Feature Interview: Dr. Plavi Mittal, Founder & CEO, In-Depth Diagnostics

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Dr. Plavi Mittal earned her Ph.D. in Biology from Brandeis University, and did her postdoctoral research in molecular oncology at Harvard Medical School. She was also a management consultant at a global consulting firm, where she worked with leading pharmaceutical companies.

After a family member was diagnosed with a rare muscular dystrophy, LGMD2B/Miyoshi, Dr. Mittal helped create the Jain Foundation. Over the last 12 years, she has led the JF team as President & CEO, and together, they partnered with dysferlinopathy researchers to realize gene therapy clinical trials and the hope for a cure. Repeatedly, Dr. Mittal has seen patients with rare disease struggle to reach a diagnosis and find a treatment best for them, despite the scientific breakthroughs advancing therapies for their condition.

Through her new non-profit organization based in Seattle, Washington, In-Depth Diagnostics [www.indepthdiagnostics.org], Dr. Mittal will continue to support the mission of the Jain Foundation while addressing this larger patient need by providing genome-level sequencing and analysis. IDD’s national diagnostic program is an unprecedented effort that will raise standards for diagnosing rare diseases and also fuel a research consortium focused on improving clinical care.

Can you tell us more about your background before starting the Jain Foundation? How did you first become interested in science, biology, and oncology?

I was always interested in Genetics and Biology for as far back as I remember. I think my interest started when I read the book, Lives of a Cell by Lewis Thomas. I was fascinated with the diversity, the resilience and the complexity of biological organisms. Later, as a PhD student, I was very keen to work on problems that would impact people suffering from diseases today. I feel that we have an urgent mission to connect the dots from everything we have already learned.

Can you tell us about your work at the Jain Foundation over the past decade, and how that led you to start In-Depth Diagnostics (IDD)? 

At the Jain Foundation, we were completely focused on pushing research towards a cure for LGMD2B, a rare form of muscular dystrophy. Over the years, our strategy of uniting researchers with the relevant expertise proved successful, and we set the stage for clinical trials. Then, I learned first-hand what industry has been struggling with for years: rare diseases are difficult to research, because the patients needed for clinical trials are very difficult to find. With the hopes of finding enough patients to develop a meaningful trial for LGMD2B, the Jain Foundation developed a free diagnostic program. We put together a panel of 35 genes linked with diseases that would have a similar presentation as our disease of interest, LGMD2B. We were able to screen 2,500 people and diagnose dozens of LGMD2B patients. This work confirmed my belief that genetic testing is a quick and efficient clinical tool for complex diagnostic cases.

What convinced you that there is a need for better diagnostics for rare diseases? Why is diagnosis so important for these patients?

While the diagnostic program was very successful at finding LGMD2B patients for the Jain Foundation patient registries, over 60% of the patients tested received no diagnosis. I felt a personal dedication to these patients who were offered the hope of an answer, only to be let down by the inherent limitations of a panel-based approach. These patients would have to wait many more months while they sought other opportunities for genetic testing, if they had the resources to do so. Given the falling price of human genome sequencing and clinical analysis, performing one thorough analysis seemed to me to be more efficient and effective than repeated genotyping. By focusing on providing comprehensive genetic analysis to these patients, I have the opportunity to provide an under-utilized, powerful diagnostic tool to patients in critical need of targeted treatment plans. And by empowering patients with their genetic diagnosis, patients can seek out research and clinical trials best suited to their condition.

How did you choose whole genome sequencing, and how does this open up new avenues for research?

By performing whole genome sequencing, we will be assessing as much of the human genome as technology currently allows. This means that, in addition to identifying known pathogenic variants for diagnostic purposes, we will be able to uncover nuanced patterns in other regions of the genome. We hope that, by strategically combining our bioinformatic analysis with information about patients’ symptoms and traits, we can highlight promising avenues for therapy development for a great number of rare neurological diseases.

What do you think distinguishes IDD from other genetic testing/analysis/diagnosis services available today? Why do you think now is the right time for IDD to open its doors?

I’ve been considering this very question for months – right now, the clinical and academic applications of genomics are booming. So many groups and companies are launching large projects or consumer products that the market appears saturated with personalized technology. However, as I’ve built IDD’s program, it has become painfully clear that the vast majority of commercial products are not able to offer a clinical diagnosis to patients seeking one, or they do not perform a full genome analysis at all. Many insurance plans do not cover comprehensive genetic testing, and patients cannot afford to pay out of pocket for this additional test when they are facing a myriad of diagnostic procedures. By offering our services to patients at no charge, and performing full genome sequencing/analysis for clinical and research applications, we are the only program working to deliver this cutting edge technology directly to patients who could benefit most.

What is your vision for In-Depth Diagnostics going forward?

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My vision is for In-Depth Diagnostics to become a leader in rare disease diagnosis and patient engagement. By gathering evidence supporting the efficiency of genetic screening for difficult-to-diagnose neurological conditions, I hope to influence a shift in clinical standards of practice. I don’t plan to measure the success of my program only by the number of patients diagnosed; my success is also contingent on creating an accessible community where patients can learn about the unique ways patient participation can accelerate and influence the development of rare disease therapies. By empowering patients and generating sufficient data, I hope IDD’s program will spark therapy development for a number of rare conditions.

What directions do you see genomic testing (including analysis, diagnosis, and counseling) taking in the future? Do you see a lot of change happening in this area? Do you think these changes are positive or negative? Why?

I think we are rapidly moving to the era of unlocking all of DNA’s mysteries, and really charging forward and diagnosing most conditions in much less time. I am not as sure that we, as a species, will take care to provide adequate support, guidance and counseling along with the diagnosis. I hope we do, and IDD is definitely striving for that deep level of engagement with the patient, becoming a source of support for them.

The changes unlocking of the DNA will bring to diagnosis is a big step forward in the right direction. Everything starts with diagnosis: by naming the suffering – then we can begin to understand the origins and begin to develop treatments.

How can members of the CEHG community get involved with In-Depth Diagnostics?

Once sufficient data is collected, IDD hopes to launch a major research effort that will combine groups across academia and industry who are studying human disease, developing therapies, or performing other computational biology projects that may benefit from data such as ours. Any researcher from the CEHG community who is interested in working with IDD’s curated database should contact the foundation for application.

CEHG’s core values are “collaboration” and “interdisciplinarity.” Are there ways you hope IDD will embody these values as well?

Absolutely! While genomic data is at the heart of this program, I know that progress in clinical care for rare diseases will only occur after combining data from numerous other health factors and biological perspectives. To put our program’s data to the best use, we must rely on collaborations with groups across industry and academia to elaborate on relevant findings and push the genetic information towards a meaningful application.

What advice would you give to early career scientists, having worked in both academia and at foundations with a patient-centric focus?

My advice is to always look 10 steps ahead and find the connection to how your research will help humans. This exercise makes everything so much more focused, and also very meaningful.

What advice would you give to patients?

Advocate for yourself; there are answers your doctor may not know. Participate in all aspects of drug development. Read and get educated about your disease.

Fellows Feature: Ryan York

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Ryan York is a CEHG graduate fellow in the labs of Russell Fernald and Hunter Fraser. He is a graduate of the University of California at Los Angeles. His research is focused on the evolutionary genomic basis of brain and behavior, with a specific interest in the courtship behaviors of Lake Malawi cichlid fish.

Can you tell us a bit about yourself, personally and professionally?

I am a graduate student in the labs of Russell Fernald and Hunter Fraser. I grew up in the Bay Area, and did my undergrad at UCLA. Before coming to Stanford, I worked as a research technician, first in Stephanie White’s lab at UCLA, studying the molecular bases of bird song, and then with John Allman at Caltech, researching neural traits unique to humans. My research is broadly concerned with understanding the evolution of brains and behaviors across disciplines, from genes to organisms. I am also a musician and artist and am interested in the intersections of art and biology.

Did you always want to be a scientist? What initially got you interested in science and genetics?

I didn’t always want to be a scientist. I was not someone who, as a child, knew they were destined to study a specific species or natural phenomenon. In fact, I began my undergraduate years as a Jazz Studies Major, having semi-professionally performed and recorded as a double bassist since the age of 14. What’s more, in high school, I was a “bad” science student, constantly feeling like I couldn’t measure up to those in my class who seemed to show natural talent for understanding and memorizing facts about enzymatic reactions and taxonomy. I was interested, but disengaged, convinced that my future lay in the Arts. Yet when I began taking classes in history and sociology in college, I realized that a whole world of interest existed for me outside of art. I caught the bug of wanting to understand human behavior, and that drive led me to crave more and more fundamental levels of understanding. Sociology led me to psychology, psychology led me to neuroscience, and neuroscience led me to genetics and molecular biology, and ultimately to where I am now.

Can you tell us about your current research and what you want to achieve with it?

My current research is focused on investigating how genomes produce the great behavioral diversity observed in animals. Despite decades of research, we still don’t fully understand how variation in genes and their regulation changes the function of the brain and its main output, behavior (especially our own). Historically, this has been due to technological constraints that incentivized researchers to focus on just a few model systems and behavioral types. Recent innovations in sequencing, neurobiology, and behavioral analysis are now allowing behavioral biologists to expand their focus to new species and groups displaying extreme behavioral diversity. My work attempts to develop methods that integrate these new approaches in order to understand how behaviors evolve and vary across biological levels.

I am primarily focused on an extremely diverse group of fish (cichlids) from Lake Malawi in East Africa. Though Lake Malawi is only around 5 million years old (i.e. very young, geologically speaking), there are already over 800 species of Malawi cichlids. Over 100 of these species perform a mating behavior, called “bower building,” that I am particularly interested in. During breeding season, males of these species will competitively build 3D structures out of sand to attract females, either in the form of a classic “sand castle” or as an excavated depression we a call a “pit”. We have shown that whether or not a male builds a castle or a pit is species-specific and innate, and that if you hybridize a pit species and castle species, the resulting hybrids will build both structures, resulting in a “pit-castle” bower.

To understand the genetic basis of this behavior, I am combining whole genome sequencing and RNA-seq in the hybrids, to uncover variants affecting the regulation of neural genes during different behavioral states. I am also using high-throughput behavioral phenotyping and genetic methods for analyzing signatures of recent neural activity to understand how variation in the cichlid genome leads to different behavioral and neural traits. I am now also working on applying these genetic methods to other types of data and species, including deer mice and fruit flies.

Were there specific people to whom you would attribute your academic and professional success?

There have been various people in my life who have had substantial impacts on my path (though not necessarily in ways that would lead one to predict that I’d end up in science). First off, my family has always been very supportive of whatever I wanted to pursue, be it jazz or evolutionary genetics, and have, at least, attempted to always show real interest in the odd topics I get obsessed with. In high school, my bass teacher, Seward McCain, supported my desire to major in music in college, but also strongly advocated for getting a full education outside of music, in order to avoid being one dimensional.

Multiple people in the sociology and anthropology departments at UCLA – Andrew Deener, Doug Hollan, Zsuzsa Berend, Jeffrey Prager, Alan Fisk – were instrumental in helping me figure out my life outside of music, and how to productively pursue my academic interests. Stephanie White charitably brought me into a real neuroscience lab as a research assistant when I, on paper, had no business being there. John Allman took my ideas seriously and guided me, with expert care, toward the better ones and away from the bad ones.

I have had a great experience working with my graduate advisors, Russ Fernald and Hunter Fraser. Both are wonderful advocates, collaborators, and mentors, and both have made possible whatever success I’ve achieved at Stanford.

Can you speak a bit to the role you see CEHG playing on Stanford campus?

I have found that CEHG provides a home for researchers who may be considered outliers or misfits in their own fields, be it due to their interdisciplinary focus or constant concern for achieving the next big thing (rather than what is currently fashionable). CEHG allows scientists to pursue these ideas at all levels – graduate, postdoc, faculty – knowing that they are supported both institutionally and intellectually.

As both a CEHG fellowship and research grant recipient, this has been really important for my growth as a researcher, and has allowed me to collect data and, in turn, produce work that is much more interdisciplinary and wide reaching than would have otherwise been possible.

What are your future plans? Where do you see yourself professionally in the next 5 or 10 years?

I am very excited to keep helping pioneer the study of behavioral evolution within the biological sciences. There is currently a small, but very motivated community of researchers who are working on ways to tackle this problem, and I would very much like to play a role in expanding this field’s focus and participation. To that end, I’m starting a postdoc this Fall in Tom Clandinin’s lab, to work on fundamental issues in the behavioral evolution of fruit fly species, and develop tools and methods that can be applied to a variety of species. In the future, I’d like to have my own lab, teach, and advocate for the benefit of using evolutionary perspectives in neuroscience, psychiatry, and human genetics.

What advice would you offer to other grad students or postdocs who are considering pursuing a similar educational and career path as you?

GET INTERESTED. It’s true that science is difficult, and to do it well requires knowledge of, and training in, an array of topics. But, in my experience, one of the main determinants of whether or not someone sticks with, and is successful in, science is their level of engagement with their topic.

Research benefits from an almost obsessive focus. Deeply wanting to know the answers to your questions somewhat forces the attainment of needed skills and knowledge. To me, this should be the way a researcher progresses, in the service of a project or question they are interested in, rather than in the service of the requirements of a graduate program or CV.

Tell us what you do when you aren’t working on research and why. Do you have hobbies? Special talents? Other passions besides science? 

I still compose, record, and perform music, though the amount depends on where my research is at any given moment. These days, I am increasingly interested in working on ways to integrate science and art, both in the production of my music and visual art, and in the way my scientific work is displayed and disseminated. I also rock climb quite a bit and am, as of recently, an extremely amateur dumpling maker.

 

Fellows Feature: Tricia Deng

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Tricia Deng is a CEHG graduate student fellow in Dr. Jin Billy Li’s lab in the Genetics Department. She got her undergraduate degree in Molecular and Cell Biology (with emphasis on Biochemistry and Molecular Biology) at UC Berkeley. Her research focuses on the evolution and function of Adenosine-to-Inosine (A-to-I) RNA editing in Drosophila

Can you tell us a bit about yourself, personally and professionally?

I’m a graduate student in Jin Billy Li’s lab in the Genetics Department. I grew up in the South Bay. I went to UC Berkeley for my undergraduate degree in Molecular and Cell Biology. After graduating, I came to Stanford through the Structural Biology program. Then, I joined Jin Billy Li’s lab, which studies A-to-I RNA editing, and the Genetics program. I enjoy combining ideas and techniques from different fields of study. I think applying computational methods to biological research will dramatically improve the pace of research and yield exciting discoveries and innovations.

What initially got you interested in genetics and science?

I became interested in scientific research when I interned at an atmospheric chemistry lab at NASA in high school. I was really excited to be part of the research process and loved the idea that research could be used to address major challenges, such as global warming. I wasn’t very interested in biology until I worked on a research project in my senior year of high school and realized that biology research was very different from biology class, which was focused on memorization. In college, I really enjoyed learning about, and conducting, research through various classes and research projects led by some very talented professors and mentors, and this led me to pursue a PhD.

Can you tell us about your current research and what you want to achieve with it?

The information encoded in DNA is used to form the proteins that make up organisms; thus, this information contributes to various characteristics of organisms, including humans. Understanding this process is important for treating diseases, understanding how and why individuals differ, and improving the quality of life.

The process by which genomic information is used to make an organism is very complex. Many important modifications are made to the information before, during, and after transcription and translation. I’m studying one of these modifications, adenosine-to-inosine (A-to-I) RNA editing, which is important for neurological and immune well-being. In A-to-I RNA editing, enzymes in the Adar protein family convert adenosines to inosines at specific sites in RNA transcripts. These A-to-I changes can affect the amino acid sequence of the resulting protein, splicing, and the structure of the RNA. The fraction of adenosines that are converted to inosines at a specific site, or the “editing level”, can vary in different tissues and across developmental stages and times of day. Thus, RNA editing is different from SNPs, which work at the DNA level, and could be used to fine-tune the information encoded genomically.

Although RNA editing occurs at thousands of sites across the genomes of various animals, the functions of nearly all editing events haven’t been studied. Along with a former postdoc in the lab, Rui Zhang, I examined the evolution of A-to-I RNA editing in Drosophila species to identify editing events that are under evolutionary constraint and therefore likely to be functionally important. Then, working with some undergraduate and high school students, I used the Cas9/CRISPR system to make fly mutants without editing at some of these sites, and we’re working with other labs to examine their phenotypes. Finally, to study how particular adenosines might be selected to be edited, we used machine learning to examine how changes to the sequence and secondary RNA structure around editing sites are associated with changes in editing levels.

Overall, I think there are many open areas of research in this field. A better understanding of how RNA editing works and what its functions are – especially the functions of noncoding RNA editing events, which are understudied – will yield important insights into how our DNA information is used to produce phenotypes, and perhaps even give us clues for how complex systems, such as the brain, work.

Were there people to whom you would attribute your academic and professional success?

Before arriving at Stanford, I was fortunate to be mentored by many amazing researchers and teachers. At Stanford, my advisor, my lab mates, and other collaborators have been indispensable. I wouldn’t have been able to do so much without their feedback and the collaborations with many lab members and interns. Also, the support of friends and family – especially, my husband Jinghao – has been essential.

Can you speak a bit to the role you see CEHG playing on Stanford campus?

When I went to my first CEHG meeting, I was amazed at the diversity of research fields and departments there. I think one of CEHG’s strongest points is the ability to connect people from various fields. Many programs and events are focused on specific departments, but CEHG is different because it encourages the flow of ideas and collaborations between these fields.

What are your future plans? Where do you see yourself professionally in the next 5 or 10 years?

After graduate school, I plan to work in industry on something that will impact the world more directly. My future plans are flexible, but, no matter what I do, I hope to continue to work at the intersection of disciplines.

What advice would you offer to other grad students or postdocs who are considering pursuing a similar educational and career path as you?

I’ve realized that it helps to go to conferences and talk to people outside your field. Getting a PhD is often portrayed as specializing in only one thing, but, in reality, no area of biological research can be truly isolated into one field. Different fields can have different research priorities and approaches. Also, a lot of innovation comes from using new technology or pulling in outside ideas.

Also: Research is really hard, and you’ll likely face many setbacks, but you can do it!

Tell us what you do when you aren’t working on research and why. Do you have hobbies? Special talents? Other passions besides science?

I enjoy baking, eating, hiking, making apps and websites, and hanging out with my pet bunny, Momo. I also enjoy traveling and, especially, eating delicious food while traveling. My most recent trips were to Iceland (husky sledding on a glacier!) and China (giant mantis shrimps!). 

Fellows Feature: Amy Goldberg

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Amy Goldberg is a CEHG predoctoral fellow in the lab of Noah Rosenberg. Amy completed her B.S. in Biological Anthropology and Mathematics at the University of Michigan, where she was an undergraduate researcher in the lab. Her interests are in human evolutionary genetics, and she is currently working on mathematical modeling and statistical problems in anthropological genetics.

Can you tell us a bit about yourself, personally and professionally?

I grew up in Michigan, but was actually born in South Africa. I’m currently finishing my PhD in Noah Rosenberg’s lab. My background is in both anthropology and mathematics, and this combination continues to shape my research interests and how I address them. I develop quantitative methods to interpret genetic and archeological data to reconstruct past human demography, adaptation, and interactions with the environment. This work mixes population genetics with math and statistics, as well as biological anthropology, archeology, and paleontology.

What got you interested in genetics and science? Did you want to be a scientist as a child? 

My parents moved from South Africa to Michigan when I was young, and this degree is exactly what they had in mind. I’ve always liked science, but, as a kid, I thought that biology was mainly memorization. I’ll be graduating from the Biology department this year. This definitely shaped my view of education and how we talk to kids. Role models can be particularly helpful—we see a lot of occupations on TV or in movies, but scientist, especially professor, is vague. I had the opportunity to see my dad go to grad school; I went to his PhD defense when I was 12.

Can you tell us about your current research and what you want to achieve with it?

Much of my work focuses on human evolutionary history during the past 20,000 years, which is recent on evolutionary timescales. This time period is associated with massive social and environmental upheavals, from the end of the Last Glacial Maximum to worldwide megafaunal extinctions and the rise of agriculture. In fact, recent genomic studies have shown that this time period has been particularly important for shaping disease risk in humans because the history of recent expansions has led to a disproportionate number of rare genetic variants in the population. I build mathematical models to understand how evolutionary and social forces impact a population, and develop statistical methods to interpret large quantities of genetic and archeological data.

Most people I meet are innately interested in learning about human history, but this work has further consequences too, from predicting disease risk in diverse populations to forecasting the impact of climate change on animal populations.

What are your future plans? Where do you see yourself professionally in the next 5 or 10 years?

I am finishing my PhD this year. I’m excited to be starting my own lab at Duke, after deferring for a short postdoc at Berkeley. I plan to continue along major lines of research developed during my time at Stanford, and hope to keep in touch with many from the CEHG community. I’ll be tackling problems in evolutionary and population genetics, human-environment interaction, and recent population history.

Were there people (or one person) in particular to whom you would attribute your professional success? 

I’ve had a series of amazing mentors. Two in particular stand out—my undergraduate advisor Milford Wolpoff and my PhD advisor Noah Rosenberg.

I cannot discuss my scientific endeavors without thinking of my first scientific mentor, Milford Wolpoff. Before meeting Milford, I was hesitant to speak up for fear of being wrong; Milford taught me to be loud, to question what I read, and to know the history of scientific fields. It is also in Milford’s lab that someone casually mentioned an interesting geneticist on the other side of campus—Noah Rosenberg.

It is absolute luck that I met Noah mere weeks before he moved from the University of Michigan to Stanford. Since then, I have benefited in untold ways from Noah’s intentional efforts to include people from different backgrounds and instill thoughtful scientific habits. His encouragement—the simple belief that I could teach myself the skills I needed to know—underlies my whole PhD. The precision and skill with which Noah thinks is something I will continue to strive towards for the length of my career.

CEHG’s core values include “interdisciplinary research” and “collaboration.” Can you speak to the ways your work has embodied these values or to their importance to your future work or past experience? 

My work is really interdisciplinary and I’ve greatly benefited from CEHG bringing together scientists from across the university. I’ve learned from the professors, but also from the opportunity to interact with all the students and postdocs and the great speakers that visit for Evolgenome. More directly, CEHG sponsored my research through their grant mechanism for a project early in my PhD, which was the first collaborative project I participated in.

Tell us what you do when you aren’t working on research and why. Do you have hobbies? Special talents? Other passions besides science? 

Since my work is computational, I try to get outside for fun. Living in the Bay Area, that is easy. I go for a hike most weekends and have recently taken up climbing. I like to travel a lot too.

What advice would you offer to other grad students or postdocs who are considering pursuing a similar educational and career path as you? 

Figure out how to like to work early on—this will help you all other decisions like choosing mentors or to your field/subfield. Having a mix of people around with different personalities and research goals really helped me find my own way. I tried to frequently solicit their advice, but you don’t always have to take it. Outside the box opportunities are often overlooked but may be very worthwhile to starting a whole new line of research or to meeting collaborators.

 

Fellows Feature: Jaehee Kim

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Jaehee Kim is a postdoctoral scholar in the Department of Biology at Stanford University. She received her B.A. in Physics and Mathematics from Columbia University and her Ph.D. in Physics from Stanford University. Her research interests include mathematical properties of admixed population phylogenetic trees inferred by neighbor-joining, the relationship between individual identifiability and ancestry information in CODIS forensic markers and non-CODIS microsatellite loci, and change of admixture fraction in a hybrid population mating assortatively based on phenotype over time. 

Can you tell us a bit about yourself, personally and professionally? 

I was born and grew up in Incheon, South Korea’s third largest city, where I was likely the most physics-y kid on the block. True to form, I received a B.A. in Physics and Mathematics from Columbia University and a Ph.D. in Physics from Stanford University. My graduate research focused on the study of quantum chemical dynamics in complex molecules. I developed an ab initio theoretical framework to numerically simulate light-induced excited state topology and nonadiabatic dynamics, as well as multidimensional statistical techniques to analyze molecular fragmentation patterns. Now, I am a postdoctoral scholar in Noah Rosenberg’s lab.

How did you end up here? What got you interested in genetics and science?

Like most physics-y kids, I always loved math and spent countless hours voraciously reading science magazines and Feynman lectures. I was amazed by how physical phenomena, from mundane everyday events to the creation of the universe, could be explained by beautiful mathematical equations. I believed that everything could ultimately be explained by the laws of physics. During graduate training in atomic molecular optical (AMO) physics, working with people from diverse fields expanded my research interests. After going to a handful of outer department talks, I was drawn to evolutionary biology—like many people, I always have the same age-old questions lingering in the back in my mind: “why are we here; where are we going?” (Charles H. Townes, 1997). The current lab is the perfect fit for me as it applies rigorous mathematical theory and statistical methods to the study of human evolution and population genetics. I still have a lot to learn, but I have been enjoying working in the lab very much so far!

Can you tell us about your current research and what you want to achieve with it? 

My current research deals with the development and application of a mechanistic model for assessing the effect of different admixture histories involving dynamic contributions of mutually isolated source populations on the ancestry of admixed human populations. Human mating is non-random to some degree, since most people marry individuals of roughly similar phenotype and cultural factors. The assortative mating alters genetic variance for the assorting trait and makes the traits more susceptible to selection over time, thereby changing the genetic structure of a population.

Since the ancestry information is propagated through genotype but mating is based on phenotype, mapping genotype to phenotype is a crucial step. Among many interesting results the model produces, correlation between ancestry proportion and phenotype is of particular interest as it gives us insight about the degree to which genetic differences give rise to phenotypic differences between human groups. This also helps us to answer important questions regarding racial classification beyond conventional phenotypic group-level differences that are believed to be a representative of a race or ethnicity, for example, skin and eye color.

Once gaining intuition from the idealized model, to simulate more realistic human population, the model can be further extended by including confounding factors such as dominance, varying heritability, effect size distribution across loci contributing to the quantitative trait, and linkage disequilibrium, as well as environmental perturbations.

Were there people in particular to whom you would attribute your professional success? What is it like working with your current lab advisor and his lab? 

My Ph.D. advisor, Prof. Phil Bucksbaum, has provided me every bit of guidance for becoming a better scientist and encouraged me to collaborate with people outside the physics department to branch out into new research areas. His genuine enthusiasm for science and encouragement kept me motivated when research progress was bumpy. From my graduate lab, Doug taught me the importance of scientific intuition over sets of equations and he has made working in the lab so much more fun and interesting. James showed me reasonable science could be extracted from suboptimal experimental data if you used good statistical methods.

My current advisor, Prof. Noah Rosenberg, believes in the interdisciplinary nature of the work and gave me a chance to work in his lab. He helped me transition smoothly into the new field by providing every possible resource, and guided me through the systematic and mathematical approach for understanding evolutionary biology. I have also enjoyed the camaraderie and benefited from the varied expertise of the group members.

What are your future plans? Where do you see yourself professionally in the next 5 or 10 years?

Long term, I see myself still working in the field of theoretical population genetics. Having my own lab and staying in academia will be the best-case scenario, but I would be happy with government labs or industry as long as I can do meaningful research with some freedom and independence.

What advice would you offer to other grad students or postdocs who are considering pursuing a similar educational and career path as you? 

  • Most physicists are proficient in math and programming, but still, the more the better.
  • Stay open-minded, look outside your department, and explore your options. There are tons of other interesting work going on that could use a physicist!
  • Have patience, and don’t rush. Research takes time, and some projects might not end up working out. Persistence is important, but at the same time, know when to stop and move on, and when to pause for now and come back later.
  • Have a life outside the lab, and cut yourself some slack. You’ll need it for your sanity.

Can you speak a bit to the role you see CEHG playing on Stanford campus?

I love the cross-disciplinary environment CEHG has created. It brings scholars from various fields, which encourages me to communicate with researchers outside my specific research area and broadens my knowledge. I believe the collaborative approach across different fields can produce creative solutions to challenging problems through a diverse array of tools.

For instance, during my graduate studies in physics, I have used techniques borrowed from biology—for example, genetic algorithm and spawning of wavepacket—in modeling complex molecular dynamics. I am excited to apply physics techniques to tackling fundamental problems in evolutionary biology and share my interests with others.

Tell us what you do when you aren’t working on research. Do you have hobbies? Special talents? Other passions besides science? 

I spend most of my free time training in the gym. I have played various sports growing up, but my current focus is in Olympic weightlifting. I also like trying out new fitness classes/workshops/gyms and enjoy reading sports science and physiology research articles.

Tweeting #CEHG17

The Fifth Annual CEHG Symposium was held in Stanford University’s Frances C. Arrillaga’s Alumni Center on March 6, 2017. It was an amazing day, with fascinating presentations on computational, evolutionary and human genomics and plenty of opportunities to visit with old and new friends over coffee and tea! And with 10 brilliant speakers, including keynote Carl Zimmer, and more than 160 registered attendees, CEHG17 was a definite success!

Did you miss the event or are you just curious what everyone was talking about? Click on the feed link below to catch up!

Read the curated twitter feed

Want to read more materials about our symposium? Check out our CEHG17 photo album on Flickr. An event report will be published shortly on our blog home page.

Want to learn more about CEHG?  Visit our website or follow us on Facebook and @StanfordCEHG.

Feature Interview: María Ávila-Arcos

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All images courtesy of Maria Avila-Arcos

María Ávila-Arcos is an Assistant Professor at the International Laboratory for Human Genome Research at the Universidad Nacional Autónoma de México/ National Autonomous University of Mexico). She was a postdoctoral researcher in the Bustamante Lab at Stanford University from February 2014 to September 2015, where she studied population genomics and global health. Before that, she studied in Denmark as a PhD student and then as a postdoc at the University of Copenhagen. She received her PhD in Paleogenomics in 2013.

This content is transcribed from an interview that took place on Stanford University campus with CEHG Director of Programs, Cody Montana Sam, and Communications and Outreach Manager, Katie M. Kanagawa. 

AfroMexico Project Description: In January 2015, a fieldwork team led by Ávila-Arcos, a CEHG postdoctoral fellow at the time, collected eighty samples from individuals living in Afro-Mexican villages in the Pacific coastal State of Oaxaca. In a pilot effort, saliva samples were collected, along with genealogical information, anthropometric and skin pigmentation measurements. Given the initial sampling success and the scaling feasibility, this effort has been expanded to analyze the genetic structure of Afro-Mexicans across the Atlantic-Pacific corridor. Mexico’s African roots have importantly impacted the current shape of the population, but they have yet to be represented in modern genomic surveys of genetic variation. The knowledge generated in this study will help characterize this important, yet neglected, third ancestry of Mexicans and will shed light on the genetic dynamics and implications of the slave trade in the Americas.

Why don’t you tell us a little bit about yourself, in the broadest sense? 

I grew up in Mexico City and I went to college in Cuernavaca, a town about 1.5 hours away. Since very young, when I was 18, I jumped straight into genomics and research. The National Autonomous University of Mexico’s (UNAM’s) campus in Cuernavaca hosts the Biotechnology and Genomic Sciences Institutes, and I was part of a very specialized, unique undergraduate program in genomics. It was kind of a pilot project with a reduced number of students and very good, research-driven work. It was apparently successful because most of us who graduated from that program found PhD or Masters degree positions abroad.

Can you talk about the intersection of medicine and genetics in your research? 

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I’m just starting now to get into that. Right now, I’m very interested in understanding the genetic structure of populations that haven’t been very well characterized from a genetics perspective, admixed populations in Mexico for example. First, you need to understand their genetics, how admixture is structuring them, and then you start to do more clinical studies on them, using this background. So it’s very basic research and then you build on it.

Since you got started in genetics, do you think the field has changed much? How so?

It was a dramatic change. Towards the end of my undergraduate program, I had to write a thesis and, in the last classes I took, I started to hear we had new sequencing machines and pyrosequencing, and there was this idea like things were happening. But then I started my PhD and the next-generation sequencing machines started this massive revolution in genomics and genetics research. So I knew nothing about how to handle this kind of data when I was an undergrad, because it was brand new. I had to learn that as a PhD student, and I had to teach myself these new programs, these new ways of handling massive amounts of data. That was a big change.

One thing we have seen, at least from your awesome lab meeting presentations, is how much you like doing fieldwork, and also making sure that community members are involved in the fieldwork and understand the research. So can you speak a little bit about that? 

Sure. Well I grew up with my dad being an epidemiologist; he did a lot of fieldwork and he would take me when I was a kid into the field. And his research focuses on children. In Mexico, we have a lot of malnutrition and basically his fieldwork involved weighing kids and giving advice to the families on how to better feed their kids. So I was part of that. I grew up doing this fieldwork with my dad, and then I went to school and I never thought I would go back to fieldwork again, but that image of him and also how involved he was with the community and how much respect he had for the community, is something that stayed with me.

And also something very important: when I came here to Stanford and I went to do fieldwork in South America with Karla Sandoval Mendoza [former Bustamante Lab member]. Her background is Anthropology and she also has a lot of experience doing fieldwork in the frame of genetics, so seeing her was really cool and seeing that we share a lot of the same philosophy on how to approach communities and talk to them. That was also something I learned from her.

So tell us about the communities where your fieldwork was located? 

South America was the most exciting. It was my first time doing fieldwork, collecting samples for genetic studies. So I went to Easter Island with Andres Moreno Estrada [Bustamante Lab alumnus] and it was really cool, because it was the second time he was visiting and he was giving results back to the community, so the effect it had on people, to get their ancestry results back, and also collecting new samples for new studies was very exciting. And I went to one community with Karla in Peru; it’s called Magdalena da Cao and we also collected samples there. More recently, I’ve been doing more fieldwork in Mexico with the AfroMexico project.

Does a particular person you’ve met while doing fieldwork, one of the community members, come to mind? And why? 

Yeah, definitely in Oaxaca, Mexico, there is Lucia Mariche, in the context of the AfroMexico project. She lives in Chacahua, an AfroMexican community, and she’s a community leader. Just being able to be in contact with her: she’s really proactive and you can see her leadership when you see her. And she’s also very nice and she was very collaborative. Basically, she was the one who opened the doors for us, to the other communities we visited. So people everywhere we went were like, “Lucy, how are you doing? How is your mom? How is your family?” She was great. She is my favorite person.

If you were to give advice to other people who are interested in doing fieldwork, who maybe don’t know how to get started with these communities, what would you say

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The first advice is you have to build or join a network that is already in place in these communities. You have to find your way through this network first to find a person who is in contact with another person, who is also in contact with another person, etc. So you just need to find that key person and then you’re part of that network, so that people in the communities will know you as part of that network and they will be more open to participating in your study.

Can you tell us a bit more about the AfroMexico project? 

Yeah, sure, that’s my favorite topic (laughs). My interest is characterizing the genetic makeup of AfroMexicans and the reason I am very interested in this is a nice story: while I was doing my PhD and I was more specialized in paleogenomics (ancient DNA), we got these samples from the Caribbean that were from the 16th century. We knew the people were born in Africa, but their remains were found in the Caribbean. Basically, the questions we had with these three ancient samples was: where were these people born? Where are they from? Because we knew, by the historical context, that they were probably brought to the Caribbean by the Transatlantic Slave Trade, and we wanted to know exactly where in Africa they were from.

In the study of the Transatlantic Slave Trade, the question of origins is a very important one and a central one. Because during the Trade, the place of origin–the geographic or ethnic origin–was erased from the records, or not even erased, but not even written or put in the record. Many people don’t have the tools to trace their actual ancestry because the record didn’t include them. So I had that question in mind, and that got me to think a lot about the slave trade in the Americas, and I started to read about the slave trade in Mexico, and the more I read, the more surprised I became, because it’s something you don’t hear much about in Mexico.

But just looking at the history, I realized that there was a lot of trade into Mexico from Africa. As I read more, I found that there are some places in Mexico where you see a higher concentration of people of African descent. So I wanted to see them and work with them because I had the same question: where did these people, their ancestors, come from and when were they brought from Africa to Mexico? That’s how I got interested. I called Carlos [Bustamante] and asked, “Carlos, can I go to collect samples?” And we had the IRB in place. The first time I went was this January. Many months in advance, I started emailing people and getting necessary contacts, so that by the time I got there, people were already waiting for me.

When you go to these communities, how do they themselves identify? 

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It’s becoming more political right now, because these people are fighting for recognition as people of African descent and a vulnerable minority as well. In Mexico, if you speak an indigenous language, then you have access to certain benefits, like scholarships or programs that support communities. But if you can’t identify as Afro-Mexican, because there is no box to check, you are also vulnerable. So if you ask people who are part of this initiative, they would say “yes, I am Afro-Mexican,” but if you ask people who are not, they would say “no, I’m Mexican, that’s just the color of my skin.” But for many people, there is a disconnect between the way they look and the slave trade many centuries ago. They don’t recognize themselves as being from Africa; they see no connection.

In the last fieldwork I did, I asked the question, “how do you self-identify?” In Oaxaca, for example, people are more politicized because there are more movements there for recognition, but in Veracruz, almost no one recognizes themselves as Moreno, or Negra, or Afro-Mexican. Very few people, so it’s interesting.

That’s interesting because there are also those types of discussion within the American black community, as to how you identify and how much you identify with the African continent. If you were to compare and contrast slave routes and the slave trade in America vs. Central America and Mexico, how would you describe it?

It’s very different, and I think that’s one of the important reasons why we need to study Afro-Mexicans, because it just has a different history. We were a Spanish colony and, as a Spanish colony, the deals they were putting in place were different than the British colonies. So, for example, the Spanish bought from the Portuguese and the Portuguese had many of their shipment stations in Angola and Mozambique and most of the people they kidnapped and traded were from those two regions. In America, the British took them from different places along the African West Coast that changed with time, So it’s a different history. It’s been studied a lot among African-Americans, but it’s a different history. You wouldn’t expect the ancestry to be the same. So that’s an argument too.

Have you begun to think about the clinical implications of studying these populations? And have you talked to them about why so many people have high blood pressure, diabetes, and those sorts of issues?

Yeah, so there are two aspects. One reason I got interested is because I started hearing, by talking to people and reading, that there’s a lot of anemia in these places. So that is something that I want to know and I can learn from genetics: if this anemia is a predisposition. The sickle cell anemia, it’s protective against malaria and if you have mild anemia, you’re protected against getting malaria. I was curious to hear if the anemia that’s been observed in these regions could be related to sickle cell, as opposed to just not having good food with enough iron. So that was the first clinical aspect that I wanted to address.

And then I am also very interested in the skin pigmentation piece. When I was there, I collected the skin pigmentation data, because that also has implications on certain things, like predispositions for skin cancer (because the color of your skin determines how much UV you filter, and also if you are more or less likely to get skin cancer). So that’s another aspect I’m researching.

What are the clinics like in the communities you visited, and how do you interact with clinicians and doctors?

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There are not many there. Like in Oaxaca, for example, many people saw us and thought we were medical doctors and they would come and say, “I have this pain here,” “I feel bad in the mornings.” They wanted advice on their health and we had to say, “No sir, we can’t.” But there is very poor health there, and that was pretty sad to see.

Also, in the second fieldwork I did, there was a breakout of the chikungunya virus and that was really bad. In Oaxaca, some people had it, but in Guerrero, almost everyone had it. It’s a virus that is transmitted by a mosquito, so many people were sick and that’s a very painful disease. It’s like a very bad flu, but with a lot of joint pain and rashes. Many people came to us and said they had it, or they had had it recently and they were still in pain. I wished I could something about that, and that was a bit frustrating.

But then in Veracruz, we were super lucky to have on our team a medical doctor, Cesar, who came with us. That was great because, as we were measuring the hemoglobin, whenever we would find a low value we would ask Cesar to talk to these people and give them some advice. The people who came to us with pain, we could direct to Cesar and that was less frustrating than in Guerrero. And people really appreciated having someone to talk to about how they feel, because they don’t normally have much access to healthcare services.

So even though you’re not technically a clinician, are you able to give results back to the communities, say about a predisposition, and direct them to a doctor or anything like that? Can you do any amount of genetic counseling when you are out in the field?

I don’t think I would, at this stage, because they are admixed populations and most of the association studies are not based on people with African or indigenous ancestry. They are mostly done on people with white ancestry. And then in terms of monogenic diseases, I couldn’t feel comfortable giving those kinds of results.

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But what I can do and what they really liked is when we were measuring hemoglobin with a portable device and we were giving their results back to them that minute. So we would take a droplet of blood and measure their hemoglobin and say you’re ok or you’re low. And we would gather the people with low values and give a talk about what they can do to increase their levels. In Oaxaca, we had Silvia, a nutritionist who lives in the area, with us. So she could tell them what food sources found in the area are good for them. In Veracruz, Cesar could tell people what they can do, and for overweight people, why that can be dangerous. But that is the extent of the clinical advice that I feel comfortable giving.

So what’s next for you?

I’m flying to Mexico in a few hours (laughs). I’m starting a new position in Mexico, and it’s the National Autonomous University, the same university where I did my undergraduate studies. I’m excited! I know it’s going to be very challenging; it’s not going to be easy, because science policy in Mexico is very different than in the States or in Denmark, where I did my PhD. There are less resources, there’s a lot more bureaucracy, we have to do a lot ourselves, and you have to secure your own funding starting on day one. That’s going to be challenging, but I also like the idea of being closer to my fieldwork, and interacting with other Mexican scientists who are there (like Karla and Andres).

Are you excited about mentoring other grad students and postdocs who are coming up in Mexico?

Yes, definitely. I like teaching and I like to give advice to people, especially Mexicans who may be afraid of going abroad. I would basically like to have people from this community doing research on themselves.

What do you see as the role of Stanford CEHG, moving forward?

I really like CEHG. They have been super supportive of my projects. I think that the role of CEHG is just making our lives easier by giving us resources to fund our research, and giving us every tool we need to do our job, which is doing research, and not worrying about anything else.