#266 Genetics Wrapped 2023

To celebrate the year coming to an end, we are reflecting back on the top genetics and genomics news stories during 2023. It’s hard to fit a year’s worth of genetics in one episode, let alone a half hour so we bring you this special double episode of DNA Today.

Our host Kira Dineen is joined by two leaders in genetics, Dr. Eric Green and Dr. Brendan Lee.

Dr. Eric Green

Dr. Eric Green is the director of the National Human Genome Research Institute (NHGRI) at the U.S. National Institutes of Health (NIH). As NHGRI director, Dr. Green leads the Institute's research programs and other initiatives. He has played an instrumental leadership role in developing many high-profile efforts relevant to genomics. Dr. Green received his B.S. degree in bacteriology from the University of Wisconsin - Madison in 1981, and his M.D. and Ph.D. degrees from Washington University in 1987. Coincidentally, 1987 was the same year that the word “genomics” was coined. Dr. Green’s relationship with the Institute began long before his appointment as director. He served as the Institute’s scientific director (2002 - 2009), chief of the NHGRI Genome Technology Branch (1996 - 2009) and founding director of the NIH Intramural Sequencing Center (1997 - 2009). Prior to that, he played an integral role in the Human Genome Project. Dr. Green is a founding editor of the journal Genome Research (1995 - present) and a series editor of Genome Analysis: A Laboratory Manual (1994 - 1998), both published by Cold Spring Harbor Laboratory Press. He is also co-editor of Annual Review of Genomics and Human Genetics (since 2005). Throughout his career, he has authored and co-authored over 385 scientific publications.

Dr. Green is a recurring guest on DNA Today, and he might hold the title as the guest who has been on the show the most times! He was featured on Episode #182 when we chatted about the Human Genome Project and the recent completion of the human genome sequence -- from telomere to telomere. Dr. Green was a panelist on the PhenoTips Speaker Series installment that our host Kira Dineen moderated about population genomics in clinical practice, this was also released on the DNA Today podcast feed as Episode #260. He was also on last year’s Genetic Wrapped episode (#214).

Dr. Brendan Lee

As a pediatrician and geneticist, the overall mission of Dr. Brendan Lee’s research program is to translate the study of structural birth defects and inborn errors of metabolism into a basic understanding of development, disease and novel therapeutic approaches. In the area of metabolism, we have applied genetic approaches to the study of biochemical genetic disorders (specifically urea cycle disorders) as models of complex diseases (those involving nitric oxide dysregulation). This has led us to study the consequences of metabolic derangements broadly in the endocrine, cardiovascular, skeletal, renal and neurological systems. In the area of structural birth defects, we have studied paracrine and endocrine signaling pathways that regulate skeletal development including morphogens (TGF, Wnt and Notch), and extracellular matrix proteins and their modifications (e.g., collagen prolyl-hydroxylation) that contribute to the human skeletal dysplasias including brittle bone diseases and connective tissue diseases like Ehlers-Danlos syndrome. These developmental pathways have led us to ask how their dysregulation contributes to common diseases such as osteoporosis, osteoarthritis and bone cancer.

The mechanistic discoveries of my laboratory research program are translated into the clinical arena via clinical research that is performed as part of the Skeletal Dysplasia Clinic and the Metabolic Disorders Clinic at Texas Children’s Hospital, respectively, and as part of two NIH rare diseases clinical research consortia (the Brittle Bone Disorders Consortium and the Urea Cycle Disorders Consortium). My clinical research program began with stable isotopic measurements in humans and urea cycle disorder patients to better diagnose and assess new treatments. These human studies evolved into the assessment of nitric oxide flux in patients with UCDs and specifically in those with argininosuccinic aciduria. I have participated in and led both investigator-initiated and industry-sponsored interventional studies including the design and implementation of Phase II and III studies of a novel ammonia scavenger glyceryl-triphenylbutyrate in urea cycle patients; combinatorial phenylbutyrate/arginine treatment and nitric oxide supplementation in patients with argininosuccinic aciduria; and phenylbutyrate in maple syrup urine disease. In the area of skeletal dysplasias, I have studied the utility of zoledronic acid, teriparatide and anti-TGF treatments in pediatric and adult osteogenesis imperfecta. Our preclinical gene therapy studies have led to a clinical trial of helper-dependent adenoviral gene therapy in osteoarthritis. Finally, I have focused on advancing the diagnosis of genetic diseases via gene discovery, multi-omic approaches to phenotyping and mechanistic studies in the NIH Undiagnosed Diseases Network.

Top 2023 Genetics Advancements

• The 20 anniversary of the completion of the Human Genome Project
  • Episode Recommendation: #182 Eric Green on the Complete Human Genome Project
  • Shoutout to listener Illham Ratbi who shared on our social media that this was among the top stories they were impressed with: “The complete sequencing of Y chromosome the last missing piece of human genome”

• New, specific gene editing may treat sickle cell disease
  • Sharma A., et al. (2023). CRISPR-Cas9 Editing of the HBG1 and HBG2 Promoters to Treat Sickle Cell Disease. N Engl J Med. 389(9), 829-832.
  • Episode Recommendation: #251 Diversifying Genetic Research with 23andMe (including sickle cell disease insight)
  • Episode Recommendation: #201 Sickle Cell Disease with Lifting the Veil
  • Episode Recommendation: #198 CRISPR Ethics with Sam Sternberg

• Maternal-only noninvasive prenatal genetic screening may be feasible and cost-effective for Mendelian disorders
  • Hoskovec, J., et al. (2022). Maternal carrier screening with single-gene NIPS provides accurate fetal risk assessments for recessive conditions. Genet Med. 25(2), 100334.
  • Concerned about BillionToOne’s BabyPeek
  • Episode Recommendation: #224 Single-Gene Noninvasive Prenatal Testing (NIPT) with BillionToOne (Author of this article, Jennifer Hoskovec, is one of the guests)

• Polygenic risk scores (PRS) and family history (FH) are independent indicators of inherited disease risk
  • Mars, N., et al. (2022). Systematic comparison of family history and polygenic risk across 24 common diseases. Am J Hum Genet. 109(12), 2152-2162.
  • Episode Recommendation: #168 Polygenic Risk Scores with Giordano Bottà

• Pharmacogenetic intervention reduces serious adverse drug events

• • Swen, J.J., et al. (2023). A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open- label, multicentre, controlled, cluster-randomized crossover implementation study. Lancet. 401, 347–356.
  • Episode Recommendation: #174 Pharmacogenomics with Fulgent Genetics
  • Episode Recommendation: #229 Pharmacogenomics with Avni Santani

• Natural language processing helps to prioritize critically ill newborns for whole-genome sequencing
  • Peterson, B., et al. (2023). Automated prioritization of sick newborns for whole genome sequencing using clinical natural language processing and machine learning. Genome Med. 15(1), 18.
  • Episode Recommendation: #226 NICU Whole Genome Sequencing with Hong Li and Madhuri Hegde (Our most shared episode of 2023 according to Spotify)

• Predictions for 2024 including artificial intelligence
  • Episode Recommendation: #231 ChatGPT and AI In Genetics with Daniel Uribe (Our most popular episode of 2023 according to Spotify)

Be sure to read “Genomic Medicine Year in Review: 2023”. It’s not published, yet but we will update these show notes/blog post with the link when it is. Many of the landmark papers we discussed are highlighted in this article. Dr. Green is one of 14 co-authors that selected these top papers for the year.

Stay tuned for the next new episode of DNA Today on Friday, December 15th! New episodes are released every Friday. In the meantime, you can binge over 265 other episodes on Apple Podcasts, Spotify, streaming on the website, or any other podcast player by searching, “DNA Today”. Episodes since 2021 are also recorded with video which you can watch on our YouTube channel, this includes some episodes recorded at NBC Universal Stamford Studios.

DNA Today is hosted and produced by Kira Dineen. Our social media lead is Corinne Merlino. Our video lead is Amanda Andreoli. Our Outreach Intern is Sanya Tinaikar. Our Social Media Intern is Kajal Patel. And our logo Graphic Designer Ashlyn Enokian.

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