Pioneers in RNA Research Awarded 2024 Albany Prize

Scientists honored for insights that have led to significant advances in the understanding of and treatments for cancer and other diseases

The 2024 Albany Medical Center Prize in Medicine and Biomedical Research has been awarded to three scientists whose discoveries concerning the mechanisms of RNA have led to significant advancements in the understanding of and treatments for a wide array of diseases, including cancer, spinal muscular atrophy, cystic fibrosis, autoimmune conditions, and muscular dystrophy.

This year’s recipients are:

• Howard Y. Chang, MD, PhD, Virginia and D.K. Ludwig Professor of Cancer Research; Professor of Dermatology, Genetics, and Pathology; Director, RNA Medicine Program, Stanford University School of Medicine; Investigator, Howard Hughes Medical Institute
• Adrian R. Krainer, PhD, St. Giles Foundation Professor, Cancer Center Program Co-Leader, Cold Spring Harbor Laboratory
• Lynne E. Maquat, PhD, J. Lowell Orbison Endowed Chair and Professor, Department of Biochemistry and Biophysics, Oncology, and Pediatrics; Director, Center for RNA Biology: From Genome to Therapeutics; Chair, Graduate Women in Science, University of Rochester

They accepted the award at a special ceremony in Albany on Oct. 8.

“Each of these innovative scientists has made distinct, significant contributions to the study of RNA-mediated gene regulatory programs within the context of human disease,” said Alan S. Boulos, MD ’94, The Lynne and Mark D. Groban, MD ’67 Distinguished Dean of Albany Medical College and chair of the National Selection Committee.

“They have illuminated the potential of RNA-based therapies and meaningfully impacted our understanding of inherited diseases like spinal muscular atrophy and Fragile X syndrome, as well as other complex diseases like cancer and autoimmune disorders,” he continued. “We’re proud to recognize them for their individual and collective discoveries and insights, and look ahead with optimism to the therapeutic advances that will surely come as they and others continue to build on these foundations.”

RNA and the Mechanisms of mRNA Decay

A molecule found in every living cell, RNA (ribonucleic acid) has many roles, but one of its most important is decoding the genetic instructions on DNA and converting those instructions into proteins. Tens of thousands of proteins carry nutrients through the body, protect us from disease, help with chemical reactions, and more.

Messenger RNA (mRNA) is a type of RNA that is read by ribosomes, small protein-creating factories located inside cells. But when a genetic mutation or an error in gene expression occurs, the mRNA carries only partial instructions, which can result in the creation of short or incomplete proteins that cause disease.

A pioneer in the study of RNA in the context of human disease, Dr. Maquat discovered the biological process known as nonsense-mediated mRNA decay (NMD). In a revolutionary paper published in 1981, she began her work on how disease-causing mRNAs are degraded by NMD. She also elucidated the role of NMD as a quality control mechanism and showed how NMD finds and destroys mRNA that not only carry bad copies of genetic instructions but also are generated by mistakes routinely made by cells, thus preventing disease. An estimated one-third of all inherited diseases, including the blood disorder thalassemia, cystic fibrosis, and muscular dystrophy, and one-third of other diseases including some cancers, are targeted for destruction by NMD, opening up the possibilities for personalized medicine.

Recently, she found that small-molecule inhibition of NMD may be beneficial to patients suffering from Fragile X syndrome, the most frequent single-gene cause of autism and intellectual disability. Her lab has also demonstrated that small-molecule inhibition of NMD increases the rate and efficacy of cancer-cell killing when used as a supplement to certain chemotherapies, including those to treat breast cancer. In addition, Dr. Maquat’s lab is developing a genetic screen for new NMD factors and designing therapies that could evade or promote NMD, with the goal of lessening the severity of nonsense-generated diseases.

A New Class of Genes and Their Influence on Disease

Whereas Dr. Maquat’s work has centered on RNAs that encode protein in human health and disease, Dr. Chang’s research has focused on the 98 percent of the human genome that doesn’t encode protein. His discovery of a new class of genes that don’t carry instructions for making proteins, called long noncoding RNA (lncRNA), opened the field.

Through a series of discoveries, he introduced the important and pervasive roles of lncRNAs in biological regulation, including how lncRNA helps control the response to infections. He has also shown how their misexpression can drive the progression of autoimmune disorders, cancer, and other diseases. Because of Dr. Chang’s work, it is now known that hundreds of lncRNAs are individually required for cell growth or viability, and that inherited variation in lncRNA genes underlie hundreds of human diseases and traits.

In one of his most recent studies, Dr. Chang showed how Xist, one type of lncRNA found on the inactive X chromosome in females, can foster the development of autoimmune diseases, offering a possible explanation as to why more women than men suffer from diseases like rheumatoid arthritis and lupus.

Dr. Chang’s impact on genome science has also extended into the technological realm. He was instrumental in the invention of ATAC-seq, a sequencing method that has revolutionized the field of epigenomics, improving the ability to map active DNA elements by one million-fold in sensitivity and by one hundred-fold in speed.

RNA Splicing Errors and an Innovative Therapy

Dr. Krainer has concentrated his work on yet another aspect of RNA — splicing. He studies the mechanisms and regulation of mRNA splicing, how this process is disrupted in genetic diseases, and various means to alter mRNA splicing of individual genes for therapeutic applications.

His research and insights led to the design and development of an effective therapy for spinal muscular atrophy (SMA), a devastating genetic neuromuscular disease that was once incurable. Discerning that SMA could be tackled by correcting a splicing error in a specific gene, Dr. Krainer and colleagues in the pharmaceutical industry developed the drug Spinraza, which is an antisense oligonucleotide – a short, synthetic DNA/RNA-like molecule that binds to the complementary sequence in its mRNA target – to correct the splicing defect. Approved by the FDA in 2016, Spinraza has since saved countless lives and is being used to treat more than 14,000 SMA patients worldwide.

Dr. Krainer has continued to use the same technology to develop therapies for other diseases caused by splicing defects, including familial dysautonomia and diffuse midline glioma, and his work has shed light on how splicing dysregulation promotes cancer progression, especially in breast, liver, brain, pancreatic, and blood cancers. Further, he developed antisense technology to stabilize mRNAs that are destroyed by nonsense-mediated mRNA decay, such as what happens with particular mutations in the cystic fibrosis gene.

The Albany Prize

In 2000, the Marty and Dorothy Silverman Foundation dedicated $50 million to award the $500,000 Albany Prize annually for 100 years. It is intended to encourage and recognize extraordinary and sustained contributions to improving health care while promoting innovative biomedical research. Each recipient is nominated by their peers, and the prize, which is shared by that year’s recipients, is one of the most significant in medicine and science in the United States.

Two previous Nobel Prize winners have been among the ranks of researchers honored with the Albany Prize, and ten recipients have gone on to win the Nobel Prize, including Katalin Karikó, PhD, and Drew Weissman, MD, PhD, for their discoveries that enabled the development of effective mRNA vaccines against Covid-19; James P. Allison, PhD, for his development of immune checkpoint blockade to treat cancer; Shinya Yamanaka, MD, PhD, a leading stem cell scientist; Elizabeth Blackburn, PhD, who discovered the molecular nature of telomeres; Bruce Beutler, MD, and the late Ralph Steinman, MD, for their discoveries regarding the detailed workings of the immune system; Robert Lefkowitz, MD, for his work on cell receptors; and Emmanuelle Charpentier, PhD, and Jennifer Doudna, PhD, for their development of a method of genome editing.

Additional information about the Albany Prize, including photos and bios of the 2024 recipients and a complete list of previous recipients, is available on the Albany Prize webpages.