your life that you're in charge of protecting. And so I would say that I'm in general a very prone to sharing my care and emotion but now as a parent I can barely keep it together sometimes.

- Back to the children not as little adults. Can you give an example that listeners can wrap their heads around about how children's biology is different than adults?

- I think one that we've been all thinking about is why on earth are children don't get us sick with COVID? And there's actually something very specific that must be happening with their biology. Because if there's a clear cliff around age 10 when children start going through puberty and become adolescents, they become equally susceptible to spreading the virus, more serious illness that as adults. But they're clearly different than kids less than the age of 10. And so what is happening? What is the switch that's both happening in the way their lungs are working and the way that they're able to generate, you know a forceful cough or the way that they aerosolized viruses or not? I think that's a very distinct change that we don't yet understand but we've seen through this pandemic.

- Another problem with studying this age group is that they're constantly changing. I mean, I'm many, many, many years from childhood and I really haven't changed in a long time. But kids are changing constantly and that must really complicate the study of their biology.

- For sure, and there is, as a scientific community to do this Human Cell Atlas work well we need to be able to both map spatially to organs and how the different cells relate to each other. But in kids we need to be able to map over the timeline of their development. And so there's a lot of really interesting data science work that needs to be done for these maps to be useful. But I also want to highlight another critical issue in building out the Human Cell Atlas. And for me, that's racial or ancestral background of the people participating in creating the reference Atlas. That I believe that the Human Cell Atlas is going to be revolutionary. And I'm incredibly proud of the work that the Chan Zuckerberg Initiative is doing in both supporting scientists in building out the data but also building tools for scientists to be able to then make use of the data. But if we're gonna make this revolutionary change in the way that we are able to study human biology, we can't leave people behind. And oftentimes in basic science research, we're often studying the biology of an average young to middle age white male. That is the most common study participant. But I want to be clear just like how kids are not the same over the course of their development, people of different ancestries have different ways that their bodies come together in terms of health and disease. And I'll give you one example that most recently happened to me. I had a serious infection last year during COVID, a bacterial infection. But when they drew my blood to look at my white blood cell count, it popped up a number and it was within the reference range. And the doctor said, "Well, your white blood cell count "is within the reference range. "Therefore you probably don't have an infection." But in fact, if you look back historically, my true normal was always on the very, very low to below normal. So that might be something about my ancestry or that might be something particular to my biology. But the reference range didn't encapsulate what was health or disease for me. And then if you take a step further for what I actually ended up having, their market increased risks for Asian American women. And so we need to be able to have this new reference point and in science and in medicine, be representative of people of all different backgrounds to actually be able to reach at least what's our audacious mission at the Chan Zuckerberg Initiative to actually cure, prevent and manage disease for everyone.

- So this is only gonna get more complicated. I was working with somebody on an essay a physician, who was looking at cholesterol levels and cholesterol risk scores. And he decided to do it for himself. He's young, he's fit, great weight and it came up as high risk because he had checked the African-American box. But he isn't totally African-American. He identifies as African-American Native American and Irish. So you're gonna get all sorts of people who don't check any particular box. And it sounds like we're gonna have to figure out references and what's healthy and what's not normal for them as well.

- Yeah, and racial background and ancestry is a very rudimentary way of understanding the ties between background in biology. There are actually intermediate markers like in the immune system, HLA phenotypes that then help you bucket it to certain categories of risk or disease. So let me break that down a little bit more. You know, the physician that you're working with has these three different racial backgrounds contributing to his biology. But we might be able to look and say, you know if you had specific HLA phenotype we would say, you actually belong into this category for this set of immune diseases. And so we would then be able to say, get more specific and beyond sort of the cultural classification into a biological classification.

- So you mentioned the Human Cell Atlas. Can you just briefly explain that a little bit. To me it's, I know what an Atlas is. I know what human cells are but I can't quite put the two together.

- The Human Cell Atlas is a collection of information that tells us how your body works and how your body is translating the information that it has from your DNA into their ability to be functioning, lung cells, kidney cells, skin cells. And we call it an Atlas because we hope that scientists and medical practitioners take it as a tool to then help drive a better understanding of disease and potential treatments.

- Five years ago you publicly asked the question, can we cure all diseases in our children's lifetime? And you told my colleague Rebecca Robins at the time that that goal was your "north star." What's your thinking on that today?

- I still love and energized by our audacious north star. And I want to be clear. This is not something that we at CZI are going to do alone or could even do alone. This is really about accelerating the pace at which we are able to make medical breakthroughs. And building tools whether it's hardware or software to be able to see the world differently. And this has happened in the past. The microscope revolutionized the way that we're able to see organisms and cells and how can we today help build tools for scientific discovery to accelerate that. So that our better understanding of human biology then translates to better human health for our generations and the many generations to come.

- So as the co-founder and co-CEO of the Chan Zuckerberg Initiative, which sounds like a pretty tall job. Do you personally help pick the projects that you will fund?

- I am involved in learning from the folks who are at the front lines of this work. I work with a lot of great scientists, Cori Bargmann being one of them. And the role that I play is I get to wear my physician lens a little bit too and say, how does this ultimately impact lives of people, adults, children all over the world. And to make sure that we have that focus, we're not just studying things because they're interesting, but we're ultimately studying things because they will change people's lives. And that's a way that I've really enjoyed keeping my doctor hat on in my role as the CEO.

- Well, that's a hugely important perspective because I've worked with scientists for a long time and they can get awfully focused on the work that they do and sometimes forget what it means for the bigger picture and by bigger picture I mean, human beings.

- Yeah, well, we all have different weighting of value. And I agree, there's a lot of scientists that have deep intellectual curiosities about things that I'm like, huh, didn't know?

- Was there anything from college or medical school or working as a pediatrician help you do your work in this role? I mean, it's quite different from I would think from being a physician but maybe not.

- At first, I thought you know, I went from being a pediatrician to being the CEO of this new organization. And I was just like, I just like let myself forget everything I had learned as a physician. And I was like, well, it's a whole new world start over. But what I realized over time is there's immense power in having a learning mentality and to being a person who asks good questions and is a strong generalist. And, you know, in medicine there's an adage. See one, do one, teach one. Like in training you're doing hundreds of things you've never before. And you're expected to watch someone do it once, do it yourself, and the next time you're expected to teach. So the learning curve has to be steep. And in my role as a leader I've embraced the, okay, I've never done this before. How can I learn from, how can I talk to someone whose done this before? Then I do one and then I have to be reflective enough to then explain to our team like, what went well, what didn't go well and how we want to do it differently the next time around.

- You know, that learn one, do one, teach one thing I think also hearkens back to your, what you did before medical school. You were a fifth and sixth grade teacher if I remember correctly.

- Yeah, I think you and I have a, my sneaky knowing about you is that we we're both teachers.

- I'm hoping none of my students are listening but I would learn something the night before and teach it the next day as if I knew it. So let's wrap up with cell biology and single-cell biology, how do you think that that's gonna be moving forward? And, you know, if we were to have this conversation 10 years from now, what might we see?

- 10 years from now I'm hoping that we actually see very concrete translations from this body of knowledge that we currently have to real world, real life, real human impact examples of how medicine is different because of this new view into the human body that we have. And it's all those human, all those examples will make it so that it's not this esoteric idea that I'm talking to you about on a podcast. But something where we're like of course, and we see and feel the impact.

- That's a great vision for the future Priscilla. This has been great, thank you so much.

- Yeah, it's been a pleasure.

- Thank you for listening to the First Opinion Podcast. It's produced by Theresa Gaffney. Our senior producer is Alyssa Ambrose and our executive producer is Rick Berke. Listeners please let me know which First Opinion contributors you'd like to hear on the show or what topics the podcast should take on. You can do that by sending an email to first.opinion@statnews.com and please put podcasts in the subject line. And if you have a minute, I'd really appreciate you reviewing or rating the podcast on whichever platform you use to get it. That's it for now, be well during this strange and uncertain time.