New Genes to Explore in Fight Against Hearing Loss
More than 360 million people have some form of hearing impairment. We know that half of these cases are due to genetics, but the vast majority of genes responsible for many hearing loss syndromes are unknown. Now, research from the Knockout Mouse Phenotyping Program (KOMP2), part of the International Mouse Phenotyping Consortium (IMPC), shows that many more genes are involved in deafness than previously known. Because mice and humans share most genes, findings from mouse genes may tell us a lot about human hearing loss. Researchers tested over 3006 genetically modified mutant mice for hearing problems, exploring nearly 15% of the mouse genome. Hearing thresholds of the mice were measured with rising volumes of sound at different frequencies. While the study detected many genes already known to be involved in hearing loss, 52 of the genes were newly associated with hearing loss. These genes coded for many different types of proteins, from structural proteins to transcription factors, reflecting the complexity of the auditory system. Also, 41 of the 52 these genes were not even part of previously known networks of genes affecting hearing – highlighting potentially unexplored pathways of hearing loss. This information provides a large and unexplored genetic landscape that may help researchers understand more about hearing loss and develop better treatments.
A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction. Bowl MR, Simon MM, Ingham NJ, Greenaway S, Santos L, Cater H, Taylor S, Mason J, Kurbatova N, Pearson S, Bower LR, Clary DA, Meziane H, Reilly P, Minowa O, Kelsey L, Tocchini-Valentini GP, Gao X, Bradley A, Skarnes WC, Moore M, Beaudet AL, Justice MJ, Seavitt J, Dickinson ME, Wurst W, de Angelis MH, Herault Y, Wakana S, Nutter LMJ, Flenniken AM, McKerlie C, Murray SA, Svenson KL, Braun RE, West DB, Lloyd KCK, Adams DJ, White J, Karp N, Flicek P, Smedley D, Meehan TF, Parkinson HE, Teboul LM, Wells S, Steel KP, Mallon AM, Brown SDM. Nature Communications. 2017 Oct 12;8 (886).
Read Press Release Here
Visualizing the Nucleus in 3D
How DNA is packaged in the nucleus determines how it is used and how genes are expressed. DNA is condensed and packaged as chromatin (a complex of DNA and proteins called histones), which constantly changes as genes are expressed. Understanding chromatin packaging may reveal the structural code for how genes are turned on or off in human health and disease. For example, understanding chromatin packaging could be used to make cancer cells with abnormally structured chromatin “remember” how to be healthier through repackaging chromatin. Toward understanding chromatin packaging in the nucleus, 4D Nucleome (4DN) program grantee Dr. Clodagh O’Shea collaborated with fellow 4DN grantee Dr. Mark Ellisman to develop a new approach to visualize chromatin in 3D space. This method, called ChromET, combines electron microscopy tomography (EMT) and a labeling method that enhances the visualization of DNA in human cell lines. An electron microscope uses a beam of electrons to create an image of a sample and is capable of seeing much smaller objects than a traditional light microscope. The 4DN researchers used ChromET to show that chromatin is flexibly disordered and packed together at different concentrations in the nucleus. This is different from the textbook model of rigid higher-order chromatin folding. This new model of diverse chromatin structures – able to bend at various lengths and achieve different packing concentrations – is important because it provides an explanation for how different parts of the genome could be fine-tuned to make different structures, at different times, with different functions. This research brings us one step closer to discovering how the structural code of our genomes could be used to advance medical care.
Reference: ChromEMT: Visualizing 3D chromatin structure and compaction of the human genome in interphase and mitotic cells. Ou, HD, Phan S, Deerinck TJ, Thor A, Ellisman, MH, O’Shea CC. Science. 2017 July 28.
Mouse Study Reveals Important Differences Between Males and Females
Historically, most researchers didn’t often study both sexes in their experiments, they assumed that results from male animals would be the same as female animals. However, we now know that sex influences the frequency, progression, and severity of the majority of common diseases and disorders, including cardiovascular and autoimmune diseases. Because of this, the NIH has mandated exploring sex as a biological variable, meaning researchers must consider sex as a biological variable in the design and analysis of their animal studies.
As part of the International Mouse Phenotyping Consortium (IMPC), Knockout Mouse Phenotyping Program (KOMP2) researchers supported by the Common Fund have explored how physical characteristics, vary by sex in normal and genetically modified mice. In the largest study of its kind, they analyzed 234 different physical characteristics in more than 50,000 mice. They found that the sex of the mice influenced many traits. For example, after accounting for weight, a known sexually dimorphic variable, 9.9% of categorical traits (things that can be put into categories, such as glucose tolerance) exhibited sexual dimorphism in normal mice. For continuous traits (things that can be measured on a scale, such as cholesterol levels), a far higher proportion exhibited sexual dimorphism at 56.6%. While some traits were expected to show differences in males and females, such as glucose levels and cardiac phenotypes, others were surprising and could not have been predicted. For example, vision abnormalities from the cornea were surprisingly found more often in female mice than males.
Not only did they study normal mice, but they also measured sexual dimorphism in many different genetically modified mice. To do this, they ”knocked out” different genes and measured whether any differences in the resulting physical traits depended on the sex. Unsurprisingly, some mutations only had effects in female mice, or vice versa. For example, only males and not females with the Usp47 gene knocked out, had high cholesterol levels, which would be important to consider in studies of heart disease or other diseases in which cholesterol is involved. The results have implications for the design of future animal studies which underpin research into treatments for human diseases. This study is a major step in highlighting the impact of sex differences in biomedicine and will help in accounting for those differences in the future biomedical studies.
Prevalence of sexual dimorphism in mammalian phenotypic traits. Karp NA, Mason J, Beaudet AL, Benjamini Y, Bower L, Braun R E, Brown S DM, Chesler EJ, Dickinson ME, Flenniken AM, Fuchs H, de Angelis MH, Gao X, Guo S, Greenaway S, Heller R, Herault Y, Justice MJ, Kurbatova N, Lelliott CJ, Lloyd KC, Mallon A, Mank JE, Masuya H, McKerlie, TF Meehan, RF Mott, SA Murray, H Parkinson, R Ramirez-Solis, Santos, JR Seavitt, D Smedley C, Sorg T, Speak A O, Steel KP, Svenson L, The International Mouse Phenotyping Consortium, Wakana S, West D, Wells S, Westerberg H, Yaacoby S, White JK . Nature Communications. 2017 June 26;8 (15475).
Read Press Release Here
New Study Offers Promise for the Safety of RNA Therapeutics
Researchers supported by the Common Fund’s Extracellular RNA Communication (ERC) program at The Ohio State University are studying the safety of delivering RNA in extracellular vesicles (EVs) as a possible disease treatment. RNA is a biological molecule that make protein. Proteins perform a variety of essential functions, from providing structure to our bodies to protecting us from bacteria. RNA is found primarily inside cells and only recently has been found outside of cells and considered as a potential treatment option. For example, some recent evidence has suggested that RNAs can be developed as therapeutics for cancer or multiple sclerosis. The natural ability of EVs to transfer biologic materials like RNA throughout the human body is an exciting system to harness. Many current efforts, including those of the ERC program, are exploring whether EVs containing RNA could be effective therapeutics or if EVs can be vehicles for drug delivery to treat diseases like cancers or brain disorders. However, scientists are working to understand the potential harmful side effects or unintended immune complications of EVs and their RNA cargo. While proving a treatment has a desired effect is critical in early preclinical studies, it can be even more critical to know if a potential treatment could have toxic side effects or may elicit a dangerous immune response.
In this study, the researchers used normal cells, which naturally produce EVs, as well as cells engineered to make EVs carrying a specific type of RNA inside them. They treated mice with EVs collected from both cell types for a three-week period and carefully monitored if normal EVs or engineered EVs caused any toxic or immune responses. They used many ways to assess this, including visual examination of mice, measuring blood chemistry profiles, dissecting organs, and measuring immune markers. Overall, using these assays they found no potential for harm coming from the EVs of normal and engineered cells, though small changes in immune responses may require further study. Next steps will determine if higher doses of EVs or a longer dosing period would be as safe, if EVs from different cell types act differently, and if EVs from human cells are immunogenic or toxic in other animal models. This study shows early promising signs for the safe use of EVs containing RNAs, and presents a standard framework for comprehensive study of immune effects and toxicity for future studies.
Comprehensive toxicity and immunogenicity studies reveal minimal effects in mice following sustained dosing of extracellular vesicles derived from HEK293T cells. X. Zhu, M. Badawi, S. Pomeroy, D.S. Sutaria, Z. Xie, A. Baek, J. Jiang, O. A. Elgamal, X. Mo, K. La Perle, J. Chalmers, T. D. Schmittgen, and M.A. Phelps. Journal of Extracellular Vesicles. Vol. 6, Iss. 1,2017.
Read more at exRNA.org
Promising New Treatment for Multiple Sclerosis
A new drug based on a compound originally discovered in a Common Fund program has passed a late phase clinical trial demonstrating its effectiveness in treating Relapsing Multiple Sclerosis (RMS). RMS is the most common form of MS and is characterized by acute attacks of impaired neurological function followed by periods of recovery. This new drug, ozanimod, is derived from one of the compounds discovered by Dr. Hugh Rosen and colleagues at the NIH Molecular Libraries Probe Production Center at The Scripps Research Institute. The research was part of the Common Fund’s Molecular Libraries and Imaging Program which discovered multiple compounds that have been developed into candidate drugs that are now in clinical trials for a variety of diseases.
In this recent phase III clinical trial involving 1,346 RMS patients, ozanimod was shown to reduce the number of relapses over a twelve month treatment period compared to a standard treatment with an interferon based therapy. The findings of this study suggest that ozanimod may prove to be an effective therapy for patients dealing with RMS. Celgene, the company currently developing ozanimod, expects to seek FDA approval for this potential new treatment towards the end of 2017.
BEST Researchers Study Career Outcomes of Postdocs
Postdoctoral scholars (or “postdocs”) are often thought of as the engine that drives scientific research. They are highly educated and trained researchers, pursuing additional training and mentoring after their PhD training. They conduct much of the day-to-day work of biomedical research. And presumably they are aiming to move on to be independent faculty researchers, though reports suggest that only a minority actually end up in those positions. If this is true, where do postdocs really find employment? Researchers in the NIH BEST Consortium are beginning to find out by tracking career outcomes of postdocs from the University of California, San Francisco (UCSF).
From their tracking and analysis, the researchers found differences in employment outcome based on whether a postdoc had a PhD versus an MD/PhD, or whether they were employed in the United States or another country. For example, around one-quarter of postdocs went on to work in other nations, but only about half of these individuals gained faculty positions in research or teaching. UCSF postdocs with both an MD and a PhD were also more likely to work in faculty positions than in non-faculty positions, either in or outside the United States. Variations in outcomes were also found to be dependent on the lab in which postdocs trained. Knowing any of this type of information ahead of time could help prospective postdocs when they consider which labs might be best for their additional training time and their future career goals.
The UCSF researchers also found general confusion with understanding of “tenure-track” positions, which are jobs on track to be a permanent academic position and not temporary or conditional. Postdocs searching for jobs are often unaware that the term “tenure-track” is over-applied. The classification of “tenure-track” versus “non-tenure-track” in job descriptions is often incorrect and fails to acknowledge many nuances. This ends up misleading postdocs as they weigh their options for employment. Many who think they are in, or are applying to, a classical “tenure-track” position really are not. Interestingly, only 21% of the postdocs who attain faculty positions at UCSF were in a bona fide tenure track position. Overall more data are needed to inform postdocs and graduate students considering a postdoc position about the realities of career opportunities, according to the UCSF researchers. These data could enhance career development experiences that would better suit the actual careers the postdocs are ending up in and that are available. More data are also needed for better transparency, giving postdocs timely and relevant information to enable them the agency to prepare for their futures.
Tracking Career Outcomes for Postdoctoral Scholars: A Call to Action. Silva EA, Des Jarlais C, Lindstaedt B, Rotman E, Watkins ES. PLOS BIOLOGY. 2016 May 14(5)e1002458. doi: 10.1371/journal.pbio.1002458
Combining Anti-RNA Treatments with Chemotherapy May Offer Benefits for Lung Cancer Patients
Chemotherapy is a standard treatment for many cancers. However, resistance to chemotherapy can develop over time, which causes cancer cells to lose the ability to respond effectively to treatment. It is unknown how this resistance develops. Researchers from the Common Fund’s Extracellular RNA Communication program have begun to examine the role extracellular RNAs may play in this resistance by studying a particular RNA called miR-155. MiR-155 is found at increased levels in many cancers. In forms of cancer that are particularly aggressive and resistant to treatment, miR-155 is found at even higher levels. The potential role of miR-155 in cancer and resistance to chemotherapy is not well-understood. Does miR-155 influence resistance to chemotherapy? Can available drugs targeted against miR-155 (“anti-miR-155”) be used to stop or reverse chemotherapy resistance? To address these questions, researchers explored how miR-155 works in lung cancer and evaluated if a treatment to inhibit miR-155 could help stop resistance to chemotherapy.
Interestingly, they showed that increased levels of miR-155 induce resistance to many different types of chemotherapeutic agents. They also demonstrated that miR-155 partners with TP53, a well-known tumor suppressor, to promote resistance. Furthermore, when they added a drug that blocks miR-155, they found resistance lessened. This means that even though resistance developed, it can be reversed and the chemotherapeutic drugs can become effective at killing cancerous cells again. Excitingly, this anti-miR-155 treatment had no toxic side effects in mice, suggesting the treatment has potential to be used in clinical trials in combination with standard chemotherapy regimens.
Combining anti-miR-155 with chemotherapy for the treatment of lung cancers. Van Roosbroeck, K., F. Fanini, T. Setoyama, C. Ivan, C. Rodriguez-Aguayo, E. Fuentes-Mattei, L. Xiao, I. Vannini, R. Redis, L. D'Abundo, X. Zhang, M. S. Nicoloso, S. Rossi, V. Gonzalez-Villasana, R. Rupaimoole, M. Ferracin, F. Morabito, A. Neri, P. Ruvolo, V. R. Ruvolo, C. V. Pecot, D. Amadori, L. Aruzzo, S. Calin, X. Wang, M. J. You, A. Ferrajoli, R. Z. Orlowski, W. Plunkett, T. Lichtenberg, R. V. Davuluri, I. Berindan-Neagoe, M. Negrini, Wistuba, II, K. Hagop, A. K. Sood, G. Lopez-Berestein, M. J. Keating, M. Fabbri and G. A. Calin. Clinical Cancer Research. 2016 November 20. doi: 10.1158/1078-0432.CCR-16-1025.
For more information see the exRNA Consortium blog!
A Guiding Light to Study Protein Assembly in Living Cells
4D Nucleome grantee Dr. Clifford Brangwynne and collaborators have developed a new tool that uses light to manipulate matter inside living cells. Called optoDroplet, this tool helps explain the physics and chemistry behind how cells assemble a mysterious structure called a membraneless organelle. An organelle is a specialized part of a cell having some specific function. For example, the nucleus is an organelle that holds most of the cell’s genetic information. Organelles like the nucleus are walled off from the rest of the cell by a membrane. The cell also uses membraneless organelles that resemble liquid droplets and exhibit dynamic behavior, such as rapid assembly and disassembly of protein building blocks that make up the organelle. When these mechanisms go awry, aggregates of the protein building blocks can form. Protein aggregation is associated with a number of diseases, including amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) and Alzheimer's disease. Understanding the process by which proteins condense into these droplet-like, membraneless organelles may be used to develop of interventions and treatments for diseases connected with protein aggregation. To better understand this process, Dr. Brangwynne’s group developed optoDroplet. This new tool relies on optogenetics, which involves proteins whose behavior can be altered by exposure to light. Using mouse and human cells, researchers showed that they could create membraneless organelles by switching on the light-activated proteins. They were also able to use this tool to generate protein aggregates, similar to those found in some diseases. The optoDroplet system will help researchers understand the basic mechanisms that underlie self-assembly of membraneless organelles in healthy living cells and may reveal how cells become diseased when this process goes awry.
Reference: Spatiotemporal Control of Intracellular Phase Transitions Using Light-Activated optoDroplets. Shin Y, Berry J, Pannucci N, Haataja MP, Toettcher JE, Brangwynne CP. Cell. 2017 Jan 12;168(1-2):159-171.e14. doi: 10.1016/j.cell.2016.11.054. Epub 2016 Dec 29.
Looking at Type 2 Diabetes from Different Viewpoints
Type 2 diabetes (T2D) is a complex disease that affects more than 29 million Americans, a number that is expected to increase in the coming decades. T2D risk factors include, but are not limited to, genetic mutations, obesity, physical inactivity, and increased age. These numerous risk factors highlight how both genetics and environmental influences can contribute to T2D. In order to develop better methods for early detection and disease treatment, scientists need a better understanding, at both the research and clinical levels, of how this disease occurs and progresses.
To gain a better appreciation of T2D, the research community must study it from different viewpoints. This concept is exemplified by the NIH Common Fund, which strives to support research relevant to multiple diseases and conditions, developing tools and resources from different biological perspectives that others can apply to specific questions. Several different scientific fields have used support from the Common Fund to deepen our understanding of T2D.
Inherited risks, such as genetic mutations, as well as environmental risks, such as obesity, physical inactivity, and age, have all been linked to T2D. Due to the complexity of factors contributing to T2D, a single type of drug or treatment procedure is likely to be ineffective, and a more personalized approach to treat specific underlying causes is needed. A recent study, supported by the Common Fund’s Illuminating the Druggable Genome program, used advanced genetic and computer analysis methods to determine three distinct subgroups of 11,210 patients with T2D based on their clinical and genetic histories. Patients were pooled based on other medical conditions, such as heart disease, cancer, and kidney disease. The study found distinct patterns of clinical characteristics as well as unique genetic markers for each subgroup. These types of results will allow doctors to create better, more detailed treatment plans for T2D patients by targeting specific risks that may be connected to the disease and may help doctors develop an early warning system for T2D in patients with other medical conditions. In addition, these results highlight the value of precision medicine and show an approach that can be applied to other complex, multifactorial diseases to develop better treatment plans and improved patient outcomes. More information on the study can be found here.
In T2D, the body does not use insulin correctly, which increases the amount of glucose (sugar) present in the bloodstream. Insulin is a hormone made by the pancreas which moves around the body and allows your cells to use glucose properly. Currently, researchers look for changes in blood glucose levels in order to monitor how certain cells of the pancreas work. This method can be insensitive and is a poor marker for how pancreatic cells are working. It can also be invasive, resulting in poor quality data and loss of patient involvement. Recent work supported by the Common Fund’s New Innovator Award Program has developed a noninvasive, high resolution system to monitor how individual cells work in real time in biological tissue. Previous methods which used cells in a culture dish, which is a poor representation of biological tissue. What makes this technology even more powerful is that the method allows researchers to study cell growth and other biological functions in addition to glucose production. Knowledge of pancreatic cell roles will allow researchers to develop better T2D treatments by monitoring improvements in pancreatic cell function in a much more detailed, real-time, and less invasive way. The full study can be found here.
A new clinical study involving the Common Fund’s Human Microbiome Project aims to examine the microbiome of 100 at-risk individuals for T2D. Microscopic study of the healthy human body has demonstrated that microbial cells outnumber human cells by about ten to one. Until recently though, this abundant community of human-associated microbes remained largely understudied, leaving their influence upon human development, physiology, immunity, and nutrition almost entirely unknown. Researchers have found that there are differences in the gut microbiome between diabetics and healthy individuals, and have also shown that the microbiome can influence glucose levels in mice. The study is expected to reveal global changes in the microbiome of T2D at-risk individuals in great detail over time. This will allow researchers to not only better understand how the microbial cells in our bodies influence our health, but also identify new molecular targets to help diagnose, treat, or potentially prevent T2D in humans. More information on the clinical study can be found here.
It is clear that there are many factors that can contribute to developing T2D. By helping support research to develop different biological tools that answer difficult biological questions, Common Fund programs are helping researchers better understand complex diseases like T2D, and ultimately, helping many patients.
Enhancing Career Preparation for Biomedical Trainees
In a recent perspective, Dr. Cynthia Fuhrmann, a PI in the NIH BEST Consortium, suggests ways to strengthen biomedical career development. Dr. Fuhrmann highlights that the national conversation is progressing and moving away from ‘‘should we be providing career development to PhDs?’’ to ‘‘how do we do so effectively?” In the present academic environment, trainees often lack knowledge about available career options. Furthermore, trainees can be unprepared to chart their own career path, to develop professional skills, or to cultivate other skills specific to their intended career path. All of this complicates their transition into any career within or beyond academia. Because of this, Dr. Fuhrmann argues that we need a “culture that encourages the career development of our trainees, and enhances our educational approach such that career exploration and development of our trainees can occur in synchrony with their research.” The culture change is starting to happen and the academic community is beginning to understand and support the fact that traditional research-intensive positions are not the only means by which PhD graduates can meaningfully contribute to the biomedical research enterprise. To help enhance career preparation, Dr. Fuhrmann recommends that institutions embrace and support the fact that trainees seek a variety of scientific careers. To support this, institutions should work to better integrate professional skills and career development workshops, courses, and assignments into the required curriculum for all trainees. Ultimately, she recommends that institutions should invest in career development as a part of their academic mission. By doing these things, and gathering data and researching how well these efforts work, trainees will be better able to efficiently move into careers that will sustain our nation's biomedical enterprise. Institutions embracing this philosophy in their curricula will attract bright and talented trainees to their doors.
Enhancing Graduate and Postdoctoral Education To Create a Sustainable Biomedical Workforce. Fuhrmann C. Hum Gene Ther. 2016 Nov;27(11):871-879.
Image courtesy of Human Gene Therapy
International Human Epigenome Consortium (IHEC) Celebrates Major Coordinated Paper Release
Investigators from the International Human Epigenome Consortium (IHEC), which includes Common Fund Roadmap Epigenomics Program grantees, have published a special collection of papers titled “Insights from the International Human Epigenome Consortium”. This collection includes 24 papers published in Cell and other Cell Press journals, plus 17 papers published elsewhere. This publication release demonstrates how the consortium’s epigenomic reference maps can help find answers to pressing questions related to the cellular mechanisms associated with numerous complex human diseases. For example, Common Fund Epigenomics grantee Dr. Aleksandar Milosavljevic and collaborators found that the epigenetic profiles of breast cancer cells are distinct from normal epithelial cells and that these epigenetic marks can be mapped to specific groups of cancer cells. This is significant because it enables the study of factors that drive tumor progression.
Building the Molecular Foundation of Alzheimer's Disease; How Multiple Common Fund Programs Develop Tools To Further Our Understanding
Alzheimer’s disease is among the leading causes of death in both the United States and the world. As medical advances increase life expectancy, it is estimated the number of Alzheimer’s cases will double over the next 25 years, leading to a significant economic and social burden. Despite our increasing understanding of Alzheimer’s disease, there is still much we do not know, primarily because the disease can attack individuals in many different ways.
Common Fund programs, while not focused on specific diseases or conditions, often support cutting edge and transformative projects that have the potential to impact many different diseases. A variety of Common Fund-supported projects have developed ideas to examine Alzheimer’s disease from different viewpoints. This multipronged model has allowed for significant advancements in our ability to understand how this disease works across different populations and individuals and may lay the foundation for future diagnostics and treatments.
A major purpose of Common Fund projects is to develop innovative research tools and ideas to support diverse research goals. A common thread amongst many diseases, such as cancer, diabetes, or Alzheimer’s disease is the discovery of chemicals within our bodies, called biomarkers, which change as the disease develops. Two Common Fund programs supporting the development of new biomarker detection tools are Epigenomics, which studies how different factors can turn our genes on or off at different times, and Metabolomics, which studies how chemicals in our bodies are broken down or used for energy. One of the biggest hurdles when studying Alzheimer’s disease is that distinct biological changes happen in our bodies long before doctors are able to diagnose the disease. Thus, by the time we know there is a problem, it is too late for treatment. Researchers have used the tools developed by Epigenomics and Metabolomics Common Fund programs to make great strides in finding innovative biomarkers for Alzheimer’s disease. For example, one study used tools from the Epigenetic program to determine the brains of patients with Alzheimer’s disease had increased changes (methylation) to their DNA compared to patients without the disease. Studies like these are the first step to better understanding the biological changes that occur in patients with Alzheimer’s disease. Researchers now have specific targets to look for in blood and other tissues to see if the same change occurs. Tools developed by the Metabolomics program help these types of studies to be performed. Researchers used methods developed by the Metabolomics program to find that patients with elevated levels of specific chemicals (fats, such as cermaide) had a higher likelihood of developing Alzheimer’s disease. These are just two of many examples of how research advances from two very different Common Fund programs can contribute to our understanding of Alzheimer’s disease.
In addition to finding biomarkers, many Common Fund programs have developed tools and resources that researchers have used to study changes in biological processes in Alzheimer’s disease. One interesting study used resources from the Metabolomics program to show that cells in the brain of Alzheimer’s patients were breaking down parts of other cells to be used as sources of fuel. These results suggest that the brains of Alzheimer’s patients may have lower energy compared to non-diseased individuals, and also highlights how loss of brain function may occur as one cell type is lost or damaged to support its neighbor. To gain a deeper understanding of how the disease works and to support data found in human patients, researchers often use animal models. One program that highlights the importance of animal models is the Knockout Mice Phenotyping (KOMP2) program, which supports efforts for researchers to generate and characterize mice that have specific genes removed. Other researchers can then use these mice to study how the genes influence diseases. Through KOMP2, the Common Fund has helped support the generation of many mouse models that have been used to study Alzheimer’s disease, such as the Alzheimer’s disease modifier genes 1-5 (Azdm1-5) or the Presenilin 1 and 2 knockouts (Psen1/2).
Several awards within the Common Fund’s High Risk High Reward (HRHR) program are also advancing research about Alzheimer’s disease. The HRHR program supports highly risky and innovative ideas that have the potential for exceptional payoff. These awards have allowed researchers to develop innovative biomarkers, more precise animal models, and groundbreaking brain imaging studies to help identify early warning signs of Alzheimer’s disease. HRHR awardees are also investigating how common, everyday mechanisms such as sleep and stress may contribute to the development of Alzheimer’s disease.
Not only do Common Fund programs contribute to understanding how Alzheimer’s disease starts and progresses, there is also substantial support for the development of future potential therapeutic studies. The Regenerative Medicine and Regulatory Science programs are working to provide resources that one day may be used by researchers to help patients with Alzheimer’s disease. Researchers supported by the Regenerative Medicine program are developing resources to accelerate development of new therapies using induced pluripotent stem cells to treat multiple diseases. These fundamental resources may one day be used by scientists to understand how to repair the neurons that are damaged in the brain during Alzheimer’s disease. The Regulatory Science program is developing interconnected model systems of different organs and cells in our body to not only better understand how cells communicate within a larger system, but to also use these models to see how organs as a whole respond to toxins, drugs, and other outside influences. These resources may one day allow scientists to develop a mini-brain model that mimics Alzheimer’s disease, allowing researchers to possibly move away from traditional animal models and to see how potential drugs may act in an environment more similar to the human disease.
Illuminating Essential Gene Function in Mice
Drs. Mary Dickinson and Steve Murray and collaborators, as part of the Common Fund’s Knockout Mouse Phenotyping Program (KOMP2) and International Mouse Phenotyping Consortium (IMPC), have been using mouse models to study essential genes, or genes that are necessary for survival. In the absence of these genes, mice die as embryos, bringing up unique challenges for their analysis. However, this embryonic death also provides evidence for the critical role these essential genes play in normal growth and development in both mice and potentially humans. As part of the overall KOMP2/IMPC effort, researchers developed a strategy to more carefully study the function of these essential genes. In their strategy, they identify and describe the exact time of mouse lethality, assign phenotypes, and use a “reporter gene” to mimic the normal expression of the gene of interest in order to describe the function of these genes. This paper, High-throughput discovery of novel developmental phenotypes, is the first international, systematic effort to comprehensively characterize the functions of these genes in mice. This effort also includes 3D high-resolution imaging of embryos that are accessible on the IMPC portal. This imaging includes use of new and high level imaging that provides a level of detail not seen until now. For example, not much is currently known about disease associations with the gene Chtop. However, imaging of Chtop knockout embryos indicate abnormal eye development and neural tube defects, suggesting critical roles for this gene in normal eye and neural tube development. These results open a new line of research for scientists interested in studying development and diseases of the eye and nervous system. These new embryonic data add to the growing understanding of genetic mechanisms required for normal embryonic growth and development, while also providing insight into human developmental disorders and gene discovery for non-lethal conditions. As part of the full IMPC data, these data are contributing to this active and growing IMPC resource that will benefit the scientific community for years to come. Data are provided in real time to the entire research community, creating an “open access” environment allowing investigators to rapidly use the data to help their own research.
More information about the mice phenotyped through IMPC here.
In the news: Read a press release from the Jackson Laboratory about the study.
High-throughput discovery of novel developmental phenotypes. Dickinson ME, Ann M, Flenniken AM, Ji ,et al. Nature. 2016 Sep 22;537(7621):508-514. doi: 10.1038/nature19356. Epub 2016 Sep 14.
Reassessing Genetic Tests for Racial Bias
Some genetic tests may misdiagnose heart condition in African Americans
Using updated information from detailed genetic databases, researchers found that genetic differences originally thought to be causative in the heart condition hypertrophic cardiomyopathy were actually harmless. These benign differences were up to 150 times more common in African Americans than in Americans of European descent. This means that African Americans were more likely to be prescribed needless tests, screening, and possibly even treatments. Dr. Isaac Kohane, a study author and NIH Common Fund grantee, says that including racially and ethnically diverse populations in clinical trials and genetic sequencing efforts is vital to ensuring information extracted from those efforts is relevant to more people. In fact, the researchers found they could accurately predict whether a genetic difference was harmful or benign 80% of the time in a study of 200 participants when one-third of the participants were African American. The study has important implications for personalized medicine where treatment decisions need to be based on data that take into account a person’s race and ethnicity.
Dr. Kohane was supported by a Common Fund grant for the Informatics for Integrating Biology and the Bedside (i2b2) center, one of the National Centers for Biomedical Computing.
In the news: Read a press release from Harvard Medical School about the study.
Reference: Genetic Misdiagnoses and the Potential for Health Disparities. Arjun K. Manrai, Birgit H. Funke, Heidi L. Rehm, Morten S. Olesen, Bradley A. Maron, Peter Szolovits, David M. Margulies, Joseph Loscalzo, and Isaac S. Kohane. New England Journal of Medicine. 2016 Aug 18;375(7):655-65. doi: 10.1056/NEJMsa1507092.
Celebrity Endorsement of Unhealthy Food and Drinks
Marie Bragg, a 2015 Early Independence awardee, found music celebrities popular among adolescents tend to endorse unhealthy food and beverages. Bragg quantified the number and type of food or beverages endorsed by music celebrities and measured the nutritional value of the products. The popularity of the celebrities with adolescents was assessed using Teen Choice Award data. Seventy-one percent of endorsed non-alcoholic beverages were sugar-sweetened, and 81% of endorsed foods were nutrient poor. While the study does not examine how celebrity endorsement influences consumption, with the rise of obesity among teenagers, celebrity endorsement of unhealthy foods can send the wrong message to youth.
- Popular Music Celebrity Endorsements in Food and Nonalcoholic Beverage Marketing. Bragg MA, Miller AN, Elizee J, Dighe S, Elbel BD. Pediatrics. 2016 Jul;138(1). pii: e20153977. doi: 10.1542/peds.2015-3977. Epub 2016 Jun 6.
- In the News: This Is How Much Celebrities Get Paid To Endorse Soda And Unhealthy Food
- In the News: Eat and Drink Like a Music Celebrity?
- In the News: Most Celebrity-Endorsed Food and Drink Unhealthy
- In the News: Almost All Food, Beverage Products Marketed by Music Stars are Uhealthy
Epigenetic Imaging Shows Gene Activation in Living Brains for the First Time
Epigenomics grantee Dr. Jacob Hooker and collaborators have used a new neuroimaging tool to show, for the first time, where genes are being turned off or on in living human brains. Histone deacetylases (HDACs) are enzymes that regulate gene expression through epigenetic modifications and are therefore useful therapeutic targets. Using a specific HDAC imaging probe called Martinostat and positron emission tomography (PET) scanning, Dr. Hooker’s group has visualized HDAC expression in the living brain of eight healthy volunteers. In addition to observing distinct regions of HDAC expression within human brains regions, they also saw strikingly conserved regions of HDAC expression levels between these individuals. These conserved patterns within and between healthy individuals are significant because this lays the groundwork for understanding epigenetic information in the human central nervous system (CNS) and related diseases. “I’m hoping these colorful maps let us compare healthy brains with the brains of people with schizophrenia, Alzheimer’s, and other diseases,” said Hooker. The authors conclude that this work provides a “critical foundation for how to quantify epigenetic activity in the living brain and in turn accomplish HDAC inhibition in the CNS as a therapy for human brain disorders”.
In the news: In living color: New technique sees gene activity in human brains, STAT News. Also featured on PBS Newshour and Scientific American.
Reference: “Insights into neuroepigenetics through human histone deacetylase PET imaging.” Wey HY, Gilbert TM, Zürcher NR, She A, Bhanot A, Taillon BD, Schroeder FA, Wang C, Haggarty SJ, Hooker JM. Science Translational Medicine. 2016 Aug 10;8(351):351ra106. doi: 10.1126/scitranslmed.aaf7551.
New Study Reveals Elaborate X-inactivated Chromosome Structure
X-inactivation is the process by which one of the two X chromosomes present in female mammals is inactivated. This prevents them from having twice as many X chromosomes gene products as males, who only have a single X chromosome. A Barr body is the structure inside of the nucleus that consists of the inactive X chromosome. Although the Barr body appears to be a condensed blob under a microscope, a new study from 4D Nucleome grantee Job Dekker, Ph.D. and collaborators reveals a highly elaborate structure. Using a variety of methods, including chromosome conformation capture technologies and mouse models, they found that the inactive X chromosome is actually composed of two distinct lobes of inactive DNA. They also found that these lobes were separated by highly repetitive segments of DNA called “microsatellite repeats”. When these microsatellite repeats were removed, the bi-lobed chromosome structure vanished. In another finding of this study, a limited number of active genes in these lobes were separated by topologically associated domains (TADs), which are regions of the genome where DNA interactions frequently occur. This finding is significant because it suggests that TADs may organize gene expression in the inactive X chromosome, at least in neural progenitor cells.
“This is the most detailed molecular view we’ve been able to obtain of the DNA inside the Barr body,” said Dekker. “Under a microscope, the inactive X chromosome is very different than other chromosomes; it looks like a condensed, undefined, inactive ‘blob.’ Our study, using a range of experimental approaches including imaging and genomic methods, describes something else entirely: a highly organized and elaborate structure, rich in features that may silence or activate genes all along the chromosome.”
In the news: Read the press release from the University of Massachusetts Medical School here.
Reference: Structural organization of the inactive X chromosome in the mouse. Giorgetti L, Lajoie BR, Carter AC, Attia M, Zhan Y, Xu J, Chen CJ, Kaplan N, Chang HY, Heard E, Dekker J. Nature. 2016 Jul 28;535(7613):575-9. Epub 2016 Jul 18.
Finding the Needle in a Haystack: New Tool to Find Significant Results from Genome-Wide Association Data
Genome-wide association studies (GWAS) have the ability to reveal thousands of genetic variants associated with a particular disease or trait (cancer, height, etc.). While GWAS studies have become a powerful new tool for researchers, they also reveal thousands of potential variants of which many are not directly related to a condition but merely associated. Finding the genetic changes that drive a disease or trait can be difficult, especially when the variants are in non-coding regions of the genome. While non-coding regions of the genome do not directly express genes, they often regulate the expression of coding areas. Dr. Sabeti, New Innovator Awardee, and colleagues have devised a new tool that can directly identify which variants are affecting expression on a very large scale. The group was able to take an existing technology (published as a companion paper in the same issue of Cell) and scale it to examine more variants while also reducing noise and increasing the sensitivity of the test. This new resource should prove to be highly effective to many researchers who already have access to GWAS data but are having difficulty interpreting their results.
Broad Institute News: A massive approach to finding what's "real" in genome-wide association data
Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay. Tewhey R, Kotliar D, Park DS, Liu B, Winnicki S, Reilly SK, Andersen KG, Mikkelsen TS, Lander ES, Schaffner SF, and Sabeti PC. Cell. 2016 Jun 2;165(6):1519-29. doi: 10.1016/j.cell.2016.04.027.
Single Cell Analysis Reveals Neuronal Subtypes of the Human Brain
The human brain contains around a hundred billion neurons densely packed into three pounds of tissue. Neurons differ from one another in structure, function, and genetic landscape. Although this complex neuronal diversity is fundamental to human brain function, it is still not known how many different types of neurons there are in the brain. This lack of knowledge has impeded our understanding of how the brain functions in health and human disease. Toward understanding brain neuron diversity, Single Cell Analysis Program researcher Dr. Kun Zhang and collaborators examined the gene expression profiles of individual neurons, isolated from post mortem human brain tissue, using single cell RNA sequencing. 3227 sets of single-neuron data from six distinct regions of the cerebral cortex were generated and 16 neuronal subtypes were identified. The authors report that this robust and scalable method lays the “groundwork for high-throughput global human brain transcriptome mapping”. This approach could provide insight into brain function, and potentially disease mechanisms, through distinct profiles of gene expression signatures.
Reference: Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain. Lake BB1, Ai R2, Kaeser GE3, Salathia NS4, Yung YC5, Liu R1, Wildberg A2, Gao D1, Fung HL1, Chen S1, Vijayaraghavan R4, Wong J5, Chen A5, Sheng X5, Kaper F4, Shen R4, Ronaghi M4, Fan JB6, Wang W7, Chun J8, Zhang K9. Science. 2016 Jun 24;352(6293):1586-90. doi: 10.1126/science.aaf1204.
Read additional commentary in The Scientist: Single-Cell RNA Sequencing Reveals Neuronal Diversity.
Bursting onto the Transcription Scene
Transcription occurs when a particular segment of DNA is expressed into RNA. This process appears to take place in intermittent bursts and has been observed in organisms ranging from bacteria to humans. Transcriptional bursting is a term that describes this highly variable occurrence. Enhancers are short regions of DNA that can significantly increase the likelihood that a gene will be transcribed. There are hundreds of thousands of enhancers in the human genome, many of which precisely regulate patterns of gene expression that are required for the differentiation and growth of cells and tissues. To better understand the relationship between transcriptional bursts and enhancers, Dr. Michael Levine, a 4D Nucleome grantee, used quantitative analysis and live-imaging methods in Drosophila embryos in real time. Using this model organism, they report that enhancers regulate the frequency of transcriptional bursts and that strong enhancers produce more bursts than weak ones. They also report that shared enhancers can drive coordinated bursting of two different reporter genes, suggesting the importance of chromosome architecture in control of gene expression.
Reference: Enhancer Controls of Transcriptional Bursting. Fukaya T, Lim B, Levine M. Cell. 2016 Jul 14;166(2):358-68. doi: 10.1016/j.cell.2016.05.025. Epub 2016 Jun 9.
Understanding Chromosome Structure and Cancer
DNA is not randomly arranged in the nucleus. Instead, nuclear organization is tightly controlled. For example, insulated neighborhoods are loops of DNA that function to maintain normal expression of genes within and outside of the loop. Defects in nuclear organization and the folding of the human genome have been linked to cancer. In a new study, 4D Nucleome investigator Dr. Job Dekker, Ph.D., Howard Hughes Medical Institute Investigator, University of Massachusetts Medical School, and collaborators investigated the causal relationship between chromosome structure and oncogene activation. Oncogenes are genes that have the potential to cause cancer, when activated through dysregulation of gene expression. Using DNA sequences from tumors and targeted mutations in cancer cell lines, they show that disruption of insulated neighborhoods can activate oncogenes. This suggests that disruption of chromatin architecture is causally linked to the formation of tumors. This work represents a step toward understanding 3D chromosome structure and the authors conclude that “understanding these regulatory processes may provide new approaches to therapeutics that have on impact an aberrant chromosome structure.
Activation of proto-oncogenes by disruption of chromosome neighborhoods. Hnisz D, Weintraub AS, Day DS, Valton AL, Bak RO, Li CH, Goldmann J, Lajoie BR, Fan ZP, Sigova AA, Reddy J, Borges-Rivera D, Lee TI, Jaenisch R, Porteus MH, Dekker J, Young RA. Science. 2016 Mar 25;351(6280):1454-8. doi: 10.1126/science.aad9024. Epub 2016 Mar 3.
Noninvasive Therapeutic Agents for Brain Cancers Show Promise in Mouse Studies
Gaining access to the brain is a major obstacle for central nervous system drug development and delivery and non-invasive approaches are greatly needed. Research supported by the Extracellular RNA Communication Program is laying the foundation for the possibility of using extracellular RNAs (exRNAs) to treat brain cancers and other diseases. In this study, Dr. Zhang and colleagues use a mouse model to demonstrate the feasibility of treating brain-related diseases with intranasal delivery of RNA. They use a unique type of exosome-like nanoparticle, called a Grapefruit-derived Nanovector, to deliver an RNA of interest to the brain. These nanovectors can be generated from grapefruit plants in large quantities. Furthermore, Zhang et al. find that a specific RNA with potential therapeutic effects, miR17, can be effectively delivered to the brain using these grapefruit vectors without observable side effects in the mice. Remarkably, not only can the RNA be delivered to a target location effectively, it can also inhibit tumor growth in cell culture and in the mice. Although more work is needed to verify the mode of action and potential utility in humans, this study demonstrates the potential for an effective noninvasive therapeutic agent for the treatment of brain diseases.
Grapefruit-derived Nanovectors Delivering Therapeutic miR17 Through an Intranasal Route Inhibit Brain Tumor Progression. Zhuang, X., Y. Teng, A. Samykutty, J. Mu, Z. Deng, L. Zhang, P. Cao, Y. Rong, J. Yan, D. Miller and H. G. Zhang. Mol Ther. 2016 Feb;24(1):96-105. doi: 10.1038/mt.2015.188. Epub 2015 Oct 7.
Image courtesy of the University of Louisville
Developing an Auto-Focusing Contact Lens Modeled after Fish
Hongrui Jiang, a 2011 New Innovator, designed extremely small, super light-sensitive sensors inspired by the highly effective light-gathering retina of elephant nose fish. Inspired by the deep cup-like structures with reflective walls found in the elephant nose fish's retina, Jiang created a device that contains thousands of small light collectors with finger-like glass protrusions covered by reflective aluminum. Incoming light hits the fingers and is focused on the reflective walls, enhancing the image. The work is a step towards creating a contact lens that autofocuses within milliseconds that can be used to treat presbyopia, a stiffening of the eye's lens that makes it difficult to focus on close objects.
- Artificial Eye for Scotopic Vision with Bioinspired All-Optical Photosensitivity Enhancer. Liu H, Huang Y, Jiang H. PNAS. 2016 Mar 14;doi: 10.1073/pnas.1517953113.
- In the News: Fish and Insects Guide Design for Future Contact Lenses
- In the News: 'Fish-Eye' Contact Lens Auto-Focuses
FTAC-MM Assesses Microbiome Research in the US
The Human Microbiome Project not only served as a catalyst for microbiome research across the National Institutes of Health (NIH), it stimulated interest in the larger growing field of microbial ecology. In the spring of 2015, the Office of Science Technology and Policy (OSTP) chartered a committee of government scientists in 14 agencies to form the Fast Track Action Committee-Mapping the Microbiome (FTAC-MM). The FTAC-MM was charged with conducting a portfolio analysis of human-, animal- and habitat-associated intramural and extramural microbiome research support over fiscal years 2012-2014. The analysis focused on the use of genome-enabled approaches to study microbial communities. It also endeavored to classify the studies into basic or applied research or tools and resource development and categorized the research into eight microbial categories and eight environments.
The results of the FTAC-MM analysis were published in the inaugural issue of Nature Microbiology (January 2016) in a paper titled “An Assessment of US Microbiome Research” . The analysis showed that microbiome research received a high level of support ($922M) in fiscal years 2012 -2014 across multiple federal agencies, with NIH-supporting the bulk of the research at 59%. The majority of the research was in human subjects (37%) or animal models (29%) and focused on the gut microbiome.
Other habitats that were examined included everything from studies on oceanic microbiomes (National Science Foundation) to the microbiomes of pollinators (U.S. Department of Agriculture), to the microbiomes of soils from the arctic, tropics, wetlands and grasslands (multiple agencies). About 70% of all research included in the analysis focused on total microbial community studies, which verified that the analysis captured the appropriate research.
A number of needs for the future health and growth of the field were identified, including the need for references and standards for the field, microbiome databases linking data from multiple habitats, further development of methods to study the functional properties of the microbiome and the need to train students in microbial ecology, multidisciplinary research and hypothesis-driven study design. Both the report and paper concluded with the recognition that the diverse group of governmental agencies with different missions and different constituencies arrived at the same common needs for advancing the field.
An assessment of US microbiome research. Stulberg E, Fravel D, Proctor L, Murray D, LoTempio J, Chrisey L, Garland J, Goodwin K, Graber J, Harris MC, Jackson S, Mishkind M, Porterfield DM, Records A. Nature Microbiology. 2016 Jan 11;1:15015. doi: 10.1038/nmicrobiol.2015.15.
This page last reviewed on October 16, 2017