Year 2. March 27. Science Monday.
Each week, faculty and trainees in the department of medicine (DoM) co-author many publications that make important contributions to knowledge. The numbers have been as high as 70 publications and average around 50 publications per week. Our faculty are engines of innovation, and we catalog their work weekly at DoM Connect. Thus, when I highlight a few papers, it is representative of a large body of work representing our highly productive faculty. The first two publications were authored by graduates of our Specialty Training and Advanced Research (STAR) program, a critical pipeline for developing physician scientists.
Gloria Yiu, MD, PhD: “Human T cell generation is restored in CD3δ severe combined immunodeficiency through adenine base editing” in Cell
A single base-pair mutation in the CD3D gene causes a rare and deadly disease - CD3δ SCID - where T cell development is disrupted and results in infant mortality. Current treatment with allogeneic stem cell transplant carries high risk of complications, creating a significant clinical need for new treatment approaches. A recent study published in Cell, shows that gene therapy via base editing can correct the mutation that causes CD3δ SCID in blood stem cells and restore their ability to produce T cells.
This work was the result of collaboration on multiple fronts. Dr. Nicola Wright, a pediatric hematologist and immunologist at the Alberta Children’s Hospital Research Institute in Canada, identified the need for better treatment options for her CD3δ SCID patients.
Wright reached out to the Kohn Lab, who are experts in gene therapy. Once Grace McAuley (co-first author and currently a MSTP candidate at UCSD), identified the base editor best suited for the disease, Dr. Gloria Yiu (co-first author, STAR graduate, clinical instructor in the division of rheumatology and an AP Giannini Postdoctoral Fellow in the Crooks Lab) showed that base editing of CD3δ SCID patient stem cells could restore T cell development in an in vitro model. Together this research establishes the basis for a one-time autologous stem cell transplant treatment for patients. This multidisciplinary team is now advancing this approach to clinical trials in patients.
“Scientific stories that have such a clear through line from clinic to bench and back again, are rare, and it has been a privilege to contribute to this work with such a collaborative team. The way that all the pieces of this puzzle came together is a real testament to how combining clinical and bench knowledge can innovate for our patients,”states Yiu.
Tien Dong, MD, PhD: “How Discrimination Gets Under the Skin: Biological Determinants of Discrimination Associated With Dysregulation of the Brain-Gut Microbiome System and Psychological Symptoms” in Biological Psychiatry
The article "How Discrimination Gets Under the Skin: Biological Determinants of Discrimination Associated With Dysregulation of the Brain-Gut Microbiome System and Psychological Symptoms" published in Biological Psychiatry explores the biological determinants of discrimination and their association with dysregulation of the brain-gut microbiome system. Discrimination can lead to negative health outcomes and impact individuals both mentally and physically. Prior research has explored this field by examining stress related hormones such as cortisol and the hypothalamic-pituitary axis. However, chronic stress can lead to multiple manifestations in the body. This study, led by Tien Dong, MD, PhD, assistant professor of gastroenterology and STAR graduate, examines how chronic experiences of discrimination can lead to dysregulation of the brain-gut microbiome system, which can result in increased psychological symptoms such as anxiety and depression.
The study that represents a collaborative effort based in the Goodman-Luskin Microbiome Center and the laboratory of Dr. Arpana Gupta, found that individuals who experience chronic discrimination are at a higher risk of experiencing gut microbiome dysregulation, particularly changes in Prevotella copri, an inflammatory associated microbe. Discrimination was also associated with changes in networks of the brain associated with emotional regulation, introspection, and cognition. This dysregulation can lead to increased levels of inflammation, which has been associated with various chronic diseases. The study also found that these changes were different by race and by what type of discrimination an individual experienced.
"The findings of this study highlight the importance of understanding the biological consequences of discrimination and their impact on health outcomes, as well as the need for interventions that address both psychological and physiological factors,"states Dong.
Orian S. Shirihai, MD, PhD: “Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies” in The EMBO Journal
In mitochondria, a key enzyme called “ATP synthase” works like an ATP-generating turbine. Like a turbine, it can rotate forward or reverse to either synthesize or break down ATP, respectively. In a paper published this week, Drs. Acin Perez and Beninca from the Shirihai Lab in the division of endocrinology show that reverse activity of ATP synthase occurs in healthy mitochondria and is increased with genetic and acquired respiratory chain defects. The team developed a compound that specifically inhibits explicitly the reverse action of ATP synthase, thereby preventing dysfunctional ATP synthase from eliminating ATP. Surprisingly, inhibition of the reverse action of ATP synthase, on its own, is sufficient to prevent ATP depletion, restore cellular function and improve muscle strength in a model of Duchenne Muscular Dystrophy.
This study reveals a new concept in treating mitochondrial diseases. While previously we would only consider restoring respiratory function as a treatment, this study shows that preventing ATP breakdown by ATP synthase can benefit tissue function, even without correcting defective respiration.
You can read more about this study at the DGSOM Blog.
David B. Shackelford, PhD: “Spatial mapping of mitochondrial networks and bioenergetics in lung cancer” in Nature
In a new study published in Nature, Dr. Mingqi Han, a postdoc in Dr. David Shackelford's lab in the division of pulmonary and critical care medicine within the David Geffen School of Medicine’s Metabolism Theme, used positron emission tomography (PET) in combination with electron microscopy to generate 3-dimensional ultra-resolution maps of mitochondrial networks in lung tumors of genetically engineered mice. They categorized the tumors based on mitochondrial activity and other factors using an artificial intelligence technique called deep learning, quantifying the mitochondrial architecture across hundreds of cells and thousands of mitochondria throughout the tumor.
The authors examined two main subtypes of non-small cell lung cancer (NSCLC) — adenocarcinomas and squamous-cell carcinomas and found distinct subpopulations of mitochondrial networks within these tumors.
Importantly, they discovered that the mitochondria frequently organize themselves with organelles such as lipid droplets to create unique subcellular structures that support tumor cell metabolism and mitochondrial activity.
“Our study represents a first step towards generating highly detailed 3-dimensional maps of lung tumors using genetically engineered mouse models. Using these maps, we have begun to create a structural and functional atlas of lung tumors, which has provided us valuable insight into how tumor cells structurally organize their cellular architecture in response to the high metabolic demands of tumor growth. Our findings hold promise to inform and improve current treatment strategies while illuminating new directions from which to target lung cancer,”says Shackelford.
Zhaoping Li, MD, PhD: “Mixed Nuts as Healthy Snacks: Effect on Tryptophan Metabolism and Cardiovascular Risk Factors” in Nutrients
In a previously randomized, controlled, two-arm study, Zhaoping Li, MD, PhD and her team in the division of nutrition, demonstrated that the consumption of a snack of 1.5 oz of mixed tree nuts as part of a hypocaloric diet (500 kcal per day) for 12 weeks resulted in weight loss, increased satiety, decreased diastolic blood pressure, and heart rate but did not change circulating lipids. Tryptophan is an essential amino acid, and tree nuts are a high dietary source. In an effort to go more in-depth with these findings, the team investigated the effect of nuts on the tryptophan–kynurenine metabolism pathway, that is associated with increased risk for heart diseases.
Compared to baseline, plasma kynurenine concentrations are significantly reduced in the nuts group at the end of calorie-restricted weight loss in 95 overweight or obese participants. Tryptophan–serotonin metabolism was also evaluated by measuring plasma and fecal serotonin levels during intervention. Both plasma and stool serotonin concentrations increase significantly with the consumption of nuts in both weight loss and maintenance periods suggesting significant impact of nuts on gut microbiome and their metabolites.
“For the 1st time it has been shown that the cardiovascular benefit of consuming tree nuts may related to its impact on tryptophan host and microbial metabolism beyond it is effects on lipid metabolism,”states Li.
In case you are wondering what tree nuts are, they include: almonds, brazil nuts, cashews, hazelnuts (filberts), macadamia nuts, pecans, pine nuts (pinon, pignolias), pistachios. I have been snacking on nuts for a while now. Good to learn what they might be doing in my body.
March marks Women’s History Month which commemorates and encourages the study, observance and celebration of the role of women in American history. Throughout the department of medicine, we recognize and celebrate the women in our department who are leading our missions every day. We will continue to build upon our values to promote equity, diversity and inclusion in the department to ensure equitable pay and opportunities for women in medicine. On behalf of the DoM, I extend our gratitude to the women faculty, staff, and trainees who are trailblazers in medicine, science, education, and patient care.
I would like to highlight that Director of Operations at UCLA Health Lariza Johnson will serve as a panelist on the upcoming Administrative Management Group’s Women Leadership Panel, hosted March 30, 2023 at 12 pm. For over 18 years, Lariza has been a part of UCLA Health, leading healthcare operations. She currently oversees operations for ambulatory services on the central coast and has been a valued partner in the opening of new clinic sites and implementing best practices to improve the quality of patient care. Join Lariza and other UCLA Health women leaders as they discuss their groundbreaking experiences in our health system.
A few weeks ago I shared a picture of my wife and mother in San Diego. Some sharp-eyed readers quickly pointed out to me that she was wearing a windbreaker from my former place of employment, causing some consternation. I now set the record straight. Now a Bruin.
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