Inside AJHG: A Chat with Stephen Kingsmore

Posted By: Sara Cullinan, PhD, Deputy Editor, AJHG

Each month, the editors of The American Journal of Human Genetics interview an author of a recently published paper. This month, we check in with Stephen Kingsmore to discuss his paper “A randomized, controlled trial of the analytic and diagnostic performance of singleton and trio, rapid genome and exome sequencing in ill infants.”

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Stephen Kingsmore, MD, DSc, holding his patient, Maverick Coltrin. The photo was taken in April 2018 at the Frontiers in Pediatric Genomic Medicine Conference.

AJHG: What prompted you to start working on this project? 

Stephen: We’ve been working on implementing rapid whole genome sequencing in infants in intensive care units since 2011. We have two Guinness world records for fastest time to genetic diagnosis (the current benchmark is 19 hours). In the first 35 infants we tested, we saved two lives by changing therapy from that based on the clinical diagnosis to that based on the molecular diagnosis. Ever since then, we’ve been on a mission to understand how to make this reality in every intensive care unit in the world.

AJHG: What about this paper/project most excites you? 

Stephen:  Randomized controlled trials are very exacting. This is just the second randomized controlled trial of clinical genome sequencing! You’re never sure whether a clinical trial will really test the desired hypothesis. I was most excited that we clearly showed that ultra-rapid whole genome sequencing, with fastest time to diagnosis, was best for seriously ill infants in intensive care units (ICUs). As with every previous study, I now know how to redo the current one!

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Stephen: This manuscript is part of a growing body of evidence that demonstrates that infants in ICUs with diseases of unknown etiology benefit from rapid whole genome sequencing by virtue of the consequent implementation of precision medicine. We anticipate that 30,000 infants per year would benefit from this in the U.S. The current study was unique since almost one half of infants in ICUs were eligible for enrollment. As a result, we found that genetic diseases are much more common than previously expected.

AJHG: What advice do you have for trainees/young scientists?

Stephen: Think about a career in genomic medicine – the genomic medicine tsunami is coming and we’ll need every genetic counselor and medical geneticist to deliver this new type of care. For the first time, genomics will save lives day in, day out.

AJHG: And for fun, tell us something about your life outside of the lab.

Stephen: I’m reading the Bible in a year. I’m 2/3 of the way through and it yields specific thoughts for each day, as well as continually adjusting my thinking to the bigger, long-term picture. It started as a chore and now is a vital part of my day.

Stephen Kingsmore, MD, DSc, is the President and CEO of Rady Children’s Institute for Genomic Medicine at Rady Children’s Hospital. He has been a member of ASHG since 2007.

Inside AJHG: A Chat with Heidi Rehm

Posted By: Sarah Ratzel, PhD, Science Editor, AJHG 

Each month, the editors of The American Journal of Human Genetics interview an author of a recently published paper. This month, we check in with Heidi Rehm to discuss her paper, “Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.”

Heidi Rehm
Heidi Rehm (photo courtesy of Dr. Rehm).

AJHG: What caused you to start working on this project? 

Dr. Rehm: We (Broad Institute and Partners Laboratory for Molecular Medicine) as well as Baylor College of Medicine were funded to provide genomic sequencing and interpretation support for Phase 3 of the eMERGE program.

AJHG: What about this paper most excites you? 

Dr. Rehm: Understanding our genomes will require large scale data sharing, harmonization and analysis across many research and health systems. This paper represents key steps in harmonizing and scaling genomics in the context of real-life healthcare systems.

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Dr. Rehm: We hope that our work sets the groundwork for more clinical laboratories standardizing the intake of genetic testing orders and output of clinical reports for consumption by electronic health systems which we hope will be embraced as we all try to best integrate genomics into the practice of medicine.

AJHG: What advice do you have for trainees/young scientists?

Dr. Rehm: Clinical genomics is an exciting field with tremendous growth happening. Come join us!

AJHG: And for fun, tell us something about your life outside of the lab.

Dr. Rehm: I have two teenagers, so life outside the lab right now is mostly following them around to sports events and college visits. Most weeks I get to play at least one game of ultimate Frisbee in the evening when I’m not traveling. And of course a favorite family activity is watching John Oliver as the only way to survive the current political climate in the U.S.!

Heidi L. Rehm, PhD, FACMG, is Chief Genomics Officer in the Department of Medicine for Massachusetts General Hospital, and Medical Director of the Broad Institute Clinical Research Sequencing Platform. She has been an ASHG member for over 20 years. 

Inside AJHG: A Chat with Natalie Telis

Posted By: Sarah Ratzel, PhD, Science Editor, AJHG 

Each month, the editors of The American Journal of Human Genetics interview an author of a recently published paper. This month, we check in with Natalie Telis to discuss her paper, “Public Discussion Affects Question Asking at Academic Conferences.”

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Natalie Telis, PhD (courtesy Dr. Telis)

AJHG: What caused you to start working on this project? 

Dr. Telis: At one of the first conferences I went to, I realized after a day that I was the only woman who’d asked a question. And I remember thinking, “That’s weird, right?”

But then I second guessed it. I said, well, there were maybe 10 questions today. If 1 in 10 people in the audience are women, that participation is actually representative. What information would I need about this conference to discover whether this is representative participation?

Part of being a computational biologist is that you have a skill set that applies to computational problems — not just biology problems. So I started drawing on that skill set to try to learn more about this problem, and things kind of evolved from there!

AJHG: What about this paper most excites you? 

Dr. Telis: I am really excited about the opportunity to explicitly set goals, and then to use these techniques to measure whether our interventions get there. If our goal is to increase proportionate participation, it’s easy to say: “Well, having 50% of people in the room be women will help us get there.” But does that actually come to bear? We can test that question now (and learn that it doesn’t work that way). That can help us build powerful interventions to change culture and reshape access for underrepresented groups in science more broadly.

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Dr. Telis: The human genetics community is still grappling with questions about representation and participation across the board, not only for women scientists but across intersectional categories. I do hope that raising these questions in a scientific way has contributed to more discussion around inclusion and representation. We definitely still need to ask, what do we want our community to look like, and how do we get there?

This work provides a precedent and hopefully a computational framework for testing that. And that’s a critical infrastructure we need to develop as we attempt to create change.

AJHG: What advice do you have for trainees/young scientists?

Dr. Telis: Any question is an opportunity to hone your scientific skills. Asking questions about questions didn’t seem like human genetics to me, but the computational techniques I’ve learned were ultimately what I used to solve that problem. Being a scientist is an opportunity to live and work on the edge of what is known — bring that curiosity in the face of uncertainty with you wherever you go!

AJHG: And for fun, tell us something about your life outside of the lab.

Dr. Telis: I don’t really believe in New Year’s resolutions or setting a goalpost (especially because I always miss them), so instead this year I started trying to numerically track things I want myself to do more of. So I’m surprised and shocked and very proud to say I’ve read 27 books so far this year! Making space for all that fiction reading, not just paper reading, has made me more refreshed, inspired, and creative in my research.

Natalie Telis, PhD, is a Staff Scientist at AncestryDNA. She has been an ASHG member since 2014.

Inside AJHG: A Chat with Lluis Quintana-Murci

Posted By: Sara Cullinan, PhD, Deputy Editor, AJHG

Each month, the editors of The American Journal of Human Genetics interview an author of a recently published paper. This month we check in with Lluis Quintana-Murci (@quintanamurci) to discuss his paper “Impact and Evolutionary Determinants of Neanderthal Introgression on Transcriptional and Post-Transcriptional Regulation.”

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Lluis Quintana-Murci (far right) with the members of his lab, including Martin Silvert and Maxime Rotival (courtesy Dr. Quintana-Murci)

AJHG: What prompted you to start working on this project? 

Lluis: My laboratory is interested in the evolution of human populations and their long-standing relationship with infectious agents; half of the lab thus works on population genetics questions and the other half focuses more on population/systems immunology. In the context of this project, it all started back in 2016, when we found that Neanderthal introgression has affected innate immunity genes as a whole, and that some innate immunity genes (e.g., the TLR1/6/10 cluster) display extremely high levels of Neanderthal ancestry (Deschamps et al. Am J Hum Genet, 2016).

Later that year, we also found that Neanderthal introgression has been pervasive among regulatory variants (eQTLs), in particular those involved in responses to viral stimuli including influenza (Quach et al. Cell, 2016). The next natural question was then to explore how Neanderthal-introgressed variants in the genomes of non-Africans have affected more generally transcriptional and post-transcriptional regulation, focusing on promoters, enhances and miRNA-mediated regulation, in different tissues and cell types.

AJHG: What about this paper/project most excites you? 

Lluis: Several things. First, although Neanderthal introgression has had relatively little effect on miRNA-mediated regulation, a mechanism that in general tolerates little variation and is highly evolutionary constrained, a few Neanderthal variants in a few miRNAs can exert a massive impact on downstream transcriptional programs. In general, I am fascinated by the fine-tuned “smart” way miRNAs function.

Second, I am excited about our results of enhancers, in particular the enrichment in Neanderthal ancestry we find in enhancers that are active in T cells (yes, sorry, I have a biased interest in all immune-related processes). What is even more interesting is that the excess of Neanderthal ancestry we observe in T cell enhancers is not due to increased Neanderthal introgression. Instead, it results from a higher human-Neanderthal divergence at these elements. This may reflect past adaptation in the Neanderthal lineage for this type of enhancers.

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Lluis: This work highlights once more the potential benefits of admixture between our ancestors and other human forms, such as Neanderthals or Denisovans. The latter were adapted to their environments, whereas our ancestors entering Europe or Asia were less adapted. In this context, acquiring advantageous variation through archaic admixture is a fascinating topic, with obvious consequences for the larger human genetics community. Indeed, such archaic admixture increasingly is being shown to affect molecular phenotypes such as gene expression or mechanisms of gene regulation (e.g., this study) and more generally, organismal phenotypes such as traits and diseases (e.g., skin pigmentation, sleeping patterns, allergies) in present-day human populations.

AJHG: What advice do you have for trainees/young scientists?

Lluis: Be open while doing research, be curious, be rigorous, exchange a lot with other trainees and PIs, read a lot, and MAINLY, have fun and be passionate! Meaning both in your working and non-working life. Enjoy the work, do not suffer from it! For me, this is rule number one. If you follow this rule, great findings will follow…and, yes, a bit of luck also helps.

AJHG: And for fun, tell us something about your life outside of the lab.

Lluis: I like to garden (actually, I can spend hours gardening), to bike, and, increasingly, to run. These three things really empty my mind and recharge my batteries. Also, I do need to go at least once per year to Mallorca (where I was born). Having lived there until I was 20 gave me a handicap for life: my need for sun and sea (and I live in Paris…). There’s nothing that relaxes me more than getting into the turquoise Mediterranean water and swimming!

I also love art exhibitions, almost exclusively modern art, and pop if possible! I spent last summer in NYC on a mini-sabbatical at Rockefeller University, and I really enjoyed the exhibitions there!

I also like to read. I can compulsively read historical biographies. When I enjoy somebody’s life, I can read 30 books about them even if most of them say the same thing. A recent example is the life of Princess Marie Bonaparte – a psychoanalyst and close friend of Sigmund Freud, whom she helped escape from Nazi Germany. I also love reading about contemporary politics: one of my preferred topics is the so-called “Spanish transition,” the period starting 1975-1980 when Spain transitioned from being under Franco’s non-democratic regime to being the modern, open-minded country that is today. Obviously, I like books about evolution, but then, that is more work-related again…

Lluis Quintana-Murci, PhD, heads the Unit of Human Evolutionary Genetics in the Department of Genomes and Genetics at the Institute Pasteur. He is a first year member of ASHG.

Inside AJHG: A Chat with Susan Slaugenhaupt

Posted By: Sarah Ratzel, PhD, Science Editor, AJHG 

Each month, the editors of The American Journal of Human Genetics interview an author(s) of a recently published paper. This month, we check in with Sue Slaugenhaupt to discuss her paper, “ELP1 Splicing Correction Reverses Proprioceptive Sensory Loss in Familial Dysautonomia”.

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Slaugenhaupt Lab (photo courtesy of Dr. Slaugenhaupt)

AJHG: What caused you to start working on this project? 

Sue: When I arrived at Massachusetts General Hospital as a postdoctoral fellow in 1991, one of the projects in Jim Gusella’s lab was focused on mapping the gene for familial dysautonomia (FD). Given my background in gene mapping, I became involved in the project and once we mapped the gene, I took over the project aimed at identifying the mutation. Once we cloned the gene and discovered that it was a mRNA splicing defect, I became fascinated by the idea of modifying splicing as a route to therapy, and my lab has worked on this ever since. I have known many FD patients and their families for over 25 years, and our work is driven by the desire to develop a disease modifying therapy for this devastating disease.

AJHG: What about this paper most excites you? 

Sue: Developing a mouse model for FD was a huge challenge since the disease is caused by a tissue-specific reduction of ELP1 protein. In 2016, we succeeded in generating a phenotypic mouse model and this paper describes the first trial of a potential therapy in our mouse. I am very excited that our treatment was able to increase the amount of ELP1 protein in the peripheral nervous system and, most importantly, rescue two of the most debilitating aspects of the disease, gait ataxia and kyphosis.

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Sue: There are many efforts underway to generate therapies that target mRNA splicing, including small molecules, antisense oligonucleotides, and exon-specific U1 snRNAs. A significant fraction of human genetic disease mutations impact mRNA splicing, so this is an exciting time. These therapies are targeted at the molecular mechanism of disease, not at symptoms, and we are likely to see new treatments for many previously untreatable genetic diseases over the next several years.

AJHG: What advice do you have for trainees/young scientists?

Sue: Find a good mentor. One who cares more about your future and your career than their own. Look outside your own lab, and fight against the tide that keeps you locked in an unproductive situation too long.

AJHG: And for fun, tell us something about your life outside of the lab.

Sue: I’m moving to a condo overlooking the beach next month and I can’t wait!

Susan Slaugenhaupt, PhD, is Scientific Director, Center for Genomic Medicine at Mass General Hospital Research Institute and Professor of Neurology at Harvard Medical School. She is a member of ASHG’s Board of Directors.

 

Inside AJHG: A Chat with Nancy Cox

Posted By: Sara Cullinan, PhD, Deputy Editor, AJHG

Each month, the editors of The American Journal of Human Genetics interview an author of a recently published paper. This month we check in with Nancy Cox to discuss her paper “GRIK5 Genetically Regulated Expression Associated with Eye and Vascular Phenomes: Discovery through Iteration among Biobanks, Electronic Health Records, and Zebrafish.”

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Nancy Cox, PhD (photo courtesy Dr. Cox)

AJHG: What prompted you to start working on this project? 

Nancy: I presented some of the preliminary studies from this work at a work-in-progress meeting at Vanderbilt, and Ela Knapik, who directs the zebrafish core here, saw the presentation and asked the question at the end, “Why don’t you knock out GRIK5 in zebrafish?” And so we talked afterward and agreed to collaborate on this project. I expected it to take forever — I was totally unprepared for how rapid CRISPR can be. But it has been a fantastic collaboration and we are working together on several additional really fun projects now.

AJHG: What about this paper/project most excites you? 

Nancy: Trying to understand how polygenic contributions to disease work is challenging because the effect sizes for any individual variant are quite small. This was a different kind of discovery because we had used a gene-based method and found associations to a pattern of phenotypes, not just a single diagnosis. I think that helped to us to focus the follow-up to the zebrafish studies more broadly and think about how we might test for a relationship between vascular development and eye disease.

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Nancy: I hope that people will begin to think more seriously about using very large-scale phenome information from electronic health records as an adjunct to genetic studies, which we can afford to do in only smaller numbers of individuals. The biobank at Vanderbilt is big — 250,000 subjects, but there are many more (millions) with quality phenome information but no DNA. Finding ways to use both should stretch our ability to make and extend discoveries.

AJHG: What advice do you have for trainees/young scientists?

Nancy: One of my mentors used to remind me on a regular basis that there is no shortage of interesting things to do in science — things that are so interesting they are hard to resist. But only a subset of those things are also important with respect to bigger picture questions or implications for other parts of biology. You have to continually ask yourself whether what you are doing is both interesting and important to insure that you are able to continue, and be funded, to do research that you find irresistible.

AJHG: And for fun, tell us something about your life outside of the lab.

Nancy: I really love the music scene in Nashville! It is amazingly diverse, and we take advantage of the opportunities to hear great music every chance we get.

Nancy Cox, PhD, is Director, Vanderbilt Genetics Institute; Professor of Medicine, Division of Genetic Medicine; Director, Division of Genetic Medicine; and Mary Phillips Edmonds Gray Professor of Genetics at Vanderbilt University. She was the  ASHG President in 2017

Inside AJHG: A Chat with Elizabeth Wright

Posted By: Sara Cullinan, PhD, Deputy Editor, AJHG

Each month, the editors of The American Journal of Human Genetics interview an author of a recently published paper. This month we check in with Elizabeth Wright to discuss her paper ‘Practical and ethical considerations of using the results of personalized DNA ancestry tests with middle-school-aged learners’.

Elizabeth Wright, PhD
Elizabeth Wright (photo courtesy Dr. Wright)

AJHG: What prompted you to start working on this project?

Elizabeth: I could give you a long answer about being a former middle school science teacher and what drove me to get a PhD in Science Education, but simply put, I am committed to finding ways for each and every student to see themselves connected to science and each other, and supporting teachers in that work.

AJHG: What about this paper/project most excites you?

Elizabeth: I am equally thrilled and cautious about having adolescents use their own personal DNA to explore who they are genetically, genealogically/socioculturally, and intentionally. We are not all of one thing and none of another. We can use what we know about pieces of ourselves to imagine something new and amazing. We can reveal these pieces of ourselves to our families and friends and see how we are connected to each other and the grander tree of life.

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Elizabeth: In the previous question I mentioned a bit about what thrills me. I am cautious because the privacy issues surrounding over-the-counter, direct-to-consumer DNA testing are monumental, and ever-shifting. It is both exciting and nerve-wrecking to ask, and watch, young scholars to embark on this intellectual journey. The engagement and electricity in the classroom when young scientists encounter themselves in new and unique ways keeps me going.

AJHG: What advice do you have for trainees/young scientists?

Elizabeth: I think the most important thing I would say is: you belong here. You belong in science. Your voice, your experiences, your viewpoint are all incredibly important. If you feel left out or unwelcome, create your own community and persevere because you are going to change things.

AJHG: And for fun, tell us something about your life outside of the lab.

Elizabeth: I’m a Red Sox season ticket holder and I love the game of baseball. I’ve been to baseball games in 27 different MLB parks, and 3 AAA baseball parks. Also, I love Orangetheory Fitness! Base-Push-All Out, that’s good advice.

Elizabeth Wright, PhD, is a postdoctoral fellow in the Jablonski laboratory at Pennsylvania State University.