Dr. Michael Kareta, who leads a combination of stem cell and cancer research, has received a $1.9 million, five-year grant from the National Institutes of Health National Cancer Institute.
In particular, Dr. Kareta studies small cell lung cancer.
“We are studying the role of classic stem cell genes and investigating the role that they play in tumor initiation and this ability of a cell to change from a relatively normal state and change identity into this devastating state that we call cancer,” he said. “We would really like to start investigating some of the mechanisms that we’ve investigated in small cell lung cancer and apply it to other cancers.”
Stem cell and cancer research are important not only for Sanford Research, but for the entire scientific community.
“It can hopefully shed new light on how these cancers are arising, the general mechanisms that underlie them, and come up with new ways for us to develop new therapies for them,” he said.
Although the principal investigator gets the recognition, it was because of the hard work of the entire Kareta Lab that he was able to get this grant. Because of that, “we are able to put together a much larger network to understand how these cancers come about. We are not on a one-gene level, we are looking at the entire genome,” he said.
In this Q&A, Dr. Kareta discusses the grant he received and what it means for the future of his lab.
How did you end up at Sanford Research?
I am native to New England. I grew up in New Hampshire and Connecticut. Through the course of my studies, I spent time in Texas. Before coming out here, I spent 13 years in California. I was at Stanford before coming to Sanford, so that made it very interesting with the transition.
I saw the job opportunities that were here and I was on the job market. It was very difficult to get an academic job. I was interviewing all over the country, but when it was time to evaluate the job opportunities and the offers that were given, this [Sanford Research] was clearly the best in terms of the collaboration that was offered, the investigators, and how well everyone works together. A relatively young group that is trying to stay on the cutting edge was very attractive to me. So I packed up and moved to South Dakota.
What grant did you receive?
NIH is the National Institutes of Health, a governmental entity that is probably the major driver of funding for research nationwide. The R01 grant is their primary research funding mechanism. They have a lot of other mechanisms as well, smaller pilot grants, training grants, and the like, but the R01 is the major way they support research.
It is about $1.9 million for five years. These funds will obviously support our research, test tubes and things like that, but also the people who do the research. Really, the most important resource the lab has is the minds and the hands that are actually doing the work. It supports them and the technologies we will be using in the course of these investigations. We are trying to do some cutting-edge stuff to incorporate next-generation genomic studies to really understand what’s going on not just in the cancer as a whole but in one cell at a time. Unfortunately, these studies are not cheap.
How did you receive this grant?
This is a standard grant for the NIH. There are three times a year you can apply for those. I had applied for it a little after my first year here. I wanted to get the process started right away knowing it could take more than a year to work through the application. It took about a year and a half to get it all the way through.
It is a competition to a degree. The NIH will bring in independent investigators from all over the country and put them up in a hotel for a weekend. They will score all the grants that were acquired in that cycle and give a percentile ranking. The NIH will then look to see what their budget is because it is coming from Congress so it is always in flux. They look to see how much they can support, set up a percentile cut-off, and say they will support everything with a lower percentile than whatever the cut-off value is. This grant was right on the edge of that.
How did the reputation of Sanford Research help in the process?
There were a few things that worked in my favor. One of them is what the NIH refers to as an ESI – an early stage investigator. This is a program that they set up to try and help out people who are just getting their laboratory set up because it is sometimes difficult to compete with established investigators who have very large labs. They give a little leeway to these ESI investigators to help them get the ball rolling.
The other thing working in my favor is the fact we are in South Dakota. There is a recognition that the distribution of these governmental funds is not equitable across the geographic United States. There’s definitely concentrations of this funding that occur in the Boston area, California, and Texas. They are trying to make sure these funds favor the U.S. as a whole. There is also some leeway given to states that are underrepresented in this funding. We are getting a lot more of these R01 grants at Sanford.
When they evaluate a proposal, they do consider where the research is going to be done. Part of the score is based on where you work. I got some pretty good scores based on what we have here at Sanford. I know others that have been applying have got good scores. We have a very good support network, great core facilities, and access to fantastic equipment.
What does this grant allow you to do?
This will allow my laboratory to study these other cancers we haven’t had the resources to study. We will be able to cast a much broader net in terms of understanding some of the mechanisms that underlie the formation of these cancers. You can think of it as a clinical trial when you might run a trial on one patient and while it might be informative, benefit really comes when you start studying it in multiple patients.
Same thing; we are studying these mechanisms but instead of studying it in one cancer, we can start to see the applicability of these mechanisms in many cancers and start trying to find general mechanisms that could be driving these various tumors. The obvious benefit for that is if we could find the general mechanism that underlies at least this subset of tumors, then maybe we could develop new therapies that instead of targeting one cancer, it might be able to target a handful.
We do quite a bit of our investigations using mouse models of cancer because certainly when you are studying some of the very basic mechanisms, these are things we would not want to do in human patients. Some of the things we can do can be quite harmful, such as creating cancer. We use animal models for discovery purposes, so once we discover these mechanisms in these animal models, then we can make an application to human patients. That is a large component of the budget.
What does this grant mean to you, personally and professionally?
Professionally, it really gives us the opportunity to start expanding what it is that we study. When you start off, you’re a small lab. You’re focused. You’re really just trying to get noticed. You can’t take too many risks and you have to chase the sure shots. Now that we have the support, we can start asking riskier questions. We can start asking more questions, and I think that is where the science gets exciting.
Sometimes discovering something that is a foregone conclusion is not really that fulfilling, but when you take a chance on something that’s a bit out there and when it happens to work, that’s a great thrill. It helps put us on the map of investigators that are recognized nationwide. To be able to get recognized by the NIH in terms of being awarded one of these grants shows that we are a serious lab doing serious things. Now we have to make good on it, but that is the fun challenge of it all.
Personally, it shows that this was the path to take. It shows that we are asking the right questions and that we can do it. When you start off, there is a very high attrition rate in the sciences. When you look at people trying to pursue a career in the academic sciences, less than 10% are actually getting careers. Many labs, very good labs, have to close their doors because funding is so tight.
I don’t want to speak totally personally in terms of it being a validation of what we are doing because I say “we”. It is not entirely my achievement. It is the folks in the lab who are doing the work every day along with our collaborators. I think it does justify us as a group that we are doing good work and the well-known folks making the decisions are recognizing that we are asking the right questions and are willing to write a check to see it happen.
At the forefront of health care innovation is the ability to harness the power and potential of big data represented within electronic medical records. Emily Griese and Benson Hsu published a short review in Pediatrics in Review on advances in big data, the possibilities that exist with its application, and its relevance to health-care professionals.
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Cellular therapies and stem cell biology
Kevin Francis recently gave an invited seminar on his research program to the Department of Pediatrics at the University of Nebraska Medical Center in Omaha, Nebraska. His seminar was titled, “Defining the impact of cholesterol homeostatic disruption on nervous system development and function using human iPSC models”. Dr. Francis also recently attended the annual meeting of the Smith-Lemli-Opitz/RSH Foundation, where he gave an invited talk titled, “SLOS and induced pluripotent stem cells: background and research updates”. The Smith-Lemli-Opitz/RSH Foundation is a family-organized group dedicated to supporting affected families and promoting research to ultimately cure Smith-Lemli-Opitz syndrome.
Ruthellen Anderson, an MD-PhD student in the laboratory of Kevin Francis, recently received an Early Career Investigator award from the Kern Lipid Conference covering lipids in health and disease. This award will support her travel and attendance at this conference, allowing her to present a poster titled, “Altered sterol homeostasis disrupts clathrin-mediated endocytic trafficking through membrane curvature dynamics”.
Proximity-based labeling methods, such as BioID, can detect candidate protein-protein interactions or map the protein constituency of a subcellular domain. Due to the popularity of BioID, Kyle Roux published a paper describing the protocol by which a BioID fusion protein can be validated and utilized for BioID pull-downs. This technical paper was published in Methods in Molecular Biology.
Environmental influences on health and disease
Infants born to diabetic or obese mothers are at greater risk of heart disease at birth and throughout life, but prevention is hindered because underlying mechanisms remain poorly understood. Using a rat experimental model of offspring of diabetic mothers, Michelle Baack identified mitochondrial fusion and fission proteins as targetable, pathogenic regulators of heart health in offspring of diabetic mothers exposed to excess circulating maternal fuels. This data was published in the International Journal of Molecular Sciences.
Stephen Herrmann co-authored a study demonstrating that handgrip strength is a simple method for helping healthcare providers determine poorer cognitive functioning. This data was published in the Journal of Alzheimer’s Disease.
Pediatrics and rare diseases
Kameswaran Surendran recently presented an invited talk titled, “Clues from mouse kidney studies as to the disease variability in ALGS” at the 8th International Symposium and Scientific Meeting on Alagille Syndrome in Cincinnati. This presentation highlighted findings from the Surendran lab from work on mouse and kidney cell models of Alagille Syndrome-associated kidney disease. Dr. Surendran also co-led a session titled, “Renal insufficiency and ALGS kidney research” and reviewed abstracts submitted in the Development, Stem Cells and Regenerative Medicine category for the Kidney week 2019 meeting of the American Society of Nephrology. This scientific meeting in nephrology will be held in November of 2019 in Washington D.C., with an anticipated 13,000 attendees from around the globe.
Neurofibromatosis type 1 (NF1) is a genetic disorder that causes a variety of symptoms, but pain in the context of NF1 remains largely under-recognized. A recent study by Jill Weimer used a miniswine model of NF1 to characterize nociceptive signaling and pain behaviors, demonstrating that the miniswine model recapitulates pain-related NF1 features and can be used for preclinical studies. This data was published in Pain.
Members of Sanford Health oncology research recently attended the American Society of Clinical Oncology (ASCO) annual meeting in Chicago. The annual meeting is the largest educational and scientific oncology conference with over 40,000 professionals worldwide. While at ASCO, the team attended research and educational sessions, poster reviews, and met with collaborators, sponsors, and key opinion leaders to develop clinical research opportunities for Sanford Health.
The Boekelheide NICU is opening the MoCHA trial (Moderately Preterm Infants with Caffeine at Home for Apnea) to find out if extending the use of caffeine to prevent apnea will allow premature babies to go home from the NICU sooner and prevent readmission to the hospital or clinic. The study is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN), which Sanford Health is a competitively selected site. The study will enroll 1,200 babies from approximately 15 NRN centers across the U.S., and Sanford Health plans to have 30 babies per year participate. Suzanne Reuter and Michelle Baack will lead the study locally.
Chad Kurthenbach and Tiffany Facile were featured on Keloland’s Health Beat regarding the MILES study, which is designed to test how procurement and application of stem cells promote healing and tissue repair from osteoarthritis. This multicenter trial compares umbilical cord stem cells, adipose-derived regenerative cells, and bone marrow concentrate regenerative cells for the treatment of knee osteoarthritis.
The Boekelheide NICU is enrolling premature babies (22-28 weeks gestational age at birth) into the PDA Trial to find out if active or expectant treatment of a patent ductus arteriosus (PDA) is better. The ductus arteriosus, a blood vessel in the heart of the fetus, should close after a baby is born, but it is common to remain open in very premature babies. Treatment can have significant side effects. This study will help doctors to have clinical guidelines with the best way to manage a PDA. The study is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN). Neonatologists Baiba Steinbrekera and Michelle Baack will lead the study locally.
Maria Bell was invited to become a member of NCI’s Clinical Trials and Translational Research Advisory Committee (CTAC). This federal advisory committee makes recommendations to the NCI on the conduct of clinical trials and translational research across the institute.
The Neonatology Research Network (NRN) Follow-up Trial recently saw its first patient in the Sanford Children’s Specialty Clinic. This study, led by Clinical Investigator and neonatologist Laurie Hogden, performs neurodevelopmental, neurosensory, and functional assessments of surviving extremely low birth-weight infants born in participating NRN centers. The goal of the study is to identify potential maternal and neonatal risk factors that may affect infant neurodevelopment. The NRN is sponsored by the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Outreach and education
Sanford PROMISE and Sanford fit co-hosted several groups of daycare children from local daycare centers. Younger children spent time with the fit team on a nature scavenger hunt around the Sanford House. Louisa Otto led the older children in a hands-on activity where they learned about, “What is it like to be a scientist?”
Ben Benson, Louisa Otto, and Rachel Heynen led the 2019 Biomedical Research Investigations Summer Chemistry Camp at the Washington Pavilion in Sioux Falls. Fifteen middle and high school students attended the four-day camp to discover the basics of biochemistry and explore polymers. Campers learned about molecules, color-changing chemicals, and colorimetry.
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