Episode 5: Science Is a Social Experiment

Cláudia Carvalho  00:01

To get gene therapy, we need to know exactly what are the alterations that cause a problem in the DNA, and we need to know exactly the gene and we need to know study the function, because with this, you only can fix something if you know why it broke.

 

Jack Faris  00:22

Hello, and welcome to our podcast, PNRI Science: Mystery and Discovery, where we go beyond the jargon to dig into the passion and people behind the science. I’m your host. Jack Faris, CEO of Pacific Northwest Research Institute, a 68-year-old genetics and genomics research institute in Seattle. I’m also a regular guy,

 

Anna Faris  00:43

Dad, no, you are not a regular guy.

 

Jack Faris 00:46

Oh boy,

 

Jack Faris  00:47

Here we go. That’s my daughter, Anna Faris, who’s going help me out, so to speak, with this endeavor. Anyway, I say I’m a regular guy who happens to spend his days around really smart people. And I’m here to interview PNRI’s brilliant scientists, to share what excites them about genetic research, what inspired them to become a scientist, and what are those myths that we would love to bust about science. Join me and Anna as we dig into the mysteries that may very well hold the key to our future health breakthroughs. 

 

Anna Faris  01:19

Dad, that was great. Oh, I’m really proud of you. Dr. Cláudia Carvalho: Science is a Social Experiment. In this episode of PNRI Science:  Mystery and Discovery, my dad, Jack, interviews PNRI Assistant investigator, Dr Cláudia Carvalho, who is working to solve the unsolved cases of rare diseases. So many families are adrift in the medical system without a diagnosis of what is afflicting their child. As a mother, I am so grateful for Dr. Carvalho’s work to bring a diagnosis to those families. She delves into how rare disease researchers and families are leading a revolution in medical science and the power of global collaborations to unravel these mysteries. My dad loves to say that research is hope at work, which we can see here. 

 

Jack Faris  02:13

There are as many as 7000 rare diseases. So in fact, rare diseases are not rare. And of course, if you or someone you love has a rare disease, it’s not rare to you. Dr. Carvalho and her colleagues around the world are bringing hope to millions of families. 

 

Anna Faris  02:31

So please keep listening and enjoy the awe inspiring power of science.

 

Jack Faris  02:41

Could you describe for us a time when you really felt, ah, this is why I wanted to be a scientist.

 

Cláudia Carvalho  02:54

I guess I have this feeling very often and in many, many situations in my career, I always like feel very good when talking to other, either collaborators or students or trainees or mentors, where we feel we reached something important and we found something important that is relevant for the field, either a discovery or sometimes an observation. That when you you study several patients, for instance, sometimes we start seeing a pattern, then I have this feeling like often. And then also, I have this feeling when we talk to to the patients or the families and they you feel that this answer we had we give to them is important for them as well. Sometimes we think something very simple is not important, but they found it relevant. That’s always give me this feeling of that’s why I’m here. That’s why it gives like a purpose to what we are doing.

 

Jack Faris  04:10

It is interesting to me that you’re describing situations not like some people have as an image of the scientists working alone in the wee hours in a laboratory, but in a social context, communicating with colleagues, explaining something to a family, it’s very interpersonal. These these times when you are feeling particularly fulfilled.

 

Cláudia Carvalho  04:36

Yeah, to me, science is a social experience, having the contribution of other people to the thinking like brainstorming ideas, brainstorming projects. It’s part of the science experience. And yeah, collaborations is in a broad way, not only with the scientists, but with families, doctors and students. It’s, it’s key to to the science we do.

 

Jack Faris  05:04

And speaking of which, just this last weekend, perhaps at the almost far end of the the social environment of doing science, you participated, in fact, organized and led an event that takes the name hackathon. Love to hear you describe what exactly happens in that and who was there and what achievements were made.

 

Cláudia Carvalho  05:29

So hackathon has the word comes from hacker and marathon together, so meaning that we are working very intensely. In this case, we were three days with a group of people that we usually often we don’t work or we work remotely. So we established some problems that we wanted to work on, not necessarily solve, but we want to work on. We start with a question and a direction that we thought would be important, but in the end, people have, you know, divided groups, and people have different perspectives and add their own creativity to the questions and bring solutions that we have not thought about before. We work like from Friday to Sunday together for hours. We had presentations every day the groups, each group had to prepare their presentations, like how they are going to start answer the questioning, then the second day, how they are answered the question, the problems and the challenges that they face, so they have to change directions quickly, and then the results that they got in the last day. And we had very, very important results.

 

Jack Faris  06:41

What was the area of content, scientific content, that were addressed by this, this group that came together?

 

Cláudia Carvalho  06:47

We wanted to to answer very specific questions during the hackathon, is like, what are the copy number variants, which are a specific type of DNA variant that We can found in rare diseases that we are studying in our lab. So we have several cohorts of rare disease patients that we are studying, and we have genome sequencing available. Part of it is from my lab, and part is from a consortium called Gregor that we are partners together with Baylor and other UW and other institutes, those patients, they are not resolved molecularly, meaning they have a disease, but the doctors do not know what is causing the disease molecularly. So our goal was trying to work in this very specific type of variant during these three days, and then we divided the three groups to look into different cohorts and look for the presence of this type of variants with copy number variants. It’s they can be deletions or duplications of the DNA, and then we want to know if those alterations could explain the phenotype of the patients. That that’s what we focus during the hackathon.

 

Jack Faris  07:59

Is it the case that your group brought together for the hackathon discovered important findings that would not have been likely to happen with each individual working alone?

Cláudia Carvalho  08:11

The difference, I would say, is like people gave provide different perspectives. For instance, one of the groups the leader was a Baylor researcher and clinician who works with primary deficiencies, and he is, he knows he’s expert in this type of disease. And one of the features of this disease is that a lot of the cause, molecular cause, are recessive, meaning you have to have contribution of two alleles from different chromosomes, one coming from the father, other coming from the mother, to get the disease. And then what he did, he did a different approach from the other groups. He was looking for copy number affecting one of these alleles, one of these chromosomes, and a point mutation, is a different type of variant in another chromosome. So he brought his knowledge to the table to try to find solutions and answers for these patients, like he could have done that by himself, or we could have done that ourselves here, but because he had this knowledge, we this was quickly put in the strategy to resolve these patients that we are working with.

 

Jack Faris  09:31

I enjoy talking about three aspects of science. One is mythology, things that people have wrong impressions of, misunderstandings, misinformation, mystique of science, the ways in which scientists can be perceived in society as being somehow extraordinary in a good way and mystery. And it seems to me that the activity of your Hackathon was very much focused on. Are taking steps forward into mysterious territory, the unknown? 

 

Cláudia Carvalho  10:04

Yes, so my lab works with hidden variants, just called hidden here variants in the genome, meaning that so these patients that come that are enrolled in our research, they actually had already some diagnostic labs or other research have already analyzed their genome to try to find alterations that could explain their disease. However, they still not don’t know the cause. So in a way, could be called the mysterious, because there is something mysterious happened in the DNA that nobody could find yet. So we use a lot of different technologies and combined methodologies to try to see why the alterations are not found. So each technology, scientific technology, has their limitations. Right? For instance, we have exome sequencing, which is a very important and relevant tool in the diagnostic labs use to try to find alterations in the coding part of the genome. However, we are very well aware of the limitations, and one of them is that variants outside of these regions are not going to be found. So knowing this, we can now use a different technology to try to find in these regions that were not used before. The other things, some certain types of variants are very challenging to find, even with the most modern genome sequencing. And for instance, inversions of the genome which change the direction of the DNA, those are very subtle alterations, and then we need to use very specific methodologies to find them, and that’s what my lab is doing, and that’s the hackathon. Tackled this a little bit, but we focus in only one type, because each variant requires different types of analysis and different types of tools. So we focus on this specific one. So there are a lot that we still have to do for those patients.

 

Jack Faris  11:59

But from the point of view of someone who’s not a genetic scientist or genome scientist. It does seem to me that the human genome project opened the door into a vast labyrinth of discovery, but also additional, in fact, unending mysteries to be attacked Is that a reasonable way of thinking about the field? 

 

Cláudia Carvalho  12:27

Yes, it opened like an enormous resource for us to look for alterations that we could not find before the human genome produce reference genomes for us. So obviously, is a reference, right? It’s like a map. It’s not necessarily, if you go to different people, you find different things that are not in the reference, but it gives a general direction to us to go. And we now know regions that are very complex, very difficult to study, and regions that are easier to study. And then we know now that we have to use different methodologies in these regions that are more complex than the ones that are easy, easier to deal with. So it’s more like it opens the possibility for us to study it doesn’t answer questions necessarily. 

 

Jack Faris  13:27

So I’m going to take you back in time to you’re even younger than you are, and ask you, when did it occur to you that you might like to become a scientist?

 

Cláudia Carvalho  13:38

Oh, since I was a five years old, I guess four years old, if you, if you go to my my toys, I had toys written like scientist and teacher, things like that. I was always like labeling myself as scientists and teachers, something like this. So you can, you can find the proof in my in my mom’s house.

 

Jack Faris  13:58

What were your interests in science? Was it the natural world or physics or astronomy? What was, what was interesting to you as a young wannabe scientist, 

 

Cláudia Carvalho  14:10

I guess, I guess more biology. I always went more for biology, although I had a time that I was very interested, like in planets or I have different phases. Actually, I was when I was very little. I like the biology. I also put that I would be a physician, which I’m not, but I work with physicians all the time. So I was more interested in human in general. But there was a time later on, a little bit, I was very interested in mysteries and mystics and like that, like where human came from, Africa, and, you know, I was reading a lot of this type of of books and the pyramids and all these questions that everybody you know think a little bit about the mystics, as you said. And so why? Humans came to be what they are, but obviously with a child mind, right? So I was interested in all of this, in the different civilization that always love history. I always was more interested in the history together with biology. I actually did. I enter in my master, because in Brazil, you have to do a master’s before you do a  PhD. I start with my master and I look for my mentor there. Actually, I was interested in his research because Fabricio, he’s my master mentor. He is one of the main researchers in Brazil in human evolution in Brazil, like he studies now, actually, he came to Science Matters in, I think was 2021, and he was starting his lab at that time. But he was already a known person in human evolution and Amerindian history in America. So I was very interested on that. But then the project that he gave me was in infertility, in male infertility, and then we use a lot of the markers that are used in human population studies. And I just got completely in love with because that led me to the rare disease. And I was like, that’s what I wanted to study. 

 

Jack Faris  16:19

It is unusual for a five year old to have an ambition to become a scientist as early as that. How did your parents respond to this interest of peers?

 

Cláudia Carvalho  16:28

My parents were they just found funny and but the person who really motivated me a lot was my grandfather from my father’s side. He was a physician, and he had so many books in his library. I used to go to his library with him, and we used to read together things and discuss about evolution or about, you know, science. And he was super excited about my interest since so he was, I remember sitting with him when I was like, nine years old, outside of the house, and looking at the stars, and he was telling me about the stars, the planets, kind of thing. And I got, you know, he was the one that really, really was motivating me, because he was a scientist. He’s so kind of he was a physician, but he would like to write books. And yeah, I guess his was my main like motivator when I was a kid.

 

Jack Faris  17:27

He sounds wonderful. Let’s travel forward in time. Let’s imagine you are some point in the distant future. A grandmother yourself and your granddaughter at the age of five, says grandma Claudia, I think I’d like to be a scientist. What should I do? What’s it like? How do you answer?

 

Cláudia Carvalho  17:46

I guess at that age, I would definitely take my grandkids to museums to do science experiments, like fun ones at home, I would definitely go to the nature and show things that are very interesting and mysterious. I guess the mysterious part of science is something that any child, if it doesn’t turn out to be scientists, are kind of fascinated by, right? The type of thing that we can try to resolve the mysterious questions in the in the nature. So I guess I would try to motivate that and stimulate more of this type of feeling, because I guess that brings you to feel that you are part of that, and you can do study and dig in more if you want. So I guess I would show the beauty of nature and more.

 

Jack Faris  18:47

So you are focused on rare diseases, and I have had my eyes opened on the reality of rare diseases, that while they are properly called rare, rare diseases as a group are not rare. There are 1000s of rare diseases. For the benefit of our listeners who don’t know much about this field. Could you describe? And I know that these can only be examples, because cases are very, very diverse, but what are the ways in which a rare disease might affect the family? 

 

Cláudia Carvalho  19:20

The rare disease we are talking about specifically are the genetic types. That’s the one we study. There are other types, right? But infectious diseases and others. But we study specifically the genetic ones, which make up about 80% of the so called rare diseases. The genetic diseases, they may have a broad implication to a family. But a lot of them affect kids. So I guess maybe 60% or 70% they affect kids, and the problem with them is that they are very rare, right? So the cause, the molecular cause, many times are unknown, and that’s a problem for any parent. You don’t know how to what’s going to happen to your kid as they grow. You don’t know if it’s going to get worse. You don’t know the type of treatment. Many times, the physicians don’t know about how to treat them or how to deal with the symptoms. And so as any parent. I’m a parent myself, and any other parent can relate to the difficulty that is dealing with this type of issue, like what my kid has, right? How is going to be an adult that has their own life or is going to be dependent the whole life? So it affects the family profoundly in this way, also depending on the disease, the family may have another kid, right? If it’s a recessive disorder, for instance, the family may have another kid with the same problem. And then you have these families with two, sometimes three, kids with the same disease. And obviously this is a very important it affects them profoundly. 

 

Jack Faris  21:01

In some cases, it’s very tragic. These are not trivial disorders. In many cases, they’re profoundly disabling. 

 

Cláudia Carvalho  21:09

Yes,many cases are profound disabling. Sometimes they pass away, or they need some sort of treatments that if the doctors don’t help, they may have problems in the future because they didn’t get the proper treatment in the beginning, but that’s because we need more studies.

 

Jack Faris  21:26

Where does rare disease research stand in the broader context of biomedical research?

 

Cláudia Carvalho  21:32

So rare diseases are leading an interesting revolution in medical science, I would say, because there are so many possibilities in terms of gene therapy that are being developed or starting to be tested in clinical trials, drug repurposing is a very interesting approach that researchers in rare disease are also pushing to try to help these kids together with other types, a lot of other types of gene therapies, and including CRISPR. So I think in this way, the rare diseases are like leading the field to try new approaches that can help these families and can help the kids.

 

Jack Faris  22:22

And you know, in under the category of myths and misunderstandings, it would probably occur to most people who learned just a little bit about some of these rare diseases that it’s a kind of a hopeless situation. But I recall one of the extraordinary advocate’s mother of two kids with very serious, rare diseases, saying, The good news is now, at least in some cases, these diseases are her words, actionable. Could you talk a little bit about how we’re our frontier is moving forward to make more and more diseases amenable to some sort of positive amelioration, if not cure.

 

Cláudia Carvalho  23:07

The role of the families in rare diseases, they are pushing the boundaries. They are really like leading a lot of these efforts themselves, and in many cases, they are bringing together scientists that they want to be involved in moving the field forward. And that’s the case of Jill Hawkins, who is the mother I’m assuming you are referring to, that talked to us recently at Science Matters. So she has been leading the foundation, the FAM177A1  Foundation, and it was incredible what she has been doing, because the cause of the DNA iterations in her kids were found by one of these big consortiums that in NIH funds, it’s a UDN, and Undiagnosed Disease Network researchers are trying to find the causes. And in this case, the alterations were found in a new gene. When I talk about new genes, I mean that this are genes that people don’t know yet. They cause diseases when they have alterations. So it’s a new gene for researchers, and there are very, very rare families known in the whole world that have alterations in these genes. As we work on the rare disease families, we found more and more genes that were not yet known to cause disease, right? And the problem with those is that many times the database, the created database that we researchers use, they don’t have information. They take time to get this information added there. And then people all over the world use those created databases. There are several of them in Europe, in us, and then people across the board, they. They need to use them, because they are the way that we interpret the variants that we find. Because everyone has alterations in the DNA, all of us have new alterations. Alterations inherit from the parents. So we need to find the ones that can be causing diseases. In this way, we need the curated databases that tell us, Oh, this gene or this type of variant are causing disease or not. So in the case of the novel genes, then this is a problem. And how do you find new patients with the same alteration? If the database are not created yet, and that has been one of the efforts of this foundation to find new patients, because with this, the researchers can study the new variants in the same gene that can cause disease and how they cause diseases. So going back to your question, there has been a lot of development in gene therapies lately, and there are several examples of gene therapies that are now working. However, to get gene therapy, we need to know exactly what are the alterations that cause a problem in the DNA, and we need to know exactly the gene and we need to know study the function, because with this, you only can fix something if you know why It broke, right, you can use drug repurposing that may ameliorate some of the symptoms, but to really solve the problem, you need to fix it, and that’s why studying those alterations is so so important, and publishing the work we are doing is so important, because then the people who work with the database curations can get this material and then put in the database that everybody’s used and spread the words. That’s why open sources are so important. That’s why publications that are free to everyone are so important, because it’s the only way that everybody can work together and help the field moving forward scientifically and the families also to receive whatever treatments available.

 

Jack Faris  27:09

 It does strike me that this is actually a model for building a better world in general. But I like to think of research as hope at work, and I prefer to be hopeful. So I really like the idea that of these seven to 10,000 rare diseases, that our ability to attack each one of them isn’t just a one at a time, individual situation of profound difficulty, although they are deeply complicated and difficult, but that as we succeed in making progress on one or two or three or four, it enables us to do a better job on five or six or seven or eight, and as we proceed, is that hope wrongly placed, or Is that valid? 

 

Cláudia Carvalho  28:05

No, this is a fair assessment rare diseases, although each gene and each variant has their own like specific features that the researcher who is studying that specific gene needs to learn. It does bring a lot of patterns for other genes. Sometimes these other genes, they may have proteins that are in the same pathway, for instance. So then we can think about other disease that are called all disease, but the alterations affect the same development pathway, for instance. Or solutions for one specific case, can help solutions to other genes, although the disease may be completely different, but you can treat in the same way, or can think about solutions similar. So the more we study, the more we learn, the more we find patterns that can be applied to different diseases and different cases. So science is all about finding patterns. 

 

Jack Faris  29:09

Actually, I begin to get a sense of the rare disease community as vast, actually, and very international and very cooperative with both in the kind of the gathering of data, that is the raw material, in a sense, of scientific investigation, and then as discoveries are made, the dissemination and sharing of that of those discoveries and that information to a broad community that can then build on them further Is that a fair description of your world?

 

Cláudia Carvalho  29:41

Yes, it’s fair, and that’s one of the more exciting parts, I think, because we work together, we wanted to share everything together, because it doesn’t make sense to do in isolation. I should say that the other thing is also, we wanted to bring other parts of the world to the table as. All, like South America, Africa, Asia and other countries that have less resources and have it open, it also helps them to be working on their families, on their own countries, in their own situation. So open sources are extremely important in general, and obviously having all countries being bringing this, because diversity in genetics is obviously huge, right? And to work with this, we need to have the contribution of every population possible every country. Doesn’t matter the language or religion, we need to bring everybody together, but they also need training, which is harder, it’s harder for them to get the training, the people the material. So yes, sharing is extremely important for our work. 

 

Jack Faris  30:56

Is the culture of science, especially the kind of science you do. Is it changing, and does it need to change?

 

Cláudia Carvalho  31:04

It is changing to be more global, as we have been discussing here, and needs to change, because otherwise we’ll not being able to resolve the problems that the challenge that the field has, and sometimes even people not work with rare disease, necessarily, but work with genomes and variation the genomes how environment affect health in general, human health in general, we need to know more about the diversity of the genome, the specific environment and situations that people live in, why you have certain diseases more prominent in certain regions of the planet compared to others, and how people are sometimes protected through certain diseases than others. We need to learn globally. And I think there are diseases are leading this, but this is happening across biology, science, human health studies, I would say.

 

Jack Faris  32:10

So you, in addition to doing your science work, find time somehow to help mentor younger scientists and students, and you also coordinate and organize a regular meeting we call Science Matters at PNRI that brings voices of expertise and shares them with the scientific community, both of which are really important contributions to the future of science. What’s your feeling about the responsibilities of the scientists that go beyond just doing the science? 

 

Cláudia Carvalho  32:49

Well, mentorship is is key to science. We need to train the next generation. We need to bring interest to the field, the field that needs development and the these kids today, they are so much into AI, into computational skills, coding. So this is really needed to move science forward. And it’s a pleasure to have them then trained as a pleasure to to bring interest to keep the field moving and expanding, we have a huge responsibility indicating the next generation, and not on the next generation, I would say, ourselves among us, our colleagues that are working in the same field. I guess we have the obligation to educate ourselves with learning from them and teaching them what we are learning in the lab. So putting our work out, giving talks, writing papers, helping with the databases, curations, sharing the work is our responsibility, because we find important discoveries in the lab and we need to make the world aware. We discuss a little bit how this affect rare diseases in general. Many times we find, if we find new genes, for instance, that are important for diseases, and the type of variants, if we need to publish them and to make them aware, because a diagnostic lab will then read and get this information and use to test new patients with the same diseases. So this is a huge responsibility for us. So education and sharing what we have and learn in general, it’s key for our mission as scientists. We started Science Matters when a year after I started at PNRI and was during COVID still was November of 2021 when we had the first Science Matters speaker, Neil Hanchard, and the goal was, for me, was like to bring together researchers that were doing some. Sort of science that have societal impact. It’s very much towards rare diseases, but we do have other researchers coming talk about genetics and population genetics and evolution. We had several examples of that, but the goal is to bring people to PNRI, either remotely or bring to spend a day with us, to teach us, the students, the staff, the trainees, the researchers, to teach everybody, and also to share what we have been doing in our labs with them. And in this way, we also bring people from other parts of the world. We have a hybrid version, and sometimes we have classes in Mexico or in Brazil, the whole class is attending Science Matters to see some specific talks that they are interested and I guess we need to spread the word. We need to bring people together. So that’s the goal. 

 

Jack Faris  35:57

That’s wonderful. So I have a very strong sense that I’m speaking to a person who’s quite positive and optimistic. So can we just imagine 10 years from now, with your field, where do you think we might be 10 years from now? 

 

Cláudia Carvalho  36:14

In 10 years, I guess we will probably be having a lot of the rare diseases with some sort of treatment on the way, either clinical trial that FDA, working with the FDA, I think we will have much more understanding of the genomics field and how the DNA varies in even the difficult regions of the genome, how it varies and how that affects and cause different phenotypes. I think we’ll have much more better understanding about environmental causes and how that affect the phenotypes, together with the diversity of the genome. I really hope we’ll have a much more global community together in human health, but that’s my hope. I’m not sure if we’ll be there, and I really hope also that other countries will be playing the game together with us, like other countries, like Brazil and other South American countries, and other countries with less resources with so many open sources, we work together in training, work together to get these students and the researchers on these places very motivated. We there are several initiatives, including South America, to include researchers there and to train people there. So I really hope this will be more broadly tackled around the world. 

 

Jack Faris  37:43

I want to thank you, Dr. Carvalho, for helping illuminate a really beautiful picture of a world that’s going to benefit from the kind of work you and your colleagues do and bring hope to many, many, many families. So thank you very much for being with us here today.

 

Cláudia Carvalho  38:00

Thank you, Jack, that was wonderful.

 

Anna Faris  38:03

Thank you for joining my father and me for this episode of PNRI Science: Mystery and Discovery to learn more about PNRI and get connected to our groundbreaking science go to pnri.org/connect. We would love for you to join us for a tour of our labs or a virtual event with our scientists. Thank you for listening, and we hope you’re inspired to learn more about genetics and chat with your friendly scientist neighbor. I’m your host. Jack Faris, CEO of Pacific Northwest Research Institute. I’m also a regular guy Dad. What do you think? How’d I do?

Jack Faris  38:38
Better!