Research: Kyle Roux pushes ‘envelope of what we understand’

Focus on diseases associated with nuclear envelope has led to breakthroughs

Kyle Roux stands in a research lab.

Dr. Kyle Roux knows something about breakthroughs. Dr. Roux leads a lab at Sanford Research, and he has seen firsthand the value of sharing those breakthroughs so other scientists can benefit, too.

His lab focuses on the nuclear envelope in a cell, which surrounds the nucleus that stores DNA. The nuclear envelope has membranes, along with mechanisms for things to pass in and out of the nucleus.

Dr. Roux’s lab work involves mutations in the genes that encode the proteins making up the nuclear envelope. A lot of these different gene mutations are associated with a lot of different rare diseases, such as some of the muscular dystrophies and progeria, or premature aging.

His lab studies protein behavior and protein interactions. But the cell structure can make it difficult to figure out which proteins are pairing up, or interacting with each other.

So Dr. Roux and his lab created a method to study protein associations that puts a “tag,” or enzyme, on a particular protein. In this method, called BioID, the enzyme “labels” the proteins that are close by over a specified time frame. Then the labeled proteins can be identified, and researchers have a clearer picture of what happens in the natural cell setting.

Before he moved to Sioux Falls, South Dakota, to work for Sanford Research, Dr. Roux hadn’t lived farther north than Atlanta and had spent most of his life in Florida. But he, his wife and two teenage children are happy they made the move eight years ago.

In this Q&A, Dr. Roux talks about how the science community builds on other findings, including the BioID method, and how his love of cooking relates to his preferred style of research.

What happened after you created the BioID method?

That became a large part of my research program when I first started here. So I really was ramping up that aspect of things. And I was also applying it to nuclear-envelope-related topics, but it was really more from a technical perspective. How does this method work? … How do we interpret our results? What are different ways it can be used?

All of these things really became our priority, and a lot of what I was doing, too, was just trying to provide this information for the rest of the scientific community. Over time, the method picked up a lot of steam and became popular, and so it’s used all around the world now by thousands of labs.

It’s gratifying, for sure. I mean, it’s not what I set out to do necessarily, but it is nice to see that you can have a broad impact in that way. And that sort of enabling technology is a powerful way to amplify other people’s research as well.

What range of uses are you seeing for BioID?

It’s really all over the place. Certainly you can pick almost any disease of interest: neurological disorders, Alzheimer’s, Parkinson’s, ALS. There’s all sorts of cancer studies that’ve been done using this. It’s been applied to investigate immune function. A lot of people have been using it for studying pathogens and, when we get infections, how the pathogens interact with the proteins in our cells and vice versa. And then there’s people using it in all sorts of plants and very different things from a biomedical perspective.

The nice thing is, other people have come along now and taken it and moved it a step forward in various ways. So there’s people that have split it into two pieces and then showing that they can put it back together again, and that’s a way you can study interactions. People have come up with faster versions of the enzyme that we can have shorter labeling periods.

If BioID can serve as one more tool in the toolbox that scientists have to ask questions, and if it allows us to break past barriers that existed — technological barriers that exist — and allows us to get access to new information, I think that would push science forward.

And then also, technical advances in how the fundamental principle of BioID is being applied, whether that’s new, different, better enzymes, or different systems or approaches to apply.

You’ve had a recent nuclear-envelope breakthrough?

We stumbled upon a protein that existed kind of everywhere in the cell. And we were seeing it going to spots on the nuclear envelope very quickly … places where we’d ruptured the nucleus. So this is a new area of nuclear envelope and nuclear biology called nuclear rupture. And we’re realizing that probably on a fairly regular basis, our nuclei can rupture.

It turns out that this protein probably is one of the first proteins, if not the first protein, on the scene at the site of a nuclear rupture. It recruits a lot of other proteins that are required to repair this rupture. If you get rid of this protein, you don’t repair those ruptures and the cell can’t go on anymore.

So what we effectively did is found the basis for how all of our cells repair these nuclear ruptures. We think there are relationships between this and disease.

Part of the reason for that is because three of the key proteins involved in this process are all mutated in progeria, this premature aging. We think it’s possible that there could be some defects in the repair process and/or increases in the rate of rupture of nuclei.

Our biggest recent publication was related to that nuclear rupture story. That’s where we first described that this system happens and that we can get the repair.

I feel like this may be a rather unappreciated phenomenon … and that we will increasingly find more and more examples where this is involved in the normal processes of development, and when development may go awry and we have diseases coming out of it. And then also, I think there could be a role for this in things like wound healing, for instance. If you have trauma to tissues in our bodies, the nuclear rupture is almost certainly going to be a part of that.

How do publications of other scientists’ research help?

We look at the papers in our fields and we read them, and that’s how we learn about new advances that are happening. Each publication has a different impact on a scientific community, depending on the nature of the paper but also depending on who you’re impacting.

Generally speaking, we all sort of stand on each other’s shoulders as we move science forward. So as long as … the science is valid and good, these publications are sort of variably, incrementally helping us move progress forward. And then occasionally, there’s big leaps that happen out there.

What do you enjoy doing in your spare time?

I like to do gardening … and I also like to cook.

I feel productive when I’m gardening. It’s the ability to create something out of nothing, almost. I think that’s what I enjoy. And to some extent, the same thing with cooking. You start with some fundamental ingredients, and you can just create something entirely different from the raw ingredients.

There’s a parallel between cooking and science. In science, in theory, you should be doing things very precisely. And so I will compare that to maybe baking, because baking you really can’t fudge and experiment and expect the outcomes to be good. Science is often like that.

However, my preference, both in science and in cooking, is to not take that approach. I like to be much more creative and experimental and less rigid. And so I think to some extent, what successes I have had have probably come from that creative side. I’m always thinking outside the box. I want to push the envelope of what we understand. And 90% of the time it doesn’t work, and you have to be OK with that. But you’re not going to get that 10% of success if you don’t take those chances.

Research notes

Dr. Roux’s work is one of the key areas of innovation at Sanford Health. More research highlights include:

Behavioral Sciences

James Mitchell published a literature review in Current Psychiatry Reports on eating pathology following bariatric surgery, “Eating pathology after bariatric surgery: an updated review of the recent literature.”

Scott Engel co-authored a comprehensive review published in Current Psychiatry Reports collating predictors and mechanisms of post-bariatric alcohol problems in order to guide future research on prevention and treatment targets, “Changes in alcohol use after metabolic and bariatric surgery: predictors and mechanisms.”

Scott Engel and Ross Crosby co-authored a study in Depression & Anxiety assessing a smartphone-based tool for examining relationships between youth anxiety and brain function during social events, “Advancing clinical neuroscience through enhanced tools: pediatric social anxiety as an example.”

Arielle Selya recently attended the Patient Centered Outcomes Research Partnership (PCORP) Summer Institute at the University of Washington in Seattle, Washington. The institute provides training on patient-centered outcomes research and comparative effectiveness research and is part of Dr. Selya’s 17-month PCORP fellowship program.

Ross Crosby co-authored a pilot study in European Eating Disorders Review testing a family-based treatment for eating disorders in overweight or obese adolescents, “Adapting family-based treatment for paediatric obesity: a randomized controlled pilot trial.”

Emily Griese was selected to the Steering Committee for Academy Health’s Learning Health Systems Interest Group. Academy Health is the leading health services research society advocating for the study of how health systems work, how to support patients and providers in choosing the right care, and how to improve health outcomes through care delivery. As a representative in this group, Dr. Griese will work alongside leaders from various health systems throughout the nation to promote the growth and rigor of learning health systems.

Cancer Biology & Immunotherapies

Paola Vermeer was interviewed for an article in Science discussing an emerging research phenomenon exploring how peripheral nerves promote cancer pathogenesis, “How the body’s nerves become accomplices in the spread of cancer.”

Evading host immune responses is critical for both persistent human papillomavirus (HPV) infection and progression of HPV-positive head and neck cancer. Chad Spanos co-authored a research article in Oncogene supporting that chemokine CXCL14 promotes anti-tumor immunity in HPV-positive head and neck cancer, “CXCL14 suppresses human papillomavirus-associated head and neck cancer through antigen-specific CD8+ T-cell responses by upregulating MHC-I expression.”

Cellular Therapies & Stem Cell Biology

Nucleoporins (nups), protein constituents of the nuclear pore complex, influence cell pluripotency but molecular mechanisms are not known. Randy Faustino recently performed gene expression profiling in nup155-deficient mouse embryonic stem cells and identified changes in several pluripotency signaling pathways. These data were published in Science Reports, “Nucleoporin insufficiency disrupts a pluripotent regulatory circuit in a pro-arrhythmogenic stem cell line.”

Graduate students in the laboratory of Kevin Francis presented their research at the recent Center for Brain and Behavior Research annual symposium at the University of South Dakota. Bethany Freel, Ph.D. candidate, received the best poster presentation award for her poster titled “Attenuated astrogenesis and neurodevelopmental deficits resulting from genetic disruption of cholesterol biosynthesis.” Ruthellen Anderson, M.D.-Ph.D. candidate, gave an invited oral presentation titled “The role of sterol homeostasis in mediating membrane curvature: implications for trafficking deficits within cholesterol synthesis disorders.”

Kevin Francis recently hosted the 4th Northern Great Plains Lipids Conference at the Sanford Center in Sioux Falls SD. The two-day conference was sponsored by the USDA, Sanford Research, SD EPSCoR, BioSNTR, SD Biotech, Avanti Polar Lipids, and the journal Lipids. Highlights of the conference include four scientific sessions focused on lipid biology, a career development session, presentations by six world-renowned plenary speakers, and attendance by approximately 100 students, trainees, and faculty from South Dakota, North Dakota, Nebraska, Minnesota and Canada. Dr. Francis and Ruthellen Anderson, an M.D.-Ph.D. candidate in the Francis laboratory, gave oral presentations on cholesterol synthesis and signaling in regard to cell and molecular biology underlying cholesterol synthesis disorders.

CoRDS

Klippel-Feil syndrome (KFS) is a fusion of at least 1 pair of adjacent cervical vertebrae. The ability to adequately describe the demographics and clinical symptoms of KFS has been limited because of absence of a KFS patient cohort. Investigators from the University of Cincinnati, University of Toronto, Rutgers University, Geneva University, Yale University and the University of Cambridge used the CoRDS registry to obtain patient-reported symptomatic information on KFS. These data were published in the European Spine Journal, “Demographics, presentation and symptoms of patients with Klippel-Feil syndrome: analysis of a global patient-reported registry.”

Diabetes

Alexei Savinov received $302,664 from NEXTCURE Inc for a grant titled “Selected aspects of human B7-H4 (VTCN1) immunobiology.” The co-stimulatory molecule, VTCN1, inhibits T cell activation; however, the exact mode of VTCN1 action is elusive. This project is designed to elucidate the molecular mechanisms by which VTCN1 supports maintenance of immunological peripheral tolerance.

Environmental Influences on Health & Disease

Constructing a durable arthroscopic knot is critical for secure tissue fixation. Ben Noonan co-authored a study published in The Iowa Orthopaedic Journal evaluating strength and integrity for three base knots with different overhand/underhand stacking combinations, “A biomechanical comparison of varying base knot configurations with different overhand/underhand combinations of reversing half-hitches on alternating posts after basic instructional training.”

The laboratory of Michelle Baack recently attended Aspen/Snowmass Perinatal Biology Symposium in Snowmass CO. This conference focused on the complex and diverse nature of perinatal exposures impacting developmental outcomes. M.D.-Ph.D. candidate Eli Louwagie received an NIH-USDA Young Investigator Travel Award and gave an oral presentation titled “Prenatal exposure to diabetes but not high-fat diet increases mitochondria-mediated cell death in adult rat cardiomyocytes.” Tyler Gandy gave a poster presentation titled “Wharton’s jelly and cord blood-derived 3D organized culture to measure biological development.”

Identifying injury risk and implementing preventive measures can assist in reducing injury occurrence and may ultimately improve athletic performance. Thayne Munce recently demonstrated that musculoskeletal deficiencies can be identified using movement and mobility tests in collegiate basketball players. These data were published in the Journal of Strength and Conditioning Research, “Evaluation of the functional movement screen and a novel basketball mobility test as an injury prediction tool for collegiate basketball players.”

Pediatrics & Rare Diseases

Kevin Francis and M.D.-Ph.D. student Ruthellen Anderson presented research updates at the Kern Lipid Conference in Vail, Colorado. The conference promotes science related to lipid and cholesterol metabolism and associated disease states. Their poster presentations were titled “Defining the developmental and functional consequences of genetic disruption of cholesterol biosynthesis using human stem cell models” and “Sterol homeostasis regulates membrane curvature generation during clathrin mediated endocytosis.”

Clinical Research

Preston Steen will lead a team after receiving $6,272,321 from the NIH-NCI Community Oncology Research Program (NCORP) to support the Sanford Community Cancer Program. The program increases patient participation in cancer control, prevention, care delivery, treatment, and imaging studies across its expanding network. Rural communities of the upper Midwest and Central Plains represent a large underserved population for cancer treatment, care delivery and clinical trials.

Internal medicine physicians and clinical investigators Cassie Hajek and Russell Wilke co-authored a framework for building a pharmacogenomics infrastructure implemented by primary care providers in Pharmacogenomics, “Implementation of wide-scale pharmacogenetic testing in primary care.”

Lora Black and Chad Kurtenbach were recently interviewed on KSOO and SDPB programs about the Multicenter Trial of Stem Cell Therapy for Osteoarthritis (MILES) multicenter clinical trial comparing the effectiveness of mesenchymal stem cell preparations for the treatment of unilateral knee osteoarthritis.

The Neurovascular team recently presented a poster on stroke outcomes following mechanical thrombectomy at the Society of NeuroInterventional Surgery (SNIS) conference in Miami, Florida. SNIS is a national conference focusing on the comprehensive, minimally invasive care of patients with stroke, brain aneurysms, and other diseases in the head, neck and spine. The poster was titled “Mechanical thrombectomy for small and medium vessel occlusion: a rural experience.”

Education & Outreach

Shelby Braun and Brittney Nathan with Sanford fit recently visited the Boys & Girls Club to provide an educational in-service to staff and educators. As part of an ongoing partnership with the Boys & Girls Club, the fit team also led after-school games and activities with the kids for a day.

Chad Spanos treated the first patient in the country as part of the Celgene-sponsored study on immune biomarker modulation in response to a toll-like receptor 8 agonist (motolimod) with an anti-PD-1 inhibitor (tislelizumab) treatment in head and neck cancer. This phase 1 study will characterize the immune-modulatory effects of tislelizumab and motolimid as single agents or in combination in patients with squamous cell carcinoma of the head and neck. Sanford is one of three currently active sites in this multicenter study.

Nursing students from Northwestern College recently visited the PROMISE Community Lab and performed a heart dissection then discussed genetic screening using the Sanford Chip with a genetic counselor.

Six summer undergraduate students from the laboratories of Jianning Tao, Michelle Baack, Randy Faustino, and Lance Lee recently presented posters at the South Dakota EPSCoR Undergraduate Symposium in Sioux Falls, South Dakota.

Amy Baete recently presented “Community Partners – Engaging Your Stakeholders” at the Sally Scherrer Leadership Summit, hosted by SHAPE America’s Central District. The event brought together physical and health educators from nine states to Sioux Falls, South Dakota. Donna Hardie also presented at the event, “Make the Connection: Action Plans for Advocacy.”

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