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New list identifies genes and proteins that cause 72 of the most common genetic diseases

Tucker Apgar in a gray, printedt-shirt.
First author: Tucker Apgar, undergraduate student

Chuck Sanders, associate dean for research in the School of Medicine Basic Sciences and professor of biochemistry, and Tucker Apgar, an undergraduate student in the Sanders lab, have compiled the first comprehensive list of genes and proteins that cause the 72 most common genetic diseases.

While many of these diseases are classified as “rare” diseases, successful drug development efforts to treat any of these conditions would be beneficial to society and would likely be profitable. In fact, despite the “rare” classification these diseases afflict at least one in 20,000 individuals, and improving treatment options would provide better quality of life for patients and caretakers alike.

One disease on the list, cystic fibrosis, is a poster child for rare diseases. Cystic fibrosis is a genetic disease that results in frequent lung infections, causing severe damage to the lungs, and limiting an individual’s ability to breathe. A recently developed drug cocktail will extend the lifetimes of many CF patients and, despite the small number of worldwide patients, will likely be a billion-dollar therapeutic.

The investigators hope that this list will help motivate new projects that unravel how mutations in these genes and proteins lead to disease. While nearly half of the diseases listed are associated with mutations in a single gene, some of the diseases are associated with mutations in any one of a number of different proteins.

“We hope this list will spur rational therapeutic development for as many of these diseases as possible,” Sanders said. Spearheading the effort will be the Sanders lab, which has already started a new project based on one of the gene-disease relationships described in the compendium.
— By Aaron Conley and Emily Overway

Apgar, T.L., Sanders, C.R. (2021). Compendium of causative genes and their encoded proteins for common monogenic disorders. Protein Science 31(1), 75–91.

Researchers complete first-ever gene expression map of an entire nervous system

Headshot of first author: Seth Taylor, research assistant professor and former postdoctoral fellow
First author: Seth Taylor, research assistant professor and former postdoctoral fellow

Research Assistant Professor Seth Taylor and Professor Emeritus David Miller, both in the Department of Cell and Developmental Biology, have established a gene expression atlas for the nervous system of the nematode worm Caenorhabditis elegans, along with scientists from Columbia University and Yale University.

Their data complement the known wiring diagram of the C. elegans nervous system—a network of identifiable, labeled neurons connected by chemical and electrical synapses—and for the first time create a complete picture of gene expression for every neuron in an entire nervous system.

The researchers used flow cytometry to capture every type of neuron for gene expression profiling, and have shared these data for anyone to investigate how individual genes in neurons contribute to the function of a nervous system. To illustrate this approach, they used computational methods to identify DNA regions that control gene expression in specific neurons, as well as adhesion proteins that may sustain the formation of synapses—the connections between neurons that drive brain activity.

With only 302 neurons the C. elegans nervous system is much smaller and simpler than the human brain with its 100 billion neurons. However, “because the genetic rules that direct the development and function of the worm nervous system are also likely to operate in mammals, we expect that this unique gene expression data set will serve as a valuable foundation for deciphering the genetic underpinnings of the human brain,” Miller said.

The C. elegans brain with all neurons expressing green fluorescent protein and a subset of neurons involved in feeding expressing a magenta nuclear marker. The brain looks like a tangle of green fluorescent string knotted on the right half of the image, with nodules of purple primarily on the left side.
The C. elegans brain with all neurons expressing green fluorescent protein and a subset of neurons involved in feeding expressing a magenta nuclear marker.

By sharing their data, the researchers aim to create opportunities for other scientists studying the nervous system and how genetic defects shape the brain’s function and design. “These data will facilitate hypothesis-driven research into how genes specify different neuron types, how they make and maintain connections, and how they influence behavior,” Miller said. By Marissa Shapiro

Taylor, S.R., Santpere, G., Weinreb, A., Barrett, A., … Miller, D.M. (2021). Molecular topography of an entire nervous system. Cell 184(16), 4329–4347.e23.

Targeting the reward system to lessen alcohol consumption

Graphic of a human head with a bullseye on its side. A person (smaller than the head) with a beard is holding a giant dart toward the center of the bullseye. Blue leaves (or blue flames?) flank the head from behind. The background is a lighter blue than the leaves/flames.

When individuals see or do things they enjoy, a reward system is activated in the brain, encouraging them to repeat the action. Many activities turn on this system, such as eating good food, being in love—and consuming alcohol.

For some individuals, the desire to consume alcohol is uncontrollable and compulsive—leading to a condition called alcohol use disorder. AUD impacts approximately 30 percent of Americans at some point during their lives and costs the United States nearly $250 billion annually. Current treatment options for AUD are limited and relapse rates are high.

Headshot of Nathan Winters.
Co-first author: Nathan Winters, Ph.D. student

Nathan Winters, a graduate student in the Department of Pharmacology, Gaurav Bedse, a postdoctoral fellow in the Department of Psychiatry and Behavioral Sciences, and Sachin Patel, a former professor of pharmacology at Vanderbilt who is now at Northwestern University, set out to investigate how a brain chemical called 2-AG—an endocannabinoid that interacts heavily with the brain’s reward system—may impact alcohol intake, with the goal of determining additional targets for the treatment of AUD. Their work, done in collaboration with the labs of Assistant Professor of Pharmacology Cody Siciliano, Associate Professor of Molecular Physiology and Biophysics David Samuels, University Professor of Biochemistry and Chemistry Larry Marnett, and Professor of Molecular Physiology and Biophysics Danny Winder, was published in The Journal of Clinical Investigation.

Headshot of Gaurav Bedse.
Co-first author: Gaurav Bedse, postdoctoral fellow

The researchers explored the 2-AG system’s effects on alcohol intake in two ways: first by using a genetically modified mouse model that lacked the enzyme  that makes 2-AG, and then by testing the impacts of a drug that inhibits that same enzyme. They found that both the genetically modified mice and the mice treated with the drug had a lower preference for alcohol than unmodified and untreated mice. Winters and collaborators also found that treatment with the drug lowered alcohol consumption in several different models of AUD, with results comparable to current clinically available treatments for AUD, albeit without an increase in anxiety or depression in the mice.

This collaborative work provides evidence that targeting the brain’s 2-AG reward system with a drug may be a viable treatment option for some individuals with AUD. By Emily Overway

Winters, N.D., Bedse, G., Astafyev, A.A., Patrick T.A., … Patel, S. (2021). Targeting diacylglycerol lipase reduces alcohol consumption in preclinical models. J Clin Invest 131(17), e146861.

Single-cell data curation with machine learning

Diabetes is caused by a combination of dysfunctional insulin-producing pancreatic β cells and an inability of the body to respond to the insulin produced. The two most common types of diabetes are type 1 and type 2, but there are other less common types, including maturity-onset diabetes of the young. MODY is caused by mutations in genes that affect insulin production, and treatments for patients differ depending on what mutation is causing the disease.

Headshot of Emily Walker.
First author: Emily Walker, former postdoctoral fellow

Former postdoctoral fellow Emily Walker, along with researchers from the labs of Roland Stein, David Jacobson, and John Stafford, professors of molecular physiology and biophysics, recently investigated the mechanisms leading to MODY in individuals with a mutation in the MafA protein. MafA is highly expressed in β cells and is essential for proper insulin secretion. This particular MafA mutation significantly increases protein stability and is more likely to cause diabetes in men than in women. The work, published in Cell Reports, provides key insights into sex-specific molecular and genetic mechanisms controlling pancreatic β cell function.

The researchers genetically modified mice to express the mutant MafA protein. In four-week-old male mice, but not female mice, researchers found an increase in the amount of the MafA protein in  β cells. Male mice with increased MafA levels developed symptoms of diabetes by five weeks of age.

In searching for molecular mechanisms responsible for diabetes development, Walker and colleagues discovered that  β cells of male mice with this mutation showed accelerated aging and increased senescence, likely contributing to the development of  β cell dysfunction. This critical research could pave the way to improved treatment options for individuals with this MODY mutation. — By Emily Overway

Walker, E.M., Cha, J., Tong, X., Guo, M., … Stein, R. (2021). Sex-biased islet β cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence in males. Cell Reports 37(2), 109813.

Microtubule-associated protein discovery

Headshot of Beth Lawrence.
First author: Beth Lawrence, research instructor and former postdoctoral fellow

Microtubules are essential for the proper functioning of our cells, fulfilling critical roles in cell structure, division, and development. Microtubule-associated proteins regulate microtubule growth in cells, but the direct effects of many of these proteins are under-studied. Researchers from the lab of Associate Professor of Cell and Developmental Biology Marija Žanić, including first author and Research Instructor Beth Lawrence, postdoc Göker Arpağ, and former graduate student Cayetana Arnaiz, sought to understand the direct effects of SSNA1, a microtubule-associated protein, on microtubules through a variety of biochemical and microscopy techniques.

SSNA1 is implicated in Sjögren’s syndrome, a highly prevalent autoimmune disease. SSNA1 plays important roles in cilia, the organelles that animal cells use to move and sense their environment, and during cell division and neuronal development. Prior to this study, the mechanism for how SSNA1 directly regulates microtubules was unknown.

A black field showing 5 lines (microtubules, red) of different length. The microtubules are punctuated by stretches of SSNA1 (cyan) so that they look like lines of alternating red and cyan. A cyan haze surrounds a couple of the shorter lines. A scale bar is on the bottom left, but no units are provided.
The Žanić lab used total internal reflection fluorescence microscopy to monitor the interplay between microtubules (red), spastin (unlabeled), and SSNA1 (cyan).

Lawrence, who was formerly a postdoc in the Žanić lab, and colleagues found that SSNA1 is involved in regulating all aspects of dynamic instability, the alternating cycles of growth and shrinkage that newly formed and growing microtubules undergo. Specifically, the researchers found that SSNA1 acts to both slow the rate of microtubule growth and protect microtubules from shrinkage, is recruited at high concentrations to sites of damage on microtubules, and can protect microtubules against spastin, a microtubule-severing enzyme.

Given its apparent role in slowing the rate of growth and shrinkage—stabilizing microtubules at whatever their current length is—SSNA1 can be classified as a microtubule-stabilizing protein. SSNA1 also serves as a sensor, detecting microtubule damage irrespective of the cause. Lawrence and colleagues’ discoveries of multiple direct functions of SSNA1 on microtubules reveal that SSNA1 may employ various mechanisms for regulating microtubules, which not only furthers biological knowledge, but could also lead to new treatments for Sjögren’s syndrome. — By Aran Sullivan

Lawrence, E.J., Arpağ, G., Arnaiz, C., Žanić, M. (2021). SSNA1 stabilizes dynamic microtubules and detects microtubule damage. eLife 10, e67282.

Discovery of small-molecule inhibitors of an immune regulator

Immunotherapy—treatments based on activating or educating immune cells to attack tumor cells—has demonstrated remarkable efficacy against some cancers. Nonetheless, not all patients respond, and there are many potential negative side effects. Researchers continue to investigate mechanisms that control the immune response to identify new ways to target it and improve existing therapies. One such novel target, a protein involved in the negative regulation of the immune response, is called TIM-3. TIM-3 is one of several proteins frequently found on so-called “deeply exhausted” T cells, which are no longer able to mount an effective immune defense against tumor cells.

Ongoing preclinical and early clinical research using antibody-based inhibitors of TIM-3 has yielded encouraging results. However, there is substantial interest in moving from antibody-based inhibitors to small molecule-based inhibitors which are much cheaper, easier to manufacture, and more easily manipulated to minimize side effects.

Headshot of Tyson Rietz.
First author: Tyson Rietz, recent Ph.D. graduate

Researchers in the laboratory of Stephen Fesik, a professor of pharmacology and biochemistry who also holds the Orrin H. Ingram II Chair in Cancer Research, led by recent Ph.D. graduate Tyson Rietz, used a fragment-based discovery method to develop small molecule inhibitors of TIM-3. In “fragment-based discovery,” researchers identify small molecules (fragments) that bind weakly to a target and combine several of these molecules to make a compound capable of binding more strongly, or with higher “affinity.”

Fesik’s group began by using a technique called protein-observed NMR spectroscopy, which identified several candidate fragments. They then used medicinal chemistry to combine several of them into optimized compounds they can study and further modify to enhance the compounds’ binding affinity for TIM-3. They found that several of the high-affinity compounds interacted with the protein at a different binding site than the one that other proteins are known to interact with. Future work will determine if, aside from binding strongly, the compounds also inhibit the function of TIM-3.

Identification of these high-affinity compounds is an important step in the development of clinically useful TIM-3 small molecule inhibitors, which will hopefully serve as immunotherapeutic agents against cancers. In the meantime, the compounds generated here will be useful tools for researchers studying TIM-3 biology. — By Wendy Bindeman

Rietz, T.A., Teuscher, K.B., Mills, J.J., Gogliotti, R.D., … Fesik, S.W. (2021). Fragment-Based Discovery of Small Molecules Bound to T-Cell Immunoglobulin and Mucin Domain-Containing Molecule 3 (TIM-3). J Med Chem 64(19), 14757–14772.

Identifying mediators of the wound response

All organisms have a method of responding to wounds. Wounds can take many different forms, but the early wound response is remarkably consistent. During this time, cells near the site of injury experience an increase in internal calcium concentrations, which triggers a variety of effects to help the cells respond to the damage. These effects begin with the cells directly involved in the wound and extend out to neighboring cells over the course of a few seconds or minutes.

Fluctuation of calcium concentrations inside cells is a critical signaling mechanism active in a plethora of contexts. In the case of wound response, however, questions remain about how cells “sense” the initial wound event and how that initial calcium response is controlled.

Headshot of James O'Connor.
First author: James O’Connor, recent Ph.D. graduate

James O’Connor, a recent Ph.D. graduate from the Chemical and Physical Biology program, and colleagues in the lab of Andrea Page-McCaw, professor of cell and developmental biology, used a fruit fly model as well as a computational model generated based on their experimental data, and identified a pathway that cells use to detect wounds.

They found that, in fruit fly larvae, a wounding event activates several nonspecific proteases, enzymes capable of cleaving, or cutting, other proteins. These proteases act on growth-blocking peptides, inactive proteins present in the tissue that become active when cleaved, which in turn activate a protein called Methuselah-like 10. Mlth10 then activates a signaling cascade that terminates in a calcium response and feeds into known wound-response pathways.

Although there are no direct equivalents to Mlth10 or the growth-blocking peptides in mammals, this research represents an important step forward in understanding the mechanisms involved in wound detection. Similar wound response mechanisms— specifically, those based on protein cleavage by pro-teases released by injured cells—have been identified in many other organisms, which suggests that wound detection depends on ancient and highly conserved strategies. — By Wendy Bindeman

O’Connor, J.T., Stevens, A.C., Shannon, E.K., Akbar, F.B., … Page-McCaw, A. (2021). Proteolytic activation of Growth-blocking peptides triggers calcium responses through the GPCR Mthl10 during epithelial wound detection. Developmental Cell 56(15), 2160–2175.e5.

Developing a framework for precision surveillance of colorectal cancer

3D illustration showing numerous polyps on the on the lining of the intestine.

A team of Vanderbilt researchers has revealed some of the mechanisms by which polyps develop into colorectal cancer, setting the framework for improved surveillance for the cancer utilizing precision medicine.

Headshot of Bob Chen.
Co-first author: Bob Chen, recent Ph.D. graduate

Their study, published late last year in Cell, describes the creation of a single-cell transcriptomic and imaging atlas—a molecular “map” describing the complete set of mRNA transcripts coupled with microscopic images of specific tissues—of the two most common colorectal polyps found in humans: conventional adenomas and serrated polyps. They determined that adenomas arise from expansion of stem cells that are driven by activation of WNT signaling, which contributes to the development of cancer, while serrated polyps derive into cancer through a different process called gastric metaplasia.

Headshot of Cherie’ Scurrah.
Co-first author: Cherie’ Scurrah, recent Ph.D. graduate

The cells from serrated polyps did not exhibit WNT pathway activation nor a stem cell signature. Moreover, the researchers observed that these cells had highly expressed genes not normally found in the colon, leading them to hypothesize that metaplasia, an abnormal change of cells into cells that are non-native to the tissue, plays a role in how serrated polyps become cancerous.

The finding about metaplasia was surprising, the researchers said.

“Cellular plasticity through metaplasia is now recognized as a key pathway in cancer initiation, and there were pioneering contributions to this area by investigators here at Vanderbilt,” said Ken Lau, associate professor of cell and developmental biology, one of the study’s corresponding authors. “We now have provided evidence of this process and its downstream consequences in one of the largest single-cell transcriptomic studies of human participants from a single center to date.”

Bob Chen and Cherie’ Scurrah, recent Ph.D. graduates from the Chemical and Physical Biology program and the Department of Cell and Developmental Biology, respectively, are the paper’s first authors. The corresponding authors are Lau, Martha Shrubsole, research professor of medicine, and Dr. Robert Coffey Jr., professor of medicine and cell and developmental biology. — By Tom Wilemon

Chen, B., Scurrah, C.R., McKinley, E.T., Simmons, A.J., … Lau, K.S. (2021). Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps. Cell 184(26), 6262–6280.e26.