Hector Mendoza
Communication and Outreach Subcommittee
University of Michigan

Research Interest

My research goals converge around the evolution of sexual reproduction. During my doctoral program, I investigated mitochondrial inheritance, a mechanism that ensures that mitochondria are only inherited from one parent. In the case of humans, children inherit mitochondria from their mothers, as the race to the egg during fertilization takes an important toll on sperm cells that damages their mitochondria. When this maternal inheritance mechanism is perturbed, rare mitochondrial diseases ensue, ranging from ophthalmic manifestations to muscular dysfunction. I decided to investigate the mechanism of biased mitochondrial inheritance from a fungal perspective. These organisms can reproduce sexually but do not differentiate into separate biological sexes. Instead, fertilization happens between two morphologically identical cells. Why would mitochondria need to be segregated appropriately? This fundamental question drives my fascination with the process of sexual reproduction and, accordingly, led to a fresh perspective as I continued my scientific training.

For my postdoctoral training, I decided to explore sex from a completely different lens, this time focusing on the mechanisms that allow for clear differences between biological sexes. Specifically, my current line of investigation focuses on the emergence and maintenance of sex chromosome systems. I am currently using the nematode C. elegans to model how sex chromosomes shape sexual dimorphism at both the genetic and developmental levels. This organism adds an additional layer of complexity to this work, as it comprises a hermaphroditic system in which males are naturally rare. Understanding and further characterizing the regulatory mechanisms behind sex chromosome can shed light on the evolutionary history of sex, in addition to potentially impacting the reproductive sciences.

As a PhD-trained scientist, you have many career options. What interests you the most?

I am interested in opportunities in academia, specifically in leading my own research laboratory and teaching both undergraduate- and graduate-level courses. As I transition into an academic position, I am still struggling with deciding what sort of institution I would like to join. While I would love to start my own research laboratory at a research-intensive institution and fully commit to training the next generation of scientists, I am very passionate about teaching and curriculum design. For this reason, I am exploring primarily undergraduate institutions, which focus on the education of undergraduates in a liberal arts context. I find this particular approach to post-secondary education quite impactful, as the undergraduate experience can be much more well-rounded and students can make the best decisions regarding their career paths. Additionally, I am quite excited to design and implement a research program that caters exclusively to undergraduate researchers, as their time in my lab will most likely be limited. The constant turnover in my lab, however, will mean that multiple students can contribute to a bigger project that can lead to a collaborative publication.

As an undergraduate, financial and time constraints prevented me from doing research and exploring how a biology degree could be used. If I am honest, I might reconsider my own decision to attend graduate school if I could turn back time. I thought it was the only logical path since I was not interested in a medical career. Thus, I want to make sure my future students are better prepared to make life-changing decisions. I am very interested in developing a strong mentorship philosophy both in the classroom and at the research bench. This interest has also made me consider administrative roles within academia and even secondary education.

In addition to your research, how do you want to advance the scientific enterprise?

I have been a non-traditional student for as long as I can remember, juggling schoolwork and multiple jobs to afford my education. I am also an immigrant, so the logistics involved in transferring colleges internationally turned out to be much more complicated than I had thought. These obstacles only made pursuing a science degree even more intimidating. I was constantly told that I was not putting in the hours needed to graduate or to move on to graduate school. Nevertheless, I persisted and completed my degree with flying colors. I will admit that I had a rough time getting to where I am today because I did not have anyone I could relate to. For this reason, I want students to realize that their paths towards their degrees will constantly evolve and will be shaped according to their own personal circumstances. I want to be part of my students’ journeys and be a guiding light when obstacles emerge.

I am also constantly educating myself on alternative science careers so that I am better prepared to provide advice and ensure students feel supported. For instance, I have experience in the clinical field, having worked as a Laboratory Clinical Processor during my doctoral training program. Though I acquired this experience out of financial necessity, I have come to realize that I can tell my students about these career paths, emphasizing that they are much shorter and inexpensive than medical or graduate school. It is still unsettling to think that the majority of STEM students go through their undergraduate careers fixated on one or two career options, even though demand is elsewhere. I want to emphasize that pursuing a scientific career can look so different for any individual. Its impact in society, however, will be rewarding and necessary.

As a leader within the Genetics Society of America, what do you hope to accomplish?

As part of the ECLP, I am thrilled to exchange ideas about effective communication and leadership. Accordingly, I am determined in establishing strong ties with colleagues in fields different from mine. As scientists, we can recite protocols from memory and perform intricate procedures with our hands. However, explaining why we do it is a creature of a different stripe. Programs like the ECLP take us out of our comfort zones, away from the bench, and challenge us to find the right word or visual to help an audience understand complex scientific concepts. During my tenure, I am hoping to venture out and explore opportunities in writing for non-academic settings and make science empowering.

Previous leadership experience

Instructor, Michigan Math and Science Scholars, University of Michigan (Summer 2024)

Editor and Translator, MiSciWriters, University of Michigan (2023-Present)

Instructional Peer Observer, Center for Academic Innovation, Schoolcraft College (2023-Present)

Executive Board Member, Multicultural Association of Graduate Students, University of Louisville (2016-2021)

A new associate editor is joining GENETICS. We’re excited to welcome Xiajing Tong to the editorial team.

Xiajing Tong
Associate Editor

Xiajing Tong obtained her BS from the University of Science and Technology of China and earned her PhD from the Chinese Academy of Sciences. She conducted her postdoctoral training with Joshua Kaplan at Massachusetts General Hospital and Harvard Medical School, focusing on the regulation of synaptic transmission by autism-associated genes using C. elegans as a model organism. Currently, she is an Associate Professor of Biology at ShanghaiTech University. Her lab utilizes C. elegans as a model organism, along with studies in mammals, to investigate how sex-specific synaptic transmission and neural circuits mediate sex-differential physiology and behaviors.

We are pleased to announce the election of four new leaders to the GSA Board of Directors:

2024 Vice President/2025 President

Brenda Andrews

Professor, University of Toronto

It’s an honor to continue my association with the Society by serving as Vice President of the Board of Directors. I have broad knowledge of the ongoing activities of the Society and see more opportunities for expanding the GSA profile internationally, including outreach to scientists in geographic regions underserved by major societies. The current International Seminar Series and this year’s International C. Elegans Conference in Glasgow are great examples of international outreach, and these types of activities should be expanded.

I will prioritize support for early- and mid-career researchers, in recognition of the challenges they face. GSA can help scientists by providing mentorship, training, and increased advocacy efforts whether for funding or communicating the value of basic research. It is important that the next generation of scientists see value in the activities supported by the Society, including our journals, which face challenges in light of the rapidly evolving landscape of academic publishing. Here, we must continue to foster relationships with authors, improving the visibility of their work, and helping to raise the profiles of our journals. All of our work must be considered in the context of GSA’s ongoing commitment to inclusivity. Here, the Society may wish to work with other groups to enable access to genetics and genomics research by young people from under-represented groups. I found that a program I started at the Donnelly Centre that supported visits to labs by local high school classes from less privileged parts of Toronto was very impactful.

Times have changed and so must GSA. I hope to learn from and listen to you as we shape GSA together.

Director

Arun Sethuraman

Associate Professor, San Diego State University

I am honored to be elected to the GSA Board of Directors. I have served as an Associate Editor at G3: Genes|Genomes|Genetics since 2017 and on GSA’s Conference Committee since 2021 as a representative of the population, evolutionary, and quantitative genetics group, and my work includes contributions to a recent training grant submitted to fund early-career and historically excluded geneticists attending TAGC 2024. I look forward to serving the GSA membership in an active Directorial role. As an early-career researcher at a Minority Serving Institution, I see this as an invaluable opportunity for me to be the voice of a largely underrepresented group of researchers in the Society. I am thrilled to have this opportunity to join a dedicated and diverse team of geneticists, editorial board members, and Society staff who are actively working to change the face and representation of our field.

My commitment to serving on GSA’s Board comes with a push to address five key issues that are close to my heart: (1) developing important training resources to actively involve undergraduates in genetics and genomics research as part of GSA’s catalog of activities and conferences; (2) changing how we teach fundamentals of genetics with exclusionary language by organizing a GSA community-wide effort to crowdsource and develop a new teaching paradigm for topics such as transmission, sex determination, polygenic selection, and genome-wide association studies; (3) interfacing with the equity and inclusion and conference committees in continuing to assess GSA’s membership demographic to build actionable items to increase participation of a diverse audience at all GSA conferences and to recruit and train a diverse group of editors, reviewers, and members; (4) actively featuring methods tutorials and blurbs of published work on the Genes to Genomes blog, specifically highlighting the work of early-career researchers, graduate and undergraduate students; and (5) increasing GSA’s representation at undergraduate and minority-focused conferences (e.g. SACNAS meetings, ABRCMS, Beckman Symposia).

Director

Eyleen O’Rourke

Associate Professor, University of Virginia

I bring to this role a strong background in molecular genetics research, having published in reputable journals, and presented my work at national and international conferences. Additionally, my experience as a teacher and mentor has enriched my understanding of the educational needs within our community. I pledge to collaborate with fellow board members and the broader GSA membership to advance our shared goals. I will listen to your feedback, actively seek your input, and work hard to represent your interests. I humbly request your support in this endeavor.

My work will be grounded in three core principles:

1. Advancing Genetics Research: I believe that supporting and promoting cutting-edge genetics research is core to our society’s mission. I will actively foster collaboration and knowledge sharing among GSA members. I propose initiatives such as promoting the selection of unpublished work for oral presentation at GSA-organized conferences. Additionally, I will advocate for increased research funding and opportunities, catering to the needs of both early-career and established researchers.
2. Education and Outreach: Genetics should transcend the confines of the laboratory. In an era where the public does not trust lifesaving vaccines, I am committed to enhancing the society’s educational initiatives. I will work on programs that promote genetics literacy and support science education at all levels. By bridging the gap between scientific discoveries and public understanding, we can strengthen our society’s impact.
3. Diversity and Inclusion: Science works at its best when it reflects the diversity of our broader community. As a first-generation high-school graduate and Latina, I have dedicated the past decade to learn, teach, and champion inclusive research and teaching practices. I have promoted minorities both locally and internationally. I pledge to carry this dedication into GSA, advocating for programs that support underrepresented groups and nations in genetics. I will work diligently to foster an inclusive environment where every voice is not only heard but valued.

Together, we can advance genetics research, education, and inclusivity. Thank you for consideration, and I look forward to the opportunity to serve you.

Director

Jason Stajich

Professor, University of California, Riverside

I am honored to have the opportunity to serve on the Board of Directors of GSA. The Society has enabled many opportunities in my career, and I am eager to contribute back. I first became a GSA member in graduate school and was completely hooked on the community and research after attending my first Fungal Genetics conference. I have served as an Associate Editor at GENETICS since 2018, and previously contributed to conferences by sitting on the Neurospora and Fungal Genetics Policy Committees. I am currently a Professor in the Department of Microbiology and Plant Pathology where I have taught in the fields of Genomics, Microbiology, and Bioinformatics for the past 14 years. I currently serve as Vice Chair of my department and previously have served the campus faculty as Chair of the Academic Senate and as chair of the Graduate Council. I am excited to contribute to the Society’s efforts in building training and mentorship for early career scientists, helping shape the advocacy for science and genetics in funding and policy decisions, and providing perspectives on the community’s needs to advance new research systems and questions.

As a member of the Board, I will continue to champion the value and importance of diverse research systems and diverse research communities to address fundamental understandings of genetics and biology. I am an omnivore of biological research systems and believe there are strengths in a collection of computational and experimental approaches across a variety of organisms. My own draw to science was found in the satisfaction of problem solving, and I will contribute my efforts to the Society as we consider different problems such as the public perception of science, retaining and recruiting a broad representation of individuals to work in our field, or the creativity needed in how societies navigate changes in journal publication strategies. The GSA Journals have been a home for my publications and the conferences and members have been a strong and supportive community for my research and development. If elected, I would dedicate the time and energy to help sustain and grow our society.

Joseph Uche Ogbede

Community and Membership Engagement

Harvard University/Boston Children’s Hospital

Research Interest

I am most interested in understanding molecular events and therefore discovering new treatment options for different human diseases. This interest has been inspired by several factors, but one of the most influential of these factors is to develop more effective medicines that can be made available to patients that appear to have lost hope. Despite advances in biomedical research, many human diseases are either difficult to treat or are untreatable with the options currently available and the pervasiveness of drug resistance continues to pose an additional significant challenge. These and other issues create serious obstacles to providing patients with the best quality of care possible. I aim to eliminate some of these obstacles with my overall research objective.

Throughout the course of my research career, I have used diverse model organisms to answer pertinent research questions, including rats, C. elegans, yeast, mice, and human cell lines. As a postdoctoral researcher at Harvard Medical School and Boston Children’s Hospital, one of my projects is focused on understanding the process of blood vessel formation and its involvement in eye diseases (retinal vascular disorders). Retinal vascular disorders including diabetic retinopathy, age related macular degeneration and retinal vein occlusion are leading causes of blindness globally. For people with any of these disorders, a primary cause is uncontrolled blood vessel formation (neovascularization) that results in leaky and bleeding blood vessels. Current treatment of these disorders has focused on agents that inhibit vascular endothelial growth factor (VEGF), which is elevated in people with retinal vascular disorders and plays a major role in angiogenesis and vascular permeability. Unfortunately, not all patients respond to anti-VEGF drugs. Recent studies have found a role of angiopoietin-1 receptor (TIE2), a tyrosine kinase that promotes vascular stability, in preventing retinal vascular disorders. My work seeks to develop a TIE2 agonist that could be used to improve current treatments. Consequently, I used a phage display library that contains approximately one billion unique peptides to identify a new cyclic peptide that binds strongly to TIE2 and stimulates its activity through phosphorylation. More in vitro, and then in vivo studies of this potential therapeutic agent are currently ongoing. Complementing this project is the mRNA-based gene therapy for multiple myeloma—a kind of blood cancer. This project seeks to help people with multiple myeloma overcome drug resistance and respond more effectively to treatment. Going forward, I want to continue to find solutions to ongoing problems in the world of biomedicine, so that my work can have a direct positive impact on the lives of many.

As a PhD-trained scientist, you have many career options. What interests you the most?

Before and during the early stage of my PhD program, I was more inclined to follow an academic career path. However, as I approached the last stage of acquiring my PhD, I started thinking about following a more industrial path instead. At present, I am most interested in continuing to develop research and leadership skills that will empower me to become an experienced research scientist, and I may be open to both academic and non-academic career tracks. My postdoctoral research fellowship would allow me to hone competitive skills that will suit either career path; however, I anticipate that by the time I am one or two years into my postdoc, I will be able to firmly decide on which path to take. My desire is to be in an environment where I can use my knowledge and skills to solve problems such as discovering more potent medicines, which I am currently doing as a postdoc researcher. Additionally, I am also interested in mentorship. I have mentored both undergraduate and graduate students; at least two of the undergraduate students whose thesis I supervised, have gotten into graduate schools. I have also reviewed several graduate school and scholarship essays, and most of these applications were successful. In addition, I am participating in the GSA mentorship program where an ECLP member is paired with a student for up to 12 months. I hope that my energy and passion continues to educate and inspire my mentees.

In addition to your research, how do you want to advance the scientific enterprise?

I will continue to advance science through volunteering and mentorship, as I have done for several years. However, in the future I also want to be involved in science communication. Being a good communicator is a strong asset for advancing science. There is currently  a huge gap between the scientific community and the public; many patients are not aware of the research efforts being made by scientists that are relevant to their treatment. And even when they are made aware, the specialized jargon in many published articles may be offputting or difficult for them to understand. I hope to bridge this gap in several ways, including engaging in events and programs where scientists can interact informally with people about their work. I am currently conceptualizing a platform that will improve how scientists communicate their work to the public, as well as to their fellow researchers and policymakers. When actualized, it would make the methods and results of research initiatives more accessible and understandable to both scientists and non-scientists alike. Nothing promotes science more than public engagement, so I hope to see a time when every scientific journal makes it compulsory for research papers to include a lay abstract that everyone can comfortably read. Doing so would allow non-experts (broadly defined) to be able to access and understand the trends in science that concern them.

As a leader within the Genetics Society of America, what do you hope to accomplish?

I want to accomplish two major things at GSA. First, I want to leave GSA better than how I found it by improving its programs and services. By doing so, I’ll continue to shape and enhance the experience of both graduate students and postdocs within GSA by working to improve existing initiatives of ECLP, such as workshops and seminars. As a member of the ECLP Community and Membership Engagement Subcommittee, I continue to be involved in the development of initiatives and content that will improve the welfare of early career scientists. And once my time with the ECLP comes to an end, I will have proposed and organized a networking event where graduate students and postdocs can join virtually to build connections. The goal would be to ensure that early career scientists have access to one another to share ideas, collaborate, or develop directions for future research and careers. 

Additionally, I hope to contribute to ensuring that GSA becomes more diverse and inclusive in its membership and programs. To achieve this, I proposed the Igbo Seminar Series as part of the GSA Multilingual Seminar Series, which was created to connect scientists so that they can talk about their work in a language other than English. The first edition of the Igbo seminar was successfully held on February 10, 2023, with five panel speakers, and more than 40 attendees. By organizing this seminar, I helped amplify GSA’s commitment to recognizing diverse languages and communities such as Igbo in science and communication.

Essentially, as a leader in GSA, I will continue to propose and support initiatives for early career scientists, while I also continue to work towards a more diverse and inclusive GSA. Both of these goals will help create an enabling and equal platform for early career scientists to thrive.

Previous leadership experience

I have assumed many leadership roles over the past years, allowing me to solve problems and acquire outstanding skills. 

Currently, I am the media chairperson of the Harvard Medical School (HMS) Black Postdoctoral Association, where I help to amplify the events and programs of black postdoc fellows within the HMS. Complementing this role is my membership of the mentorship subcommittee of the Boston Children’s Hospital (BCH) Postdoc Association, where I help in organizing events and programs that allow BCH postdoc fellows thrive in their current and prospective career endeavors.

As a co-chair of the Liu Institute Network for Africa at the University of British Columbia (UBC)—a network of stakeholders willing to address research and policy issues affecting Africa—I worked with fellow co-chairs in developing projects to meet our mission. This included organizing an inaugural symposium as well as webinars on the impacts of the COVID-19 pandemic on African economies, health systems and education, among others.

I was the student representative on the Steering Committee of the Genome Science and Technology (GSAT) graduate program at UBC. This position allowed me to review essential issues facing the GSAT program, as well as students and faculty, and then provided feedback and recommendations for an improved learning environment.

I was also the student council representative for the GSAT program (Graduate Students Society, UBC) and the Medical Genetics & Genomics program (​​Glasgow University Students’ Representative Council). These positions allowed me to learn how to play active roles in decision-making processes. I consulted with students, shared their views in meetings, and liaised with faculty, staff, and students alike to enhance students’ learning experiences. I have also played several other roles in supporting students and the scientific community; these include event manager at the Glasgow Explorathon 2016 (European Researchers’ Night Explorathon) and chairperson for the 2017 Medical Genetics & Genomics Symposium at the University of Glasgow.

Moreover, I have worked to create opportunities and have served as an agent of change. In October of 2016, a few months after starting my MSc study at the University of Glasgow, UK, I dedicated myself to devising an avenue to change by using campaigns and advocacy to solve social problems. I learned about Oxfam, a not-for-profit organization involved in the fight against poverty and inequality. Finding that the Students’ Oxfam Society on campus was defunct, I engaged in consultations, and through my strong interpersonal and networking abilities, I reached out to various students and re-instated the association. As the elected president, I worked with other executive members to sustain the society with exciting weekly activities: campaigns, fundraisers, social events, and discussions related to Oxfam’s mission. I succeeded in this role because of my initiative, commitment, and organizational skills. We raised several hundred pounds (donated to Oxfam Scotland to support humanitarian aid). By the time my term as president was complete, we had reached 55 members.

At the community level, I have served as the youth secretary (2019–2021) for the Nigeria-Canada Association of British Columbia (NCABC). This not-for-profit organization strives to support Nigerians in British Columbia, and to promote Nigerian culture. This position allowed me to interact with young people and deliver projects that met their needs. For instance, with five other persons, I organized and facilitated Vancouver’s #EndSARS in October 2020 with more than 800 attendees; #EndSARS was a global social movement where Nigerians protested against police brutality and social injustice in Nigeria. These experiences have shaped my values, molded my outlook, and improved my approach to tasks as both a scientist and a leader.

This article is part of a series of posts outlining the history and impact of research in experimental organisms. The series is developed in collaboration with the GSA Public Communications and Engagement Committee.

By the time Bertrand Might was six months old, it was clear something was amiss. His muscles weren’t developing normally; he was “jiggly” and had little motor control. As he got older, new symptoms emerged, including seizures, sugars in his urine, and an inability to produce tears. Bertrand’s parents spent countless hours consulting with medical specialists to track down the cause of Bertrand’s illness. In 2010, when he was four years old, the Mights enrolled Bertrand in a clinical trial of a then-novel technology: DNA exome sequencing. Sequencing revealed that he had inherited two different nonfunctional copies of a gene called NGLY1.

With that DNA test, Bertrand became a medical and scientific pioneer—the first patient ever diagnosed with NGLY1 deficiency. But because the disease is so rare, there were no therapies that could cure or treat it at its source; doctors could only try to relieve Bertrand’s symptoms as best they could.

To raise awareness, Bertrand’s dad, Matt Might, published a post on his popular computer science blog detailing the family’s diagnostic odyssey. Over time, the Mights connected with dozens of families also coping with the condition. Interestingly, the collection of symptoms varied quite a bit from case to case,
and genetic sequencing helped a number of families finally put a name to their diseases.

Doctors learned more about the disease with every new patient that came forward. But to really understand how the loss of NGLY1 can cause devastating symptoms throughout the body, scientists would have to take a different path: studying NGLY1’s function in the body at a molecular level. They needed to explore the biochemistry of the protein that NGLY1 encodes, find other molecules that interact with it as it performs its functions, and map out the ripple effects of losing the gene. To capture that level of detail requires controlled studies at a huge scale, something only possible in fast-reproducing research organisms, such as fruit flies and nematode worms.

The not-so-lowly worm

Around the time that doctors were beginning to recognize the clinical effects of NGLY1 deficiency in people, a researcher named Nicolas Lehrbach was making his own surprising discovery about NGLY1, in a different context. Now an assistant professor at Fred Hutchinson Cancer Center, Lehrbach first stumbled across NGLY1 while doing his postdoctoral research at Harvard Medical School.

Lehrbach studies how cells take out their molecular trash, or, more specifically, he studies how cells can compensate when their trash-disposal system isn’t working. When we talk about cellular “trash,” generally that means protein molecules that are damaged, misfolded, or otherwise no longer needed. The cellular machine that breaks down these proteins is called the proteasome. Lehrbach studies the proteasome in the tiny nematode C. elegans—colloquially called “the worm” in biology labs.

“If you think about the fundamental machinery needed by every cell, whether it’s in a human or a worm or a fungus or a plant, there are some basic processes that are simply required for life,” Lehrbach explains. “The underlying molecules that do those jobs are almost the same in any living thing.” The proteasome does one of those essential jobs required by every living animal cell. So by figuring out what molecules keep the proteasome humming along in worms, Lehrbach could also learn something about what makes the proteasome tick in humans.

Worms are inexpensive and quick to breed in the lab—a worm matures from embryo to adult in three days, and each worm produces about 300 offspring.This means that researchers can do thousands of experiments at once looking for rare mutations that affect some aspect of the animal’s development or behavior. Suppose you’re trying to understand how the nervous system develops. First, you would feed the worms a chemical that increases the chances of genetic mutations, and then you’d examine thousands and thousands of mutated worms to find the handful whose nerves didn’t develop properly. By analyzing the genes of those animals, you’d discover which genes contained mutations that caused the defect.

Lehrbach applied this approach to studying proteasome function. He designed a genetic screen to hunt for genes that, when mutated, boost the cell’s production of the proteins that make up the proteasome. “If the proteasome is not working well, one of the ways that our cells can cope with that is just to make more proteasomes to compensate,” Lehrbach says. His experiment revealed that the worm relies on a version of NGLY1 for that process.

“The power of that method is that it doesn’t presuppose any model or hypothesis about what kind of genes are going to be involved,” Lehrbach explains. Rather than choosing a gene and seeing whether it does something important, the researchers can do a wide-ranging search and see what turns up. “I would have never in a thousand years—if I were searching in a more targeted, hypothesis-driven way—I would never have thought the NGLY1 gene would have that role,” he says.

Proteasome failure is a hallmark of various human diseases, including neurodegenerative diseases like Parkinson’s and Alzheimer’s, but Lehrbach wasn’t narrowly focused on pathways involved in disease. The worm studies exemplify how expanding our knowledge of basic cellular processes can lead to unanticipated clinical benefits. “When you have a patient with clinical symptoms, but you want to get back to the molecular mechanism, that’s a really hard puzzle to solve,” Lehrbach says. “That clue from genetics, which really came out of the blue from doing a very open experiment, provided an insight that helped accelerate the process of understanding NGLY1 deficiency.”

Of flies and men

After receiving Bertrand’s genetic diagnosis, the Might family started a foundation, NGLY1.org. Through the foundation, they reached out to geneticist Clement Chow at University of Utah Health for help to uncover more information about how the lack of NGLY1 was making their son ill.

Chow’s lab studies protein misfolding and how the cell deals with incorrectly-folded proteins when they build up in a part of the cell called the endoplasmic reticulum. NGLY1 plays a role in clearing those misfolded proteins, and Chow set out to uncover exactly what that role is.

Using the fruit fly Drosophila in the lab, Chow and his colleagues genetically engineered different flies with different NGLY1 mutants, to see what effect each mutation would have on the fly. Some mutations might completely destroy the NGLY1 protein, while others might just make it weaker or less efficient at doing its job. Flies with mutations in NGLY1 had delays in development, and some died in the larval stage. Others matured to adulthood but still died sooner than normal flies.

Chow also investigated how the loss of NGLY1 changed the expression of other genes. Genes can be turned on or off, meaning they actively produce their protein or they lie idle. They can also be adjusted up or down, like twisting a volume knob on a stereo, so they produce a little more or less protein. Often, these adjustments are managed via biochemical feedback pathways in the cell. NGLY1 removes sugar molecules called glycans from various proteins, and when that function is lost, the excess of glycans alters the activities of those proteins. These changes can have a cascade of effects that lead to changes ingene expression. For instance, there is a protein called Nrf1 whose job is to turn on several genes that make components of the proteasome, to ramp up new production when it detects proteasome failure. It can do this only after NGLY1 removes a glycan from a key building block molecule in the protein, chemically changing its identity. Without NGLY1 there to strip off the glycan, Nrf1 can’t activate those genes, and the cell can no longer compensate for proteasome failure.

By comparing gene expression between healthy flies and those without NGLY1, Chow discovered that losing NGLY1 caused a drop in the level of a protein that helps make a sugar called GlcNAc. Adding and removing GlcNAc from proteins is one key way the cell directs their activity. Currently, GlcNAc is sold over the counter as a supplement. “What’s exciting about this is that patients had already been thinking about using this particular sugar,” Chow says. Because GlcNAc is easy to get, parents of kids with NGLY1 deficiency had tried it at home. “There had been anecdotes that it was providing relief, especially with tear production,” says Chow. When he gave GlcNAc to the mutant flies, they tended to live longer than those that didn’t receive the supplement. A clinical trial of GlcNAc eye drops in kids with NGLY1 deficiency is getting underway at Mayo Clinic to test how well the supplement performs at increasing tear production in these kids who have NGLY1 deficiency.

The GlcNAc discovery in flies not only helped explain how the supplement was helping kids with NGLY1 deficiency, but it was powerful in another way, as well: it validated the fly as a model of how NGLY1 was working in human cells. “That was kind of our first foray into thinking about NGLY1 and what we can do with the fly,” Chow explains.

The next step for the Chow lab was to understand how other genes interact with NGLY1, creating variation in the disease presentation. Among the patients with NGLY1 deficiency, the severity of symptoms ranged widely; for example,the second NGLY1 patient to be identified, Grace Wilsey, learned to crawl, talk, and follow simple directions, skills that Bertrand Might never acquired. Human NGLY1 patients are too few, and too genetically complex, to support clinical studies of genetic interactions that may provide clues to why disease presentation is so variable. Using fruit flies enables researchers to study thousands of animals from genetically controlled populations.

To look at how variants in NGLY1 interacted with other genes in the genome, Chow’s lab turned to the Drosophila Genetic Reference Panel, a collection of fruit fly lines that all carry slightly different genetic changes. The flies were bred from the same original population, so they mostly share the same genome, and each line’s genome sequence is well-documented. By disabling the NGLY1 gene in each different fly population, then documenting the number and severity of the symptoms, they uncovered a gene called NKCC1.

The fruit fly experiments were invaluable to test a large number of genetic interactions in a short period of time, but to fully characterize how the NGLY1 and NKCC1 proteins interact, Chow turned to mice. Experiments in mouse cells grown in the lab revealed exactly how NGLY1 chemically modifies NKCC1 to keep it working properly. “We started out with this very basic tool that fly genetics labs use all the time, which is a genetic screen, and they brought us all the way to thinking of finding defects in mammalian cells in a pretty quick order,” Chow said. “That tells us that the flies are modeling exactly the same thing we see in mice and humans.”

Studying mammalian cells or even human cells grown in a dish in the lab may sound like a more representative model for human disease, but these lab-grown cells can’t perfectly replicate what’s happening in a live animal. To understand the complex interactions between the many genes and proteins over the course of a life cycle, nothing can replace an intact, living animal, even if it’s a miniscule worm or a fruit fly. “There are certain processes, like communication between different types of cells within an organism, that are impossible to model with a layer of cells in a dish, which are all undifferentiated and more or less identical to one another,” Lehrbach says.

And while a worm or a fly can’t exhibit speech delays or intellectual disability, the genes responsible for these issues in people perform largely the same functions on the cellular level in all creatures. “These are mutations in basic housekeeping genes that every organism needs to have functioning,” Chow said. “While their disease may not perfectly match what we see in humans, the cellular process and the biological process is nearly identical in flies and humans, so that makes it a pretty good model for disease.”

For Bertrand Might, genome sequencing revealed the cause of his disease, marking the end of the family’s diagnostic odyssey. At the same time, the diagnosis was only the beginning of a new odyssey: a quest to find a treatment that could compensate for the loss of NGLY1. Sadly, there’s not yet any cure for
NGLY1 deficiency, nor a treatment that directly addresses the genetic cause of the disease. But ongoing research to understand all the different ways that NGLY1 manages important cellular functions is leading to interventions that can lessen the impact of losing NGLY1. While Bertrand himself died in 2020, the research he inspired—including a Precision Medicine Institute at the University of Alabama at Birmingham, which Matt Might directs—aims to someday help other children with NGLY1 deficiency and other rare disorders to live longer, healthier lives.

To learn more about the ways that model research organisms contribute to the study of rare disease, visit any of the links below.

1. GENETICS: https://academic.oup.com/genetics/article/214/2/233/5930504
2. Undiagnosed Diseases Network: https://undiagnosed.hms.harvard.edu/
3. MARRVEL: http://marrvel.org/
4. ModelMatcher:  https://onlinelibrary.wiley.com/doi/10.1002/humu.24364
5. Rare Diseases Models and Mechanisms Network: http://www.rare-diseases-catalyst-network.ca/
6. The Jackson Laboratory Rare Disease Translation Center: https://www.jax.org/news-and-insights/2022/December/jax-strives-to-advance-rare-disease-research-andreatment-options
7. Zolgensma for Spinal Muscle Atrophy: https://www.pennmedicine.org/news/news-releases/2019/may/zolgensma-based-on-delivery-system-discovered-by-penn-gene-therapy-pioneer
8. Zolgensma for Spinal Muscle Atrophy:   https://www.sheffieldchildrens.nhs.uk/news/edwards-story-the-world-is-his-oyster-after-gene-therapy-treatment/ 
9. Charcot-Marie-Tooth: https://www.jax.org/news-and-insights/2018/August/kathy-morelli-finding-cures-for-rare-diseases 

We’re taking time to get to know the members of the GSA’s Early Career Scientist Committees. Join us to learn more about our early career scientist advocates.

Elizabeth DiLoreto

Policy and Advocacy Subcommittee

Worcester Polytechnic Institute

Research Interest:

I have always wondered why. “Why do we make certain choices?” “Why does the smell of cookies bring up a specific memory?” My desire to know why drove me into science as I was growing up. Heading into higher education at Assumption University, I explored the field of neuroscience and began learning how the brain processes information.

As an undergraduate student, I researched neuroscience from the biochemistry perspective in the lab of Dr. Jill Zitzewitz at the University of Massachusetts Chan Medical School. I learned more about how amyotrophic lateral sclerosis (ALS) forms its toxic protein aggregates. “Why are these proteins associated with this motor neuron disease? Are they the cause or an effect of the disease?” Being so focused on a single protein, matrin 3, took me in a different direction when I started wanting to learn the why in neuroscience. After graduating college, I went in a more behavioral direction.

I found my way into the lab of Dr. Jagan Srinivasan at Worcester Polytechnic Institute as a research technician, where we work on deciphering neural circuits in the model system C. elegans. “Why do these worms behave the way they do?” Many of our projects originate in trying to understand the olfactory mechanism that these worms use to communicate with one another using pheromones called ascarosides. From first identifying the individual neurons that respond to exposure of these chemicals to then narrowing our focus to find the individual receptors that enable the neuron to respond, we attempted to understand how this little worm moves throughout the world.

After a few years as a research technician, I joined the Srinivasan lab as a graduate student. Since then, my work has taken me in disparate directions that will really enable me to understand why. “Why is it important for C. elegans to communicate to one another?” To understand this, I am involved in a project to develop a new technique to study the function of individual neuropeptides, first in C. elegans before expanding the technology to other organisms. I have also been able to explore other whys. “Why, in a population where half of the people will experience an instance of trauma in their lives, do 5% of people develop post-traumatic stress disorder? Why are females twice as likely to be diagnosed with PTSD?” The social implications of this project make it incredibly difficult to tease apart the factors and adverse childhood experiences (ACEs) that may predispose some and not others to PTSD, but I am attempting to develop a model for PTSD using C. elegans to begin to understand some of the genetic markers that may lead to resilience during trauma.

I hope to continue to learn why.

As a PhD-trained scientist, you have many career options. What interests you the most?

In graduate school, I am really taking the time to learn about all different career options. Talking to more scientists, I realize how many specialized fields a PhD can get you into. I was already aware of options in academics and large-industry research, but I am currently exploring careers outside of the lab and academics.

My first motivation for pursuing the PhD path was my interest in education. I am very interested in teaching and participate in many teaching and mentorship programs targeted at high school and middle school students. It is immensely satisfying to fuel someone’s passion and spark their interest. I am currently expanding my teaching portfolio so that I can effectively teach a wider variety of students with different interests.

On the Policy and Advocacy Subcommittee, I am discovering other options that exist in advocating for science policy. On more of the science communication side, I am interested in paths that enable scientists to communicate more effectively with non-scientists. This underlies an essential part of being a scientist in the modern age: being able to communicate the work being done and advocate for its importance and relevance. This skill exists in many future careers, though the audience may change.

Overall, I am still in the process of exploring avenues for the future and am open to what may come next.

In addition to your research, how do you want to advance the scientific enterprise?

I want to make STEM accessible to all people. I am starting by facilitating young scientists’ entry into research. I spend time in graduate school mentoring middle school to undergraduate students who are interested in STEM. This research mentorship is very important because not only is it relevant to the research being done, but we are also building young scientists’ skills and confidence in their abilities.   I try to instill the belief that we can explore fields and have the perseverance to surmount troubles we encounter.

I also teach and mentor outside of the lab, with students who are interested in science. I run biology camps during the summer for high school students who are looking to dive into science outside of the classroom. It was in a summer biology camp when I was in high school where I really discovered my passion for science and learned about neuroscience for the first time, so I understand the potential of these programs.

After graduate school, I intend to continue my outreach and science education activities by promoting leadership in communities lacking a clear path into research. I will accomplish this after graduating by moving into education and policy development to improve scientific communication on a larger scale. To prepare for this, I will be taking courses in my graduate career to identify and shape my teaching pedagogy and skills in policy development. On a shorter timescale, I am working to create a program at my graduate school to create a program to fund undergraduate research opportunities during the academic year with a focus on making research accessible to our larger community. The goal of this program is to afford economically challenged students the funding and resources necessary to perform research and promote scientific outreach in underreached communities.

As a leader within the Genetics Society of America, what do you hope to accomplish?

I am looking to connect with a passionate community of scientists outside of my institution. After attending the International C. elegans Conference in 2021, I learned about this early career leadership panel and what kinds of programs were organized. I would love to contribute to the network of scientists within our community while also reaching those outside it. Communication is an essential skill, and while in graduate school, I am honing the ability to talk to others within my field about my work. One underdeveloped yet essential skill for many is the ability to communicate what we are working on to people outside our field. It is often more difficult to communicate with someone who doesn’t know what you’re doing and why it is important. I think that this skill can be achieved through the Early Career Leadership role.

On the Policy and Advocacy Subcommittee, one initiative I am finding very interesting is our interview series. Here, we are interviewing scientists who are involved in advocating for science policy, have worked in a space where they communicate with lawmakers, or have a passion for advising socially responsible researchers. In a few interviews, scientists have shared their perspective in communicating with policymakers. In these discussions, they mention that it’s important to not enter conversations with a deficit mindset: “If only they had the information I do, they would change their mind.” This is difficult ground to build a conversation on. Recognizing this mindset, we learn to appreciate different perspectives that others bring, and together we can find a more harmonious solution. It sounds so simple, but it’s important to remember that we are all humans just trying to do the best we can.

While providing information on what careers in science policy look like, our subcommittee also supplies resources for scientists looking to get involved in science policy. We have a science policy fellowship database where we accumulate all the active fellowships into a searchable database to provide researchers paths into this field.

Previous leadership experience

• NASPA Peer Health Educator, elected to represent New England on Panel, at Assumption University
• Program Coordinator for Women in STEM Leadership Academy at Worcester Polytechnic Institute