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Posted on by Dr. Francis Collins
You might recall learning in biology class that the cells constantly replicating and dividing in our bodies all carry the same DNA, inherited in equal parts from each parent. But it’s become increasingly clear in recent years that even seemingly healthy tissues contain neighborhoods of cells bearing their own acquired genetic mutations. The question is: What do all those altered cells mean for our health?
With support from a 2018 NIH Director’s New Innovator Award, Po-Ru Loh, Harvard Medical School, Boston, is on a quest to find out, though without the need for sequencing lots of DNA in his own lab. Loh will instead develop ultrasensitive computational tools to pick up on those often-subtle alterations within the vast troves of genomic data already stored in databases around the world.
How is that possible? The math behind it might be complex, but the underlying idea is surprisingly simple. His algorithms look for spots in the genome where a slight imbalance exists in the quantity of DNA inherited from mom versus dad.
Actually, Loh can’t tell from the data which parent provided any snippet of chromosomal DNA. But looking at DNA sequenced from a mixture of many cells, he can infer which stretches of DNA were most likely inherited together from a single parent.
Any slight skew in those quantities point the way to genomic territory where a tiny portion of chromosomal DNA either went missing or became duplicated in some cells. This common occurrence, especially in older adults, leads to a condition called genetic mosaicism, meaning that, contrary to most biology textbooks, all cells aren’t exactly the same.
By detecting those subtle imbalances in the data, Loh can pinpoint small DNA alterations, even when they occur in 1 in 1,000 cells collected from a person’s bloodstream, saliva, or tissues. That’s the kind of sensitivity that most scientists would not have thought possible.
Loh has already begun putting his new computational approach to work, as reported in Nature last year . In DNA data from blood samples of more than 150,000 participants in the United Kingdom Biobank, his method uncovered well over 8,000 mosaic chromosomal alterations.
The study showed that some of those alterations were associated with an increased risk of developing blood cancers. However, it’s important to note that most people with evidence of mosaicism won’t go on to develop cancer. The researchers also made the unexpected discovery that some individuals carried genetic variants that made them more prone than others to pick up new mutations in their blood cells.
What’s especially exciting is Loh’s computational tools now make it possible to search for signs of mosaicism within all the genetic data that’s ever been generated. Even more importantly, these tools will allow Loh and other researchers to ask and answer important questions about the consequences of mosaicism for a wide range of diseases.
 Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations. Loh PR, Genovese G, Handsaker RE, Finucane HK, Reshef YA, Palamara PF, Birmann BM, Talkowski ME, Bakhoum SF, McCarroll SA, Price AL. Nature. 2018 Jul;559(7714):350-355.
Loh Lab (Harvard Medical School, Boston)
Loh Project Information (NIH RePORTER)
NIH Director’s New Innovator Award (Common Fund)
NIH Support: Common Fund; National Institute of Environmental Health Sciences
Posted on by Dr. Francis Collins
It’s not every day you get to perform with one of the finest voices on the planet. What an honor it was to join renowned opera singer Renée Fleming back in May for a rendition of “How Can I Keep from Singing?” at the NIH’s J. Edward Rall Cultural Lecture. Yet our duet was so much more. Between the song’s timeless message and Renée’s matchless soprano, the music filled me with a profound sense of joy, like being briefly lifted outside myself into a place of beauty and well-being. How does that happen?
Indeed, the benefits of music for human health and well-being have long been recognized. But biomedical science still has a quite limited understanding of music’s mechanisms of action in the brain, as well as its potential to ease symptoms of an array of disorders including Parkinson’s disease, stroke, and post-traumatic stress disorder (PTSD). In a major step toward using rigorous science to realize music’s potential for improving human health, NIH has just awarded $20 million over five years to support the first research projects of the Sound Health initiative. Launched a couple of years ago, Sound Health is a partnership between NIH and the John F. Kennedy Center for the Performing Arts, in association with the National Endowment for the Arts.
With support from 10 NIH institutes and centers, the Sound Health awardees will, among other things, study how music might improve the motor skills of people with Parkinson’s disease. Previous research has shown that the beat of a metronome can steady the gait of someone with Parkinson’s disease, but more research is needed to determine exactly why that happens.
Other fascinating areas to be explored by the Sound Health awardees include:
• Assessing how active music interventions, often called music therapies, affect multiple biomarkers that correlate with improvement in health status. The aim is to provide a more holistic understanding of how such interventions serve to ease cancer-related stress and possibly even improve immune function.
• Investigating the effects of music on the developing brain of infants as they learn to talk. Such work may be especially helpful for youngsters at high risk for speech and language disorders.
• Studying synchronization of musical rhythm as part of social development. This research will look at how this process is disrupted in children with autism spectrum disorder, possibly suggesting ways of developing music-based interventions to improve communication.
• Examining the memory-related impacts of repeated exposures to a certain song or musical phrase, including those “earworms” that get “stuck” in our heads. This work might tell us more about how music sometimes serves as a cue for retrieving associated memories, even in people whose memory skills are impaired by Alzheimer’s disease or other cognitive disorders.
• Tracing the developmental timeline—from childhood to adulthood—of how music shapes the brain. This will include studying how musical training at different points on that timeline may influence attention span, executive function, social/emotional functioning, and language skills.
We are fortunate to live in an exceptional time of discovery in neuroscience, as well as an extraordinary era of creativity in music. These Sound Health grants represent just the beginning of what I hope will be a long and productive partnership that brings these creative fields together. I am convinced that the power of science holds tremendous promise for improving the effectiveness of music-based interventions, and expanding their reach to improve the health and well-being of people suffering from a wide variety of conditions.
The Soprano and the Scientist: A Conversation About Music and Medicine, (National Public Radio, June 2, 2017)
NIH Workshop on Music and Health, January 2017
Sound Health (NIH)
NIH Support: National Center for Complementary and Integrative Health; National Eye Institute; National Institute on Aging; National Institute on Alcohol Abuse and Alcoholism; National Institute on Deafness and Other Communication Disorders; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute of Nursing Research; Office of Behavioral and Social Sciences Research; Office of the Director
Posted on by Dr. Francis Collins
The standard view of biology is that every normal cell copies its DNA instruction book with complete accuracy every time it divides. And thus, with a few exceptions like the immune system, cells in normal, healthy tissue continue to contain exactly the same genome sequence as was present in the initial single-cell embryo that gave rise to that individual. But new evidence suggests it may be time to revise that view.
By analyzing genetic information collected throughout the bodies of nearly 500 different individuals, researchers discovered that almost all had some seemingly healthy tissue that contained pockets of cells bearing particular genetic mutations. Some even harbored mutations in genes linked to cancer. The findings suggest that nearly all of us are walking around with genetic mutations within various parts of our bodies that, under certain circumstances, may have the potential to give rise to cancer or other health conditions.
Efforts such as NIH’s The Cancer Genome Atlas (TCGA) have extensively characterized the many molecular and genomic alterations underlying various types of cancer. But it has remained difficult to pinpoint the precise sequence of events that lead to cancer, and there are hints that so-called normal tissues, including blood and skin, might contain a surprising number of mutations —perhaps starting down a path that would eventually lead to trouble.
In the study published in Science, a team from the Broad Institute at MIT and Harvard, led by Gad Getz and postdoctoral fellow Keren Yizhak, along with colleagues from Massachusetts General Hospital, decided to take a closer look. They turned their attention to the NIH’s Genotype-Tissue Expression (GTEx) project.
The GTEx is a comprehensive public resource that shows how genes are expressed and controlled differently in various tissues throughout the body. To capture those important differences, GTEx researchers analyzed messenger RNA sequences within thousands of healthy tissue samples collected from people who died of causes other than cancer.
Getz, Yizhak, and colleagues wanted to use that extensive RNA data in another way: to detect mutations that had arisen in the DNA genomes of cells within those tissues. To do it, they devised a method for comparing those tissue-derived RNA samples to the matched normal DNA. They call the new method RNA-MuTect.
All told, the researchers analyzed RNA sequences from 29 tissues, including heart, stomach, pancreas, and fat, and matched DNA from 488 individuals in the GTEx database. Those analyses showed that the vast majority of people—a whopping 95 percent—had one or more tissues with pockets of cells carrying new genetic mutations.
While many of those genetic mutations are most likely harmless, some have known links to cancer. The data show that genetic mutations arise most often in the skin, esophagus, and lung tissues. This suggests that exposure to environmental elements—such as air pollution in the lung, carcinogenic dietary substances in the esophagus, or the ultraviolet radiation in sunlight that hits the skin—may play important roles in causing genetic mutations in different parts of the body.
The findings clearly show that, even within normal tissues, the DNA in the cells of our bodies isn’t perfectly identical. Rather, mutations constantly arise, and that makes our cells more of a mosaic of different mutational events. Sometimes those altered cells may have a subtle growth advantage, and thus continue dividing to form larger groups of cells with slightly changed genomic profiles. In other cases, those altered cells may remain in small numbers or perhaps even disappear.
It’s not yet clear to what extent such pockets of altered cells may put people at greater risk for developing cancer down the road. But the presence of these genetic mutations does have potentially important implications for early cancer detection. For instance, it may be difficult to distinguish mutations that are truly red flags for cancer from those that are harmless and part of a new idea of what’s “normal.”
To further explore such questions, it will be useful to study the evolution of normal mutations in healthy human tissues over time. It’s worth noting that so far, the researchers have only detected these mutations in large populations of cells. As the technology advances, it will be interesting to explore such questions at the higher resolution of single cells.
Getz’s team will continue to pursue such questions, in part via participation in the recently launched NIH Pre-Cancer Atlas. It is designed to explore and characterize pre-malignant human tumors comprehensively. While considerable progress has been made in studying cancer and other chronic diseases, it’s clear we still have much to learn about the origins and development of illness to build better tools for early detection and control.
 RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Yizhak K, Aguet F, Kim J, Hess JM, Kübler K, Grimsby J, Frazer R, Zhang H, Haradhvala NJ, Rosebrock D, Livitz D, Li X, Arich-Landkof E, Shoresh N, Stewart C, Segrè AV, Branton PA, Polak P, Ardlie KG, Getz G. Science. 2019 Jun 7;364(6444).
The Cancer Genome Atlas (National Cancer Institute/NIH)
Pre-Cancer Atlas (National Cancer Institute/NIH)
Getz Lab (Broad Institute, Cambridge, MA)
NIH Support: Common Fund; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; National Institute of Mental Health; National Cancer Institute; National Library of Medicine; National Institute on Drug Abuse; National Institute of Neurological Diseases and Stroke
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