Highlights


EIGHT COMMON FUND SUPPORTED INVESTIGATORS HONORED BY ELECTION TO THE NATIONAL ACADEMY OF SCIENCES

Common Fund Supported Investigators Honored by Election to prestigious science academy

Common Fund Supported Investigators Honored by Election to prestigious science academy


Each year, the National Academy of Sciences elects new members in recognition of their distinguished and continuing achievements in original research. Becoming elected as a member of the Academy is regarded as one of the highest honors that a scientist can receive for their academic accomplishments. In 2013, the academy elected a total of 84 new members in conjunction with its 150th annual meeting. Of this select cohort, eight have received funds from the NIH Common Fund to pursue highly innovative biomedical research. Each of these eight senior investigators contributed valuable research with potential for accelerating human health. The newly elected members to the academy who were supported in part through the Common Fund are:

  • Barres, Ben A.; professor and chair, department of neurobiology, Stanford University School of Medicine, Stanford, Calif.

  • Boeke, Jef D.; professor of molecular biology and genetics, department of molecular biology and genetics, Johns Hopkins University School of Medicine, Baltimore

  • Quake, Stephen R.; investigator, Howard Hughes Medical Institute, professor, departments of bioengineering and of applied physics, Stanford University, Stanford, Calif.

  • Breaker, Ronald R.; investigator, Howard Hughes Medical Institute, and Henry Ford II Professor, department of molecular, cellular, and developmental biology, Yale University, New Haven, Conn.

  • Singer, Robert H.; co-director, Gruss Lipper Biophotonics Center, and professor and co-chair, department of anatomy and structural biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y.

  • Turrigiano, Gina; professor, department of biology, Brandeis University, Waltham, Mass.

  • Wagner, Gerhard; Elkan Rogers Blout Professor of Biological Chemistry and Molecular Pharmacology, department of biological chemistry and molecular pharmacology, Harvard Medical School, Boston

  • Willard, Huntington F.; Nanaline H. Duke Professor of Genome Sciences and director, Institute for Genome Sciences and Policy, Duke University, Durham, N.C.

Read more about all of the newly elected membersExit Disclaimer
 

Scientists Bioengineer Transplantable Kidney In Rats

SCIENTISTS BIOENGINEER TRANSPLANTABLE KIDNEY IN RATS

New Innovator Harald C. Ott and his colleagues at Massachusetts General Hospital (MGH) have developed a new method to bioengineer kidneys that could someday enable scientists to generate and transplant patient-specific bioengineered organs into patients. Kidneys play a critical role in the maintenance of homeostasis in the body by filtering waste and excess fluid from the blood. There are approximately one million patients in the U.S. with kidney failure, or end-stage renal disease (ESRD); the only possible cure is kidney transplantation. Currently, the waitlist for kidney transplants in the U.S. is more than three years long. Even with successful transplantation there is a high risk for transplant rejection or loss of transplant function over time.

The scientists from MGH were able to remove cells from cadaver kidneys, not normally suitable for transplantation, to create a cell-free kidney scaffold that maintained the protein structure and composition of normal functioning kidneys. Once the host cells were removed, the researchers used human umbilical vein cells and neonate mice kidney cells to repopulate the kidney. Following an incubation that mimics the human body environment, the researchers showed that the patient-specific kidneys had restored function and were able to reabsorb electrolytes and sugars, and produce urine both in the laboratory and in kidneys they transplanted into rats. These bioengineered kidneys could potentially address two major issues currently challenging kidney transplantations. First, they provide the initial steps towards developing kidneys in the lab that can be transplanted into patients, effectively reducing the wait time for critical ESRD patients. Second, developing the technology to repopulate bioengineered kidneys with patient-specific cells could result in a reduction in the risk of kidney rejection after transplantation. While these bioengineered kidneys still need to be developed further before they become a fully implantable treatment option in human patients, this new technology can be applied to other organs, and is leading the way toward organ bioengineering.


  • Watch Dr. Ott describe this work on the NatureVideoChannel here Exit Disclaimer

  • Read the MGH News Release hereExit Disclaimer

  • Read more about the NIH Director’s New Innovator Award Program here.


Reference:

Song JJ, Guyette JP, Gilpin SE, Gonzalez G, Vacanti JP, Ott HC. Regeneration and Experimental Ortotopic Transplantation of a Bioengineered Kidney. Nature Medicine, April 14, 2012. DOI: 10.1038/nm.3154.


 

Research enhances CLARITY of the brain in neurological disease

CLARITY: fully-assembled biology

A major challenge to researchers studying the brain has been the inability to study a fully intact brain, from both the global and microscopic perspectives. For example, researchers might want to examine the way a chemical interacts with brain cells, or neurons, both in the context individual neurons and of long neural circuits across the entire brain. Previously, researchers had to choose either to study a fully intact brain, which involves a lengthy sample preparation process and potential structural dissimilarities compared to the original organ, or to study small sections of the brain where one can examine fine molecular and cellular interactions without knowledge of the original complex structure of the neural circuit and structure of the intact brain. Dr. Karl Deisseroth, a 2012 Transformative Research Awardee from Stanford University and his colleagues, have combined tools from the fields of chemical engineering, computational optics, and molecular genetics to develop a new technology to solve this problem by transforming a fully intact mouse brain into a completely clear gel-based brain with all structural and molecular integrity intact. This new technology, named Clear Lipid-exchanged Anatomically Rigid Imaging/immunostaining-compatible Tissue hYdrogel (CLARITY) replaces lipids, or fats, which make the brain appear white outside of the body, and help form the structural basis for the brain, with a clear gel-like material that binds to cells, proteins, DNA, RNA, and other small molecules in the brain. The result is a completely clear brain with a gel-like consistency that maintains the same molecular and cellular relationships and structure as the original brain.

The new process, allows researchers to fluorescently tag small molecules and specific cell types to visualize individual molecular interactions as well as entire cellular networks in 3-D providing insight at both the molecular and whole system level which previously was not possible. CLARITY can be used by researchers to observe fine details of brains from animals and human patients with symptomatic neurological diseases without losing the larger-scale whole system perspective, potentially leading to new insights into diseases that affect the brain.



  • Read more about this exciting new technology and watch videos of mouse brains transformed using CLARITY in the NIH Press Release here

  • Read about this exciting new technology in the NIH Director’s Blog here

  • Read the New York Times Article here Exit Disclaimer


Reference:

Chung K, Wallace J, Kim S-Y, Kalyanasundaram S, Andalman AS, Davidson TJ, Mirzabekov JJ, Zalocusky KA, Mattis J, Denisin AK, Pak S, Bernstein H, Ramakrishnan C, Grosenick L, Gradinaru V, Deisseroth K. Structural and molecular interrogation of intact biological systems. Nature, April 10, 2012. DOI: 10.1038/Nature12107.


 
New findings lead scientists to a better understanding of an elusive microbe and oral health

New findings lead scientists to a better understanding of an elusive microbe and oral health

A team of scientists at the Oak Ridge National Laboratory (ORNL) funded by the NIH Common Fund Human Microbiome Project (HMP) have made new discoveries about a microbe that is important in human oral health. Using cutting-edge technology, the team was able to complete full sequencing of the genome from a single cell. The ability to isolate just a single bacterial cell and sequence the genome is an important component of examining the human microbiome because it allows for the study of species that cannot be cultured in the lab. The organism the examined is most closely related to sulfate reducers, which are normally found in salt marshes, sewer pipes, hot springs, and surprisingly the human mouth. Studies have shown that this type of bacteria is elevated in patients suffering from periodontitis, a disease marked by swelling and infection of areas that support our teeth. New findings presented in the current study show that this species uses a unique coding scheme that likely allows it to successfully compete in the complex oral microbial environment. The technology advancement and scientific findings reported in this study will increase our understanding of the role that our microbes play in oral health.

For more information, please read the press release from Oak Ridge National Laboratory here


Reference:

Campbell JH, O'Donoghue P, Campbell AG, Schwientek P, Sczyrba A, Woyke T, Söll D, Podar M. UGA is an additional glycine codon in uncultured SR1 bacteria from the human microbiota. Proc Natl Acad Sci USA 2013, Mar 18. PMID: 23509275.


 

Researchers define precise EEG Signature of Anesthesia-Induced Unconsciousness

Researchers define precise EEG Signature of Anesthesia-Induced Unconsciousness
More than 60,000 patients in the United States undergo general anesthesia for surgery every day. Currently, doctors use indirect measures of the brain state, such as heart rate and blood pressure, along with drug pharmacokinetics, pharmacodynamics and exhaled anesthetic gas typically are converted to a simple index score to indicate if a patient is adequately anesthetized during surgery. These indices are neither entirely reliable nor very informative. Inadequately administered anesthesia can result in intraoperative awareness and post-operative delirium. Drs. Emery N. Brown and Patrick L. Purdon, former NIH Director’s Pioneer Awardee and current NIH Director’s New Innovator Awardee, respectively, have studied brain activity during propofol-induced anesthesia using electroencephalogram (EEG) technology, which measures scalp electrical potentials, to better understand the mechanism of unconsciousness and to establish a direct method of tracking the transition between consciousness and unconsciousness during general anesthesia. In this study, the researchers gradually administered and reduced the anesthesia drug propofol in patients, while monitoring brain activity and behavioral loss of consciousness by asking patients to respond to auditory stimuli. This gradual induction and emergence from anesthesia allowed the researchers to precisely define an EEG brain signature, as well as behavioral markers that are associated with consciousness, unconsciousness, and the transition between these two states in patients undergoing propofol-induced general anesthesia. This research has provided a deeper understanding of the mechanism of propofol-induced loss of consciousness, and could be used to determine the EEG brain signatures of other anesthetics. Additionally, these results could be used to develop more direct and reliable methods for monitoring brain states of patients undergoing general anesthesia and could lead to new insights into the tailoring of drug dosage in real-time.

Reference:

P. L. Purdon et al., Electroencephalogram signatures of loss and recovery of consciousness from propofol. Proceedings of the National Academy of Sciences, (March 4, 2013, 2013).
 

New approach to attacking viruses: Researchers discover effective inhibitor to control herpesvirus infection and reactivation

New approach to attacking viruses: Researchers discover effective inhibitor to control herpesvirus infection and reactivation
Members of the herpesvirus family establish life-long dormant infections in people that can reactivate at any time to cause disease. Presently, there has been a focus on treatments that target the late stages of infection in those with herpes, particularly simplex virus (HSV) types 1 and 2, which cause oral and genital herpes. Furthermore, serious illness occurs when immune-compromised patients previously infected with another type of herepesvirus, human cytomegalovirus (CMV) suffer a reactivation. To date, drugs have been developed to target late stages of infection, with some success. In a new study, a probe developed from the NIH Chemical Genomics Center (NCGC), which is funded by the NIH Common Fund Molecular Libraries program, has been shown to be effective during lab studies at repressing early expression genes and therefore preventing infections from establishing. This molecule works by targeting human proteins to fight infections. Their studies also demonstrate that reactivation can be inhibited by the probe compound. Overall, there are implications for the prevention of infections as well as long-term treatment in infected patient to prevent reactivation episodes. This new area of research is beginning to show results for a number of viral diseases.

Read more about this research advance here.

Reference:

Liang Y, Vogel JL, Arbuckle JH, Rai G, Jadhav A, Simeonov A, Maloney DJ, Kristie TM. Targeting the JMJD2 Histone Demethylases to Epigenetically Control Herpesvirus Infection and Reactivation from Latency. Sci Transl Med. 2013 Jan 9. PMID: 23303604.
 

NIH Common Fund Awardees Selected for Breakthrough Prize in Life Sciences

NIH Common Fund Awardees Selected for Breakthrough Prize in Life Sciences
Three NIH Common Fund Awardees, Drs. Titia de Lange, Eric S. Lander, and Lewis C. Cantley, were selected as inaugural winners of the Breakthrough Prize administered by the Breakthrough Prize in Life Sciences Foundation. The Breakthrough Prize in Life Sciences Foundation is a non-profit corporation, founded by technology innovators, Sergey Brin and Anne Wojcicki, Mark Zuckerberg and Priscilla Chan, and Yuri Milner, developed with the goal of “advancing breakthrough research, celebrating scientists and generating excitement about the pursuit of science as a career.” Prizes are awarded based on past achievement, and in addition to the distinction of the being an awardee, winners receive three-million dollars to inspire more freedom and opportunity to pursue groundbreaking research.

Dr. Titia de Lange, a 2005 NIH Director’s Pioneer Award recipient, and Leon Hess Professor at the Rockefeller University, was selected for her trailblazing work on telomeres, illuminating how they protect chromosome ends and their role in genome instability in cancer. Drs. Lander and Cantley both received funds through the NIH Common Fund Molecular Libraries program. Dr. Lander, President and Founding Director of the Broad Institute of Harvard and MIT and Professor of Biology at MIT, was selected for the discovery of general principles for identifying human disease genes, and enabling their application to medicine. Dr. Cantley, Margaret and Herman Sokol Professor and Director of the Cancer Center at Weill Cornell Medical College and New York Presbyterian Hospital was awarded the prize for the discovery of PI 3-Kinase and its role in cancer metabolism.

Read more about NIH-funded scientists in the inaugural class of laureates on the NIH Director’s Blog here.

Read more about the Breakthrough Prize in Life Sciences Foundation, the Breakthrough Prize in Life Sciences Award, and the eleven inaugural awardees here. Exit Disclaimer

 

Self Assembling DNA Bricks

Self Assembling DNA Bricks
Dr Peng Yin and Dr. William Shih, both awardees of the Common Fund NIH Director’s New Innovator Award program, have described a new method to construct complex three dimensional structures by using short synthetic DNA strands which the investigators call “DNA bricks.” In this paper, the investigators used 32-nucleotide DNA strands which self-assembled into prescribed 3D structures without scaffolds. Each DNA brick can bind up to four local neighbors, and in a manner similar to Lego® bricks can be used to build complicated structures. This self assembly has allowed the investigators to create over 100 distinct structures which can be found here. Exit Disclaimer This method may have a large variety of applications such as to develop smart drug delivery particles or provide a better way for nano-scale fabrication of inorganic materials.

Reference:

Yonggang Ke, Luvena Ong, William Shih, Peng Yin Three-Dimensional Structures Self-Assembled from DNA Bricks, Science - 30 November 2012 (Vol 338, pp1177-1183) More information describing the self assembly process can be found in the two videos below:

Video 1 Exit Disclaimer Animated video containing narration which describes how 3D structures of DNA bricks are assembled.

Video 2 Exit DisclaimerAnimated video which depicts the nanofabrication technique called “DNA-brick self-assembly” using short synthetic strands of DNA that work like interlocking Lego® bricks.

Read more about New Innovators Awards...


 
Photo credit:
NIGMS Image Gallery β2-adrenergic receptor Photo credit: NIGMS Image Gallery

NIH Common Fund awardee wins Nobel Prize in Chemistry

Dr. Brian Kobilka, a grantee of the Common Fund Structural Biology program, has been awarded the Nobel Prize in Chemistry along with Dr. Robert Lefkowitz for their groundbreaking studies of G-protein coupled receptors (GPCRs). GPCRs are proteins located in cell membranes that transmit important information about the environment outside the cell, including light, smell, taste, hormone levels, and neurotransmitters. GPCRs mediate a wide range of medically-relevant biological processes, and are the target of almost half of pharmaceuticals on the market (see also “Why care about GPCRs?”). A major goal of the Structural Biology program is to determine the unique three-dimensional structure of membrane proteins such as GPCRs, in order to inform the design of therapeutics that specifically fit inside the target protein, thereby improving drug efficacy and reducing side effects.

Dr. Kobilka’s Common Fund-supported research helped develop new methods for producing and stabilizing GPCRs in large enough amounts to allow scientists to precisely determine their protein structures. Dr. Kobilka and colleagues at Stanford University pioneered the use of a novel approach to protein structure determination that involved fusing a small protein called T4 lysozyme, or T4L, into a part of GPCRs that is very flexible and therefore poses challenges to structure determination. He first used this technique in collaboration with Dr. Raymond Stevens and colleagues at The Scripps Research Institute to determine the structure of the β2-adrenergic receptor (β2AR), a protein critical in cardiac and pulmonary function. The T4L fusion strategy has proven to be broadly applicable in determining the structure of a number of biologically important GPCRs involved in a wide range of diseases, including many structures discovered by researchers in the Common Fund Structural Biology program (see http://commonfund.nih.gov/structuralbiology/ for examples).  Dr. Kobilka’s catalytic and transformative approach to protein structure determination is an excellent example of the nature of Common Fund supported research, which aims to accelerate biomedical research that is relevant for multiple diseases and conditions. In addition to support from the Common Fund Structural Biology program, Dr. Kobilka has also received support from the National Institute of General Medical Sciences, the National Institute of Neurological Disorders and Stroke, and the National Heart, Lung, and Blood Institute. Dr. Lefkowitz has received support from the National Heart, Lung, and Blood Institute as well.



 
NIH Common Fund researchers link genetic variants and gene regulation in many common diseases

NIH Common Fund researchers link genetic variants and gene regulation in many common diseases

Researchers supported by the NIH Common Fund have discovered that genetic differences linked to a wide variety of diseases influence how genes are turned on, or expressed. Many genetic differences, or variants, that are associated with disease do not fall within genes themselves, but are in stretches of DNA between genes, called non-coding DNA. For many years, scientists were unsure whether or not non-coding DNA served any purpose in the cell, or what the purpose could be. It is now known that these non-coding regions have important roles in regulating gene expression, but linking genetic variation in these regions with disease risk has been challenging. Dr. John Stamatoyannopolous M.D., and colleagues, funded in part by the Common Fund’s Epigenomics program, report that the majority of genetic variants linked to risk for a number of common diseases are located in non-coding DNA regions that regulate gene expression, providing new insight into how, when, and why many diseases occur. Their findings are published in the Sept. 5 online issue of the journal Science.

Dr. Stamatoyannopolous and colleagues found that some of the genetic variants linked to adult-onset diseases lie in regions of DNA that regulate genes during the early stages of development, providing a potential mechanism to explain the observation that some environmental exposures in utero or during early childhood are known to increase risk of diseases that produce symptoms years or even decades later. The researchers were also able to link genetic variants in non-coding regions with the genes they regulate, which has been a major challenge in genetic studies because the genes are often located a great distance away. In addition, researchers were able to pinpoint which cell types are affected by different diseases. These results provide new insight into disease mechanisms, and suggest novel targets for therapeutics development and disease prevention strategies.

Reference:

Humbert R, Maurano MT, Rynes E, Thurman RE, Haugen E, Wang H, et al. Systematic localization of common disease-associated variation in regulatory DNA. Science, 2012 Sept 5.

 
Slowing Cancer Cells: New Findings Increase Molecular Understanding of Tumor Growth

Slowing Cancer Cells: New Findings Increase Molecular Understanding of Tumor Growth

Cancer cells need more sugar than average mammalian cells so that they can replicate rapidly to form tumors. Pyruvate kinase, an enzyme that is fundamental for converting glucose to cellular building blocks and energy, has been long studied in an attempt to understand cancer cell metabolism. In a new advance for the cancer field, a team of researchers, funded in part by the NIH Common Fund’s Molecular Libraries and Imaging program, have characterized molecules that activate a specific form of the enzyme, pyruvate kinase m2 (PKM2). It has been known that cancer cells use PKM2 instead of PKM1 because its slower activity promotes the accumulation of glucose byproducts that can be used as building blocks for new cancer cells instead of for metabolic energy. The Molecular Libraries and Imaging program supported a collaboration between the laboratory of Dr. Matthew Vander Heiden of the Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology and the NIH Chemical Genomics Center (NCGC) screening center to identify molecules that selectively activate PKM2. In a newly published study, the research team tested the molecules in mice and illustrated that the addition of the compounds interfered with the ability of cancer cells to form tumors. They then determined the structure and properties of the molecules and showed that the molecules bind to a region of the enzyme different from that bound by the natural activator of PKM2. The novel binding mechanism is critical because it allows the molecules to resist natural inactivating proteins. Thus, discovery of this mechanism may facilitate the design of experimental cancer therapeutics that effectively activate PMK2. This research is still in its early stages, but Dr. Vander Heiden’s team and others now have insightful information that may ultimately prove valuable in the fight against several types of cancers.



 
Cell Volume 150, Issue 3 August 3, 2012

Cell Volume 150, Issue 3 August 3, 2012

Common Fund Researcher Studies the Genome Sequences of Diverse African Hunter-Gatherers

Dr. Sarah Tishkoff’s groundbreaking studies of human genetics landed her research on diverse African hunter- gatherers on the cover of Cell magazine. Dr. Tishkoff is a geneticist at the University of Pennsylvania and 2009 NIH Director’s Pioneer Award recipient. Dr. Tishkoff’s research team was able to sequence the whole genomes of five individuals in three different hunter-gatherer populations: Pygmies from Cameroon, Khoesan-speaking Hadza and Sandawe from Tanzania. They were also able to identify targets of natural selection that effect immunity, reproduction, metabolism and height in diverse hunter-gatherer populations. The research team believes continued studies will provide insight into human evolutionary history and the origin of traits that make each of us unique.

Reference:

Joseph Lachance, Benjamin Vernot, Clara C. Elbers, Bart Ferwerda, Alain Froment, Jean-Marie Bodo, Godfrey Lema, Wenqing Fu, Thomas B. Nyambo, Timothy R. Rebbeck, Kun Zhang, Joshua M. Akey, Sarah A. Tishkoff
Evolutionary History and Adaptation from High-Coverage Whole-Genome Sequences of Diverse African Hunter-Gatherers, Cell - 3 August 2012 (Vol. 150, Issue 3, pp. 457-469) PMID: 22840920



 
June 13, 2012 NIH Human Microbiome Project Completes Seminal Study of Microbial Diversity in Healthy Volunteers

NIH Human Microbiome Project Completes Seminal Study of Microbial Diversity in Healthy Volunteers

The NIH Common Fund’s Human Microbiome Project (HMP) has just published two seminal papers in the June 14, 2012 issue of Nature and a series of additional papers in several PLoS journals (click here Exit Disclaimer for more), the NIH announces on June 13, 2012. These milestone studies are centered on the project’s ambitious and unparalleled examination and analysis of the microbiomes of a healthy cohort consisting of over 240 individuals. The resources and resulting analysis shed light onto the intricate details of the complete healthy human microbiome and pave the way for future studies in the field. The diversity both within and among body sites highlights an important and complex association between humans and associated microbes.

A comprehensive community resource

One of the two Nature papers from the June 14 issue examined a population of 242 healthy adults, each of whom were sampled at 15 (male) to 18 (female) body sites, with each person sampled on one to three  distinct occasions. This unparalleled effort led to DNA sequencing of microbial eukaryotes, archaea, bacteria, and viruses (both mammalian and bacterial). Using standardized protocols and methods across the four sequencing centers, the consortium was able to generate 5,177 unique microbial taxonomic profiles (from 16S rRNA gene sequences) and over 3.5 Tbp of metagenomic sequence. Furthermore, their studies led to the assembly of hundreds of reference genomes Exit Disclaimer from the human microbiome. These efforts have led to an expansive generation of genomic data and also extensive data related to functional proteins and site-specific metabolism. The targeted approach of assembling data in a site-specific manner allowed the researchers to assemble less abundant organisms that were common across the cohort. In addition to the microbial analyses, healthy cohort subjects also submitted blood samples so that human genome analysis and cell-line development can be implemented in future studies. This foresight in the project’s planning unlocks an area of great potential for benefits to human health. Much of the data, other than protected health information, is publicly available via NCBI HMP project page and the HMP Data Analysis and Coordinating Center (DACC). Exit Disclaimer      

Extensive analysis of the healthy human microbiome

After establishing standards for data generation, the HMP consortium continued on to conduct a comprehensive analysis of the largest human cohort and set of distinct, clinically relevant body habitats to date (five major habitats). This is the first study to include metagenomic data (data that does not rely on culturing microbes) across body habitats from a cohort of this magnitude, in an attempt to describe the basics of overall host associated microbial life as well as the basics of microbial life for each host site examined. The research team found that there was strong site specialization both within and among subjects but that the diversity and abundance of each habitat’s signature microbes varied widely among the healthy subjects. Somewhat surprisingly based on the genetic sequence with large phylogenetic variations and general variation among the individual samples, there was remarkable functional stability. In essence, the authors illustrate that while the compositions vary widely the functionality is similar, meaning that there are many ways to construct microbial communities to perform similar functions.

Through this analysis, the consortium was also able to make general characterizations about the human microbiome. One finding was a limited, but commonly detectable, number of pathogens, leading to speculation that a low abundance of potentially harmful microbes might in some cases be beneficial to the host. Another interesting finding was patterns of alpha and beta diversity, where alpha diversity is defined as the diversity within a site and beta diversity is defined as that observed among subjects. For example, saliva was shown to have high alpha diversity (many different taxonomical units) but low beta diversity (very similar among the cohort). Human sites varied widely in alpha and beta diversity and future characterizations of the microbiome and its relation to human diseases will likely shed further light onto the importance of these variations in healthy and disease states.  

A major finding from the analysis of the healthy cohort was a number of well-validated correlations of taxa (groups of organisms) and function with host phenotypes. Some of the greatest correlations observed were between ethnicity and microbiome composition across all body habitats and a positive correlation of vaginal pH to microbial diversity (higher pH having higher diversity). Furthermore, there was an intriguing association of age with skin microbiome-associated metabolic pathways and oral microbiome composition, and a modest correlation between microbial composition and body mass index. Overall, many correlations were observed but as of now most of the data is not fully understood and requires future studies and examinations of additional factors including diet and host genetics.

A true team effort

The results presented in these papers highlight a remarkable level of collaboration among a large number of researchers. Interactions and collaborations among the two clinical centers and four sequencing centers were paramount for success. During the early stages of the program, data were being generated at an exponentially faster rate than analyses could be performed. To address these issues, the consortium formed the Data Analysis Working Group (DAWG), which consists of members from the genome centers and computational tools groups in addition to several experts not directly supported by the HMP. This was critical for the success of this large-scale and collaborative process. The partnerships and synergism from this teamwork will continue to fuel microbiome research.

The two landmark papers and the series of companion papers establish a foundation to catalyze and aid a myriad of studies ranging from basic to translational to clinical. For more information about the NIH Common Fund Human Microbiome Project please visit the Common Fund HMP and HMP Data Analysis and Coordinating Center (DACC) Exit Disclaimerwebsites.  



 
May 31, 2012 Researchers Discover Structure of Opioid Receptors

RESEARCHERS DISCOVER STRUCTURE OF OPIOID RECEPTORS

Opioid receptors are proteins found on the surface of cells in the nervous and digestive systems that bind opioid proteins, molecules that naturally occur in the body and play a role in regulating pain, pleasure, mood, addiction, and digestion.  An array of legal and illegal drugs such as morphine, codeine, and heroin also bind to these receptors and control their activity, but usually with unwanted side effects such as hallucinations and addiction, which limits their clinical use. The development of selective therapeutics that control the activity of opioid receptors without these side effects holds great promise as pain relievers, anti-depressants, and anti-anxiety treatments. The development of such agents could have a revolutionizing effect on the treatment of acute and chronic pain, several neuropsychiatric disorders, and addiction.

Dr. Raymond Stevens, partly funded by the NIH Common Fund’s Structural Biology program and the National Institute of General Medical Science’s Protein Structure Initiative, along with colleagues, has published the three-dimensional structures of two members of the human opioid receptor family- the kappa opioid receptor (KOR) and the nociceptin/orphanin FQ peptide receptor (NOP). As reported in the May 17, 2012 issue of Nature, these structures reveal unprecedented detail about the shape of these receptors, which may allow researchers to design drugs that can interact with these receptors in specific ways to elicit only the desired effects. KOR is the only receptor that binds the active ingredient in the plant Salvia divinorum (also known as “Salvia” or “Magic Mint”), which has recently gained popularity as a recreational drug of abuse causing hallucinations and psychedelic experiences (see the National Institute of Drug Abuse InfoFacts: Salvia). The part of the receptors where drugs and other molecules bind, called the binding pocket, is very large in both KOR and NOP. KOR and NOP differ in only a few specific places within the binding pocket, but these differences result in significant changes in the shape of the pocket, explaining why some molecules specifically bind to one receptor, but not the other. In the same issue of Nature, Dr. Brian Kobilka and colleagues published the structures of the mu and delta opioid receptors; collectively, these four papers reveal the structures of the entire family of human opioid receptors. Drs. Stevens and Kobilka used sophisticated techniques, developed in part through previous Common Fund support, to create the protein crystals needed to reveal the underlying protein structure. These studies provide a major clue in understanding the selectivity of opioid receptors, opening up new avenues of research into basic research about brain function and consciousness, as well as the development of clinically useful therapeutics.   


References:

Wu H, Wacker D, Katritch V, Mileni M, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC. Structure of the human kappa opioid receptor in complex with JDTic. Nature, 2012 Mar 21 (online publication date); 485(7398): 327-32. PMID: 22437504.

Thompson AA, Liu W, Chun E, Katritch V, Wu H, Vardy E, Huang X-P, Trapella C, Guerrini R, Calo G, Roth BL, Cherezov V, Stevens RC. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature, 2012 May 16; 485(7398):395-9. PMID: 22596163.

Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S. Crystal structure of the mu-opioid receptor bound to a morphinan antagonist. Nature, 2012 Mar 21 (online publication date); 485(7398): 321-6. PMID: 22437502.

Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS, Weis WI, Kobilka B. Structure of the delta-opioid receptor bound to naltrindole. Nature, 2012 May 16; 485(7398): 400-4. PMID: 22596164.

 

A highly adapted genome: Sequence of immune-regulating bacteria reveals why culturing attempts have been unsuccessful


A highly adapted genome: Sequence of immune-regulating bacteria reveals why culturing attempts have been unsuccessful A team of researchers, funded in part by the NIH Common Fund’s Human Microbiome Project, have sequenced and analyzed a class of unique bacteria that has eluded growth in the lab setting for over forty years. These segmented filamentous bacteria (SFB) are found in mice and other mammals and are known as the first commensal (non-pathogenic) bacteria identified that affect the host immune system. In the current study, researchers collected droppings from mice that were only colonized with SFB and used next generation sequencing platforms to obtain the sequence and construct the complete genome. They found that the genome was much smaller than closely related species and similar to other “minimal” bacteria that have been studied. This was due to a lack of many genes related to metabolism. It appears that much of the genetic material was lost because the bacteria rely on the host for a great deal of what they need to grow and survive. In fact, one of the few classes of genes in abundance are those related to transport of metabolites from the environment (host gut). These findings explain why is has been so difficult to grow these organisms outside of the host and highlights the close association of these bacteria with their host. This incredibly close association between host and microbe could be one reason as to why these bacteria help recruit immune cells that protect their host from pathogenic enteric bacteria. Although SFB have yet to be discovered in humans, the findings from this study will be an important resource for further examination of the role microbes play in host immune systems and overall metabolism.



Reference:
Sczesnak A, Segata N, Qin X, Gevers D, Petrosino JF, Huttenhower C, Littman DR, Ivanov II. The genome of th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. Cell Host Microbe. 2011 Sep 15;10(3):260-72. PMID 21925113.

 

A Forty Year Study: Self control behavior largely unchanged from childhood to adulthood

A Forty Year Study: Self control behavior largely unchanged from childhood to adulthood

Temptation and self-regulation are issues that everyone experiences. However, a new research study funded in part by the NIH Common Fund’s Science of Behavior Change Program has now examined, in detail, delayed gratification responses in a group of subjects over the course of four decades. In their current study, the researchers selected a group of subjects now in their mid forties who were previously tested for delay-of- gratification responses in preschool. Their main objective was to examine the neural basis of self-regulation. In the ~60 subjects tested, the researchers found that those who performed poorly as preschoolers also showed similar performance levels throughout their 20s, 30s, and now 40s. The researchers showed that these “low delaying” participants performed more poorly than high delayers when having to suppress a response to a happy face but not to neutral or fearful faces, suggesting that sensitivity to specific types of cues plays an important role in one’s ability to suppress actions. The results show that impulse control is difficult only when the tested cue is alluring to the subject, highlighting that the behavioral response is specific to compelling cues. The study then went on to examine a smaller subset of the participants using functional imaging, something that had not been conducted on any of the subjects previously. Examining both high and low delayers using alluring cues, the authors showed consistent differences in brain circuitry responses. The findings of this study show that the delay-of-gratification test serves as a good method for examining motivational and control processes, which appear to be stable from preschool through adulthood.


Reference:
Casey BJ, Somerville LH, Gotlib IH, Ayduk O, Franklin NT, Askren MK, Jonides J, Berman MG, Wilson NL, Teslovich T, Glover G, Zayas V, Mischel W, Shoda Y. Behavioral and neural correlates of delay of gratification 40 years later. Proc Natl Acad Sci U S A. 2011 Sep 6; 108(36): 14998-5003. PMID: 21876169.
 
February 16, 2012 S1P1 receptor with target molecule. Image courtesy of Raymond Stevens, The Scripps Research Institute

COMMON FUND RESEARCHERS UNCOVER STRUCTURE OF IMPORTANT TARGET FOR DRUG DESIGN

Researchers supported by the NIH Common Fund and the National Institute of General Medical Sciences teamed up to characterize an important G Protein-coupled receptor (GPCR). GPCRs are a class of membrane proteins involved in an array of physiological functions and human diseases, including multiple sclerosis. Importantly, these receptor proteins are the target of approximately 40% of all medications currently on the market. Using technology developed in part through support from the Common Fund’s Structural Biology Program, the research teams of Drs. Raymond Stevens and Hugh Rosen at The Scripps Research Institute teamed up to examine the GPCR sphingosine 1-phosphate 1 (S1P1) bound to different activators and inhibitors developed through the Common Fund’s Molecular Libraries and Imaging Program. S1P1 receptors play critical roles in controlling multiple sclerosis and other diseases, making the discovery useful for advancing treatment options. Advances made in this study allowed the researchers to identify how molecules bind in different ways to the receptor and better understand at a detailed level how access to the binding pocket is gained. These advances pave the way for more targeted drug design that will yield highly effective therapeutics with fewer side effects than current treatments. These findings were published in the February 17, 2012 issue of the journal Science.

References:

Hanson MA, Roth CB, Jo E, Griffith MT, Scott FL, Reinhart G, Desale H, Clemons B, Cahalan SM, Schuerer SC, Sanna MG, Han GW, Kuhn P, Rosen H, Stevens RC. Crystal structure of lipid G protein-coupled receptor. Science, 2012 Feb 17; 335(6070): 851-5. PMID: 22344443.

 
December 15, 2011New material holds promise for drug delivery, medical implants

BACK TO THE BASICS TO FIND A CURE FOR TUBERCULOSIS

It’s estimated that about one third of the world’s population is infected with Tuberculosis. Treatment of Tuberculosis usually involves a combination of antibiotic drugs that often leaves behind drug resistant strains. Dr. Sarah Fortune, an immunologist at the Harvard School of Public Health, and recipient of the NIH Director's New Innovator Award believes that the variation in the growth rate and size of mycobacterial cells (the causative agents of Tuberculosis) is a factor in how receptive the cells are to antibiotics.

Dr. Fortune and colleagues sought to measure the growth and antibiotic susceptibility of mycobacteria at the single cell level. The research team used live cell imaging techniques on fluorescently labeled Mycobacterium smegmatis (which is closely related to Mycobacterium tuberculosis) to observe the cells growing and replicating. The research resulted in the discovery that the Mycobacterium smegmatis cells divided asymmetrically causing diversity in the subpopulation of cells. Noticeably, the divided subpopulation of cells differed in size and growth rate. The physiological differences in the cells led the researchers to speculate about the cells susceptibility to antibiotics. Thus, the subpopulations of cells were treated with various antibiotics. Dr. Fortune and colleagues reported that from the heterogeneous subpopulation of cells some of the cells were inherently tolerant to the antibiotics and some were not. The researchers suggest that the variation of the subpopulation of cells could be an explanation as to why tuberculosis is difficult to cure. This research is a significant step towards understanding the properties and behavior of mycobacteria, which could improve Tuberculosis diagnosis, treatment, and prevention strategies.

References:

Aldridge BB, Fernandez-Suarez M, Heller D, Ambravaneswaran V, Irimia D, Toner M, Fortune SM. Asymmetry and Aging of Mycobacterial Cells Lead to Variable Growth and Antibiotic Susceptibility.Science, 2011.Dec15.PMID: 22174129

 
October 3, 2011New material holds promise for drug delivery, medical implants

New material holds promise for drug delivery, medical implants

Dr. Adah Almutairi, a 2009 NIH Director’s New Innovator awardee, and colleagues at the University of California San Diego, have developed a new type of “smart” polymeric material that may have widespread medical and biological applications. Reported in the journal Macromolecules, the new material disassembles in response to harmless levels of near infrared (NIR) irradiation, which can penetrate up to 10 centimeters (almost 4 inches) into the body. Both the material itself and its breakdown products are well-tolerated by living cells, suggesting this material would potentially be safe for use in humans. This type of material could be used as a capsule for a drug, allowing doctors to only release the drug in a specific area, such as right next to a tumor. It could also be used in tissue engineering, implants, wound-healing, and biosensors. Dr. Almutairi and colleagues are now working on improving the design of this polymeric material, so that it becomes even more sensitive to NIR, allowing a more controlled disassembly of the material. This research is a significant step forward in the development of light-sensitive materials that will allow doctors and researchers to target previously inaccessible sites with precise spatial and temporal control.

References:

Fomina N, McFearin CL, Sermsakdi M, Morachis JM, and Almutairi A. Low power, biologically benign NIR light triggers polymer disassembly. Macromolecules, 2011. 44: 8590-7. PMID: 22096258.

 
December 1, 2011Epigenomics researchers uncover new chemical modifications on DNA associated proteins

Four Human Microbiome Project (HMP) Investigators Honored by Election to the Institute of Medicine

Four Human Microbiome Project (HMP) Investigators Honored by Election to the Institute of Medicine
Each year, the full membership of the IOM elects up to 65 new members and five foreign associates. Election to the IOM is one of the highest honors bestowed upon professionals in the fields of health and medicine. To be elected, individuals must display outstanding professional achievement and commitment to service. Membership in the IOM reflects the pinnacle of professional achievement. On October 17, 2011 in conjunction with its 41st annual meeting, new members for the class of 2011 were announced. Among the 65 newly elected members are four investigators supported by the NIH Common Fund Human Microbiome Project (HMP).

  • Martin J. Blaser, M.D., Frederick H. King Professor of Internal Medicine, chair, department of medicine, and professor of microbiology, New York University School of Medicine, is funded by the HMP to examine and evaluate the cutaneous microbiome in psoriasis.
  • Claire M. Fraser-Liggett, Ph.D., director, Institute for Genome Sciences, and professor of medicine, microbiology, and immunology, University of Maryland School of Medicine, has received two awards to study aspects of the human microbiome. She is focusing on the role of the gut microbiota in obesity in the Amish and also analyzing the structure and function of the human gut microbiota in Crohn's disease.
  • Richard A. Gibbs, Ph.D., Wofford Cain Professor, department of molecular and human genetics, and director, Human Genome Sequencing Center, Baylor College of Medicine, is funded to develop a microbial genome reference platform for metagenomics.
  • David A. Relman, M.D., Thomas M. and Joan C. Merigan Professor, departments of medicine and microbiology and immunology, Stanford University School of Medicine, has been awarded a grant aimed at optimizing a microfluidic device for single bacterial cell genomics.

Read more about the IOM class of 2011Exit Disclaimer



 
Epigenomics researchers uncover new chemical modifications on DNA associated proteins November 8, 2011

Epigenomics researchers uncover new chemical modifications on DNA associated proteins

Epigenetic marks are chemical modifications to the genome that regulate which genes are active and which proteins are made in a cell. These marks are found on DNA as well as on the histone proteins that DNA is wrapped around. Epigenetic marks help regulate the expression of genes involved in cell development and function, and are also implicated in a growing number of diseases such as cancer, diabetes, autoimmune diseases, and mental illness (see “A Scientific Illustration of How Epigenetic Mechanisms Can Affect Health”). Drs. Yingming Zhao and Bing Ren, supported in part by the Common Fund’s Epigenomics program, along with their colleagues, have expanded our understanding of epigenetics by identifying a wealth of novel histone modification sites, as well as histone modifications that have never been described before. Using a combination of approaches in the most thorough examination of histones to date, the researchers identified 67 new histone modifications, increasing the number of known histone marks by about 70%. Some of these newly discovered histone marks correspond to types of chemical modifications that had already been described in other regions of histone proteins, but others represent an entirely new type of chemical modification of histones. One such novel modification, lysine crotonylation or Kcr, was found to label regions of the genome that are actively making proteins. In particular, Kcr modifications were found associated with genes that are activated in the testes of male mice at a specific time during development, suggesting that Kcr may regulate genes that are important for aspects of sperm cell maturation and function. The discovery of these new histone modifications expands our understanding of epigenomics, and opens the door to further research into the epigenome that regulates health and disease.


Reference:

Tan M, Luo H, Lee S, Jin F, Soo Yang J, Montellier E, Buchou T, Cheng Z, Rousseaux S, Rajagopal N, Lu Z, Ye Z, Zhu Q, Wysocka J, Ye Y, Khochbin S, Ren B, and Zhao Y. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell, September 16, 2011. 146: 1016-28. PMID: 21925322.


 
Hitting the Target: Molecule Hones in on Cancer Cells

Hitting the Target: Molecule Hones in on Cancer Cells

A major obstacle in the fight against cancer is finding treatments that target and kill only the cancerous cells without damaging healthy cells. Drs. Todd Golub and Stuart Schreiber, supported in part by the Common Fund’s Interdisciplinary Research Consortium for Genomic Based Drug Discovery, along with their colleagues, have discovered a molecule that can selectively kill cancer cells but does not harm normal cells. As reported in the July 14 issue of Nature, this cancer-fighting molecule is piperlongumine, a natural product derived from the plant Piper longum (long pepper). Piperlongumine inhibited tumor growth in mice that were injected with human bladder, breast, lung, or melanoma cancer cells, as well as in mice genetically engineered to develop breast cancer, and it did so more effectively than the chemotherapy drug Taxol (paclitaxel). In both cell cultures and in mice, piperlongumine had no detectable toxic effects on healthy cells, even at extremely high concentrations.

The researchers found that piperlongumine works by targeting a cellular process that differs between cancer cells and normal cells. Cancer cells have a much higher rate of metabolism than normal cells, and consequently they have increased levels of toxic reactive oxygen species (ROS). To tolerate high levels of ROS, cancer cells rely heavily on several different anti-oxidative enzymes that protect against these harmful molecules. Piperlongumine diminishes anti-oxidative enzyme activity, causing ROS levels in cancer cells to increase beyond the threshold for cell death. Normal cells, which have slower metabolic rates and lower levels of ROS, are not as dependent on these anti-oxidative enzymes and so are not harmed by piperlongumine. These exciting results demonstrate a novel strategy for the treatment of cancer by targeting a previously unexplored cellular pathway, and may pave the way for future development of effective cancer drugs with limited side effects.


References:

Raj L, Ide T, Gurkar AU, Foley M, Shenone M, Li X, Tolliday NJ, Golub TR, Carr SA, Shamji AF, Stern AM, Mandinova A, Schreiber SL, and Lee SW. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 2011; 475(7355):231-4. PMID: 21753854.


 
New Understanding of Dangerous Flu-Related Complication September 15, 2011

New Understanding of Dangerous Flu-Related Complication

The immune system is often thought of as an ally in the fight against invading pathogens that make us sick. But in the attempt to destroy pathogens, sometimes the immune system’s response can be more harmful than the invaders it is trying to defend against. In the 1918 Spanish flu pandemic and the recent avian and swine flu outbreaks, scientists have proposed that an excessive immune reaction flooded patients’ lungs with fluid and disease-fighting cells, contributing to the abnormally high fatality rate. This severe immune reaction involves the production of large amounts of proteins called cytokines, and hence is often called a “cytokine storm.” Because cytokine storm can be deadly, medical interventions aimed at blunting this response are extremely desirable.

Recent work by Dr. Hugh Rosen, a researcher in the Common Fund’s Molecular Libraries and Imaging program, has led to a breakthrough in our understanding of the biological processes underlying cytokine storm. In a study published in the September 16, 2011 issue of Cell, Dr. Rosen and colleagues identify a small molecule compound that blocks cytokine storm and improves survival in mice infected with a strain of influenza virus that is normally fatal. This compound interacts with a protein called S1P1, a receptor on the surface of cells that binds to specific molecules and elicits a cellular response. When the researchers treated influenza-infected mice with the compound, they discovered that the cytokine storm response was diminished and survival was improved. Intriguingly, the researchers also discovered that the cells coordinating cytokine storm were not immune cells or cells from the inner surface of the lungs, as was previously thought. Instead, the cytokine storm was mediated by endothelial cells, which line the inside of blood vessels. These new insights about the role of endothelial cells and the S1P1 protein in the development of the cytokine storm response may help scientists predict which patients are most at risk for this potentially deadly complication, and also suggests potential new therapeutic targets for drug development efforts.


References:

Teijaro JR, Walsh KB, Cahalan S, Fremgen DM, Roberts E, Scott F, Martinborough E, Peach R, Oldstone MBA, and Rosen H. Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell, September 16, 2011. 146(6):980-991. PMID: 21925319

Iwasaki A and Medzhitov R. A new shield for a cytokine storm. Cell, September 16, 2011. 156(6): 861-2. PMID: 21925310.


 
Stem Cell August 19, 2011

Novel stem cell technique creates neurons

Drs. Kang Zhang and Sheng Ding, funded in part by the NIH Director’s Transformative R01 (T-R01) Award program, have unlocked the key to transforming human embryonic stem cells (hESCs) into a type of precursor cell that can be produced in large quantities and has the potential to become many different types of brain cells. Their findings, published in the May 17, 2011 issue of Proceedings of the National Academy of Sciences, represent a huge leap forward in stem cell science. hESCs, with their ability to become any cell type in the human body, hold great potential for repairing or replacing damaged tissues. However, a number of obstacles have prevented hESCs from fulfilling this promise. Scientists have faced challenges finding the right method to change hESCs into more specialized precursor cells, which can self-renew to produce large quantities of cells while also retaining the ability to become many different cell types within a specific tissue. Additionally, hESCs can cause the formation of tumors, which prohibits their use for therapeutic purposes. Drs. Zhang, Ding, and colleagues used a novel combination of small molecules to induce hESCs to become primitive neuronal stem cells (pNSCs), a cell type that can be directed to make many different types of neurons, or brain cells. Unlike hESCs, pNSCs did not induce tumor formation when injected into mice, which opens the door for potential therapeutic use. The researchers coaxed the pNSCs to form the types of neurons damaged by Parkinson’s disease and Lou Gehrig’s disease (amyotrophic lateral sclerosis; ALS), and suggest that pNSCs could be used to make many other types of neurons as well. This same method could be modified to direct hESCs to make other types of stem cells that could then be used to make heart, pancreas, or other tissue types.  Future studies will need to examine how these cells could be used to treat a variety of human diseases.



Reference:

Li W, Sun W, Zhang Y, Wei W, Ambasudhan R, Xia P, Talantova M, Lin T, Kim J, Wang X, Kim WR, Lipton SA, Zhag K, and Ding S. Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecules inhibitors. Proceedings of the National Academy of Sciences, 2011 May 17; 108(20): 8299-8304. PMID: 21525408.


 
Brain stem cell environment July 13, 2011

Location, location, location: Scientists uncover new information about brain stem cell environment

The adult mammalian brain contains several specialized areas where stem cells capable of producing new neurons reside. Dr. Chay Kuo, an NIH Director’s New Innovator Award recipient, has identified key components of one such specialized area, or niche, that is critical for the production of new neurons. Published in the July 14, 2011 issue of Neuron, Dr. Kuo and colleagues demonstrate that two proteins, Foxj1 and Ank3, are critical for maintaining the cellular niche around brain stem cells.

Foxj1 is a transcription factor, a type of protein that regulates when and where other genes are expressed. Within the stem cell niche studied by Dr. Kuo, the Foxj1 protein causes the Ank3 protein to be expressed. The Ank3 protein then helps assemble groups of ependymal cells, a type of cell that surrounds the brain stem cells and provides support for the production of new neurons. Without Foxj1 and Ank3 proteins, the niche is disrupted and stem cells fail to produce new neurons.

Currently, when neural stem cells are studied in the laboratory, they are not surrounded by these ependymal cells. Under these conditions, it is extremely difficult to make the stem cells produce neurons. The findings of Dr. Kuo and colleagues suggests that in the laboratory setting, scientists may need to recreate the same kind of support provided by ependymal cells in the brain stem cell niche. By understanding the local cellular environment that helps support production of new neurons, researchers hope to improve future therapeutic strategies that use stem cells to produce neurons for repairing or replacing damaged tissue.

References:

Paez-Gonzalez P, Abdi K, Luciano D, Liu Y, Soriano-Navarro M, Rawlins E, Bennett V, Garcia-Verdugo JM, and Kuo CT. Ank3-dependent SVZ niche assembly is required for the continued production of new neurons. Neuron, July 14, 2011. 71: 61-75. PMID: 21745638.


 
Autoimmune Diseases

Overcoming Obstacles to Analyzing Complex Biological Data

Biomedical research data generated from genomics analyses, imaging, biochemistry and other assays are abundant yet difficult to integrate using conventional approaches and databases. To address this need, Dr. Peter Sorger and colleagues at Harvard Medical School, Massachusetts Institute of Technology, and the University of Applied Sciences in Germany, researchers supported through the Common Fund’s Library of Integrated Network Based Cellular Signatures (LINCS) program, have developed an innovative new adaptable method that allows different types of complex data sets to be stored, analyzed and extended. In a recent paper in Nature Methods, they demonstrate the utility of the approach, which exploits useful aspects of two data file formats (HDF5 and XML), for analyzing a complex imaging data set reflecting 160 experimental conditions in over a million different single cells. The approach led to the discovery of new pharmacological relationships between compounds that bind and inhibit epidermal growth factor receptors (EGFR), providing insights into cell-to-cell variability in response to drugs.


References:

Millard BL, Niepel M, Menden MP, Muhlich JL, and Sorger PK. Adaptive informatics for multifactorial and high-content biological data. Nat Methods. 2011. Vol 8(6):487-493.


 
Autoimmune Diseases April 28, 2011

New Compound Targets Autoimmune Diseases

Researchers supported by the Molecular Libraries and Imaging program have helped to develop a novel chemical that blocks TH17 cells, immune cells implicated in numerous autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Dr. Patrick Griffin and colleagues from the Scripps Research Institute Molecular Screening Center published a study in the April 28, 2011 issue of Nature describing SR1001, a new compound that blocks the development of TH17 cells and slows disease progression in a mouse model of multiple sclerosis. TH17 cells are part of the body’s natural defense against disease-producing pathogens. However, in some autoimmune disorders, the inflammatory chemicals, or cytokines, produced by TH17 cells harm the body’s own tissues. SR1001 blocks TH17 cells by interfering with the action of two proteins critical for TH17 cell development, called RORα and RORγt. When SR1001 blocks the action of RORα and RORγt in the precursors to TH17 cells, these cells can no longer develop into TH17 cells and do not produce the cytokines normally produced by functioning TH17 cells. Treatment with SR1001 delays disease onset and reduces the severity of symptoms in a mouse model of multiple sclerosis, a well-studied model for TH17-mediated autoimmune disease. These results suggest an exciting new way to target several different autoimmune disorders in which TH17 cells play a role.


References:

Solt LA, Kumar N, Nuhant P, Wang Y, Lauer JL, Liu J, Istrate MA, Kamenecka TM, Roush WR, Vidovic D, Schurer SC, Xu J, Wagoner G, Drew PD, Griffin PR, and Burris TP. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature, April 28, 2011. 472: 491-494. PMID: 21499262. Jetten AM. Immunology: A helping hand against autoimmunity. Nature, April 28, 2011. 472: 421-422. PMID: 21525918


 
Molecules March 14, 2011

Fueling Structure-based Drug Discovery

Researchers in the Common Fund’s Structural Biology program are changing the way companies are thinking about designing new drugs -- by using 3-D images of membrane proteins in cells to help identify and screen potential drug molecules. Membrane proteins span the membrane of cells and provide a pathway for signals outside the cell to be transmitted inside. G-protein-coupled receptors (GPCRs) are an important class of membrane proteins involved in many different biological pathways that are essential to health and response to therapeutics. Although almost 40% of all drugs on the market target GPCR signaling pathways, drug discovery remains slow and arduous because membrane proteins are very difficult to isolate, stabilize, and characterize structurally. Understanding the 3-D structure of a membrane protein can accelerate the discovery process because it shows all the “pockets” of the protein where molecules or drugs can bind and change how the protein signals to the inside of the cell. The structures can be used to test how a specific GPCR changes when it is bound by different molecules that may turn “on” or “off” the receptor. While pharmaceutical companies are eager to get hold of 3-D crystal structures for GPRCs for use in drug discovery, they often find it difficult. A new trend reported in Chemical and Engineering News (March 14, 2011) shows drug companies are teaming up with academic researchers who have worked out these 3-D structures to overcome this problem.

Dr. Raymond Stevens and colleagues at the Scripps Research Institute, funded through the Structural Biology Program, have perfected a technique to stabilize and characterize the 3-D crystal structure of several GPCRs, including most recently, the A2A adenosine (A2A) receptor involved in control of inflammation and oxygen and blood flow through the heart. As reported in Sciencexpress (March 2011), the team developed an approach to stabilize the A2A receptor and then determine its 3-D crystal structure while a small “activator” molecule was bound to it. The structure provides a view into how GPCRs become activated when bound by a specific small molecule. Having this 3-D structure for the A2A receptor enables drug companies to prioritize which small molecules to test first, for similar activity, during drug discovery. A company co-founded by Dr. Stevens adopted this technique and used it to successfully determine the structure of another GPCR, sphingosine-1-phosphate receptor subtype 1 (S1P1), involved in multiple sclerosis, a degenerative disease of the nervous system. Recently, they identified a small molecule derived from a chemical “hit” discovered through the Common Fund’s Molecular Libraries and Imaging Program which effectively binds to and activates S1P1. The molecule is being tested further as a potential new therapy for multiple sclerosis. The synergy between the two programs, Structural Biology and Molecular Libraries and Imaging, represents a growing trend in partnerships between academic and private sector researchers to tackle difficult problems in drug discovery.


 
DNA March 10, 2011

Mouse Genetics Leads to New Clues for Human Psychiatric Disorders

Several psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), drug and alcohol addiction, and schizophrenia, are characterized by poor impulse control and difficulty inhibiting certain behaviors. These traits are referred to as behavioral inflexibility, which is thought to be partially under genetic control. However, the genes responsible have been difficult to identify in humans. In a paper available online March 10, 2011 in the journal Biological Psychiatry, researchers in the Common Fund’s Interdisciplinary Research program’s Consortium for Neuropsychiatric Phenomics report that they have identified several genes associated with behavioral inflexibility in mice, and that these findings might be applicable to humans as well. To identify genes that underlie behavioral inflexibility, Dr. David Jentsch and colleagues from the University of California Los Angeles and the University of Tennessee first tested 51 genetically different strains of mice for the ability to reverse their behavior in a learned task. To successfully complete this task, mice had to learn to poke their nose into an opening either on the left or right side of the cage in order to receive a food reward. Once the mice mastered this skill, they had to unlearn which side to poke their nose into, and re-learn to poke their nose on the opposite side. The number of tries it takes a mouse to reverse its behavior indicates how much behavioral flexibility and impulse control the mouse has. The researchers reasoned that by looking at both the genes and behaviors of the mice, they could find genetic differences that were associated with the behavioral differences. Indeed, the researchers zeroed in on a region of the mouse chromosome 10 that contains several genes that influence behavioral flexibility. One gene, Syn3, regulates chemical communication in the brain and has been inconclusively linked to schizophrenia in humans. Another gene, Nt5dc3, is a gene of unknown function that has been associated with ADHD. The current research suggests that both of these genes should be investigated further to discover what role they may play in human psychiatric disorders, and also demonstrates a new way to use mouse behavior and genetics to find genes that may contribute to complex behaviors in humans.

Reference:

Laughlin RE, Grant TL, Williams RW, Jentsch JD. Genetic dissectioin of behavioral flexibility: reversal learning in mice. Biological Psychiatry, 2011 June 1; 69(11): 1109-16. Epub 2011 March 9. PMID: 21392734.


 
Drug TherapiesMarch 3, 2011

Scientists Uncover How Tuberculosis “Pumps-Up” Tolerance To Drug Therapies

Shortening the time required to treat tuberculosis (TB) is key to reducing the development of drug resistance and lowering worldwide rates of TB infection and mortality. Reducing treatment duration however depends on: (1) understanding how Mycobacterium tuberculosis (Mtb), the bacteria that causes TB in humans, becomes tolerant to antibiotics; and (2) devising ways to prevent or overcome drug tolerance. NIH Director’s Pioneer Award recipient Dr. Lalita Ramakrishnan and colleagues at the University of Washington, in collaboration with Dr. Paul Edelstein at the University of Pennsylvania, report in a study appearing in the April 1, 2011 issue of Cell, that the development of drug tolerance in Mtb is due in part to the activity of “efflux” pumps in the cell membrane that presumably flush away any antibiotic agents that penetrate the Mtb cells. The authors found that these pumps are stoked into action by host cells called macrophages that are, ironically, part of the body’s frontline defenses against foreign invaders. Based on these findings, the study authors suggest that expanding treatment to include medications that inhibit these pumps could dramatically shorten the time needed to cure infection. While Mtb can infect many body tissues and organs, it primarily attacks the lungs. Once inside the lungs, the bacteria infect the aforementioned macrophages. The macrophages and other types of immune cells respond by aggregating into structures called granulomas which are thought to contain the spread of persistent pathogens. Having taken up residence within macrophages, some populations of Mtb cells quickly become tolerant to anti-TB drugs. Nearly all models of Mtb drug tolerance postulate that this temporary resistance to antibiotics arises when the bacterial cells enter a dormant state in which they stop replicating. Because most antibiotics are only effective against bacterial cells that are reproducing, dormant cells are effectively resistant to antimicrobial agents. In their latest paper however, Dr. Ramakrishnan and colleagues report finding multi-drug tolerant Mtb populations that were actively growing and reproducing inside of host macrophages suggesting that residence within macrophages rapidly induces tolerance. The study authors also found that, having infected macrophages, the Mtb cells deploy effNovel Blood ux pumps that are essential for the Mtb cells to grow within the macrophages and may be used by the bacterial cells to remove toxic substances such as antimicrobial agents. In addition to expanding our understanding of the pathogenesis of TB and drug tolerance, these findings suggest that inhibiting the activity of macrophage-induced bacterial efflux pumps using currently available drugs such as verapamil may be an effective means of reducing the duration of TB treatment. Shorter treatment is likely to translate into increased adherence which will in turn slow the development of multi-drug resistance, reduce transmission of infection to new hosts, and reduce TB-associated mortality around the world.

Reference:

Adams KN, Takaki K, Connolly LE, Wiedenhoft H, Winglee K, Humbert O, Edelstein PH, Cosma CL, Ramakrishnan L. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell, 2011 April 1; 145(1): 39-53. PMID: 21376383.


 
EmbryonicFebruary 3, 2011

Embryonic And Induced-Pluripotent Stem Cells Reveal Own Molecular Signature

New discoveries in stem cell biology are fueling the development of new cell-based therapies for diseases such as Parkinson’s and diabetes where tissues may become diseased or damaged. Before this potential can be reached, an important, yet unanswered question is whether adult cells that are “induced” to become like embryonic stem cells – so called induced pluripotent stem cells (iPS cells) -- are actually equivalent to embryonic stem cells and can be used in cell-based therapies. Researchers in the Common Fund’s Epigenomics program are tackling this question. In the February 3, 2011 issue of Nature, Dr. Joseph Ecker and colleagues at the Salk Institute investigated this question by comparing the pattern or “fingerprint” of DNA modifications made by the attachment of a methyl group to a specific DNA base across the genome in iPS cells, human embryonic stem cells, and iPSCs that are coaxed to “return to adulthood.” They found that pattern of DNA methylation for iPS cells is different from true human embryonic stem cells, especially in the middle and ends of the chromosome. At other locations along the genome, the DNA methylation pattern in the iPS cells was similar to that of the adult cells and was retained when the iPS cells were converted back to their “adult” state. Because DNA methylation helps to control gene activity in a cell, the differences in methylation pattern across cell types signal that iPS cells may have a unique molecular “identity” compared to embryonic stem cells. Understanding these differences between iPS and embryonic stem cells is an important step toward harnessing the potential of iPS cells to treat injury and disease.

Reference:

Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O’Malley R, Castanon R, Klugman S, Downes M, Yu M, Stewart R, Ren B, Thomson JA, Evans RM, and Ecker JR. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature. Mar 2011. 471:68–73. PMID: 21289626



 
Novel Blood TestJanuary 27, 2011

From The Lab To The Clinic: Discovery From Molecular Libraries Program Enters Clinical Trials

Researchers in the Common Fund’s Molecular Libraries and Imaging program are tackling a tough biological problem—finding potential drug candidates that target G protein-coupled receptors (GPCRs). Dr. Hugh Rosen, funded in part by the Molecular Libraries and Imaging program, is a scientific founder of Receptos, Inc., a GPCR drug discovery and development company. GPCRs are proteins found on the cell membrane that transmit signals from the outside of the cell to elicit responses inside the cell. GCPRs play many important roles in the body, including hormone signaling, cellular communication in the brain, vision, and cardiac function. Because GPCRs are crucial to many biological processes, they are also implicated in a number of different diseases. One such GPCR, called sphingosine-1-phosphate receptor 1 (S1P1), plays a role in multiple sclerosis, an inflammatory and autoimmune disease which causes damage to the protective myelin sheaths of nerve cells and to the underlying nerve fibers. The current focus of Receptos, Inc. is to conduct clinical trials for a novel compound that targets S1P1, called RPC1063, in the hopes that this potential treatment will suppress circulating immune cells to blunt the underlying cause of multiple sclerosis. The discovery of this novel compound originated from the Molecular Libraries and Imaging program. The first phase 1 clinical safety study of RPC1063 was launched in January 2011, and Phase 2 Proof of Concept studies are expected in 2012. This research has the potential to improve the treatment of multiple sclerosis, and many other diseases that involve signaling by GPCRs.

Reference:

Reddy MM, Wilson R, Wilson J, Connell S, Gocke A, Hynan L, German D, Kodadek T. Identification of candidate IgG biomarkers for Alzheimer’s disease via combinatorial library screening. Cell, 2011 Jan 7; 144(1): 132-42. PMID: 21215375.




 
Novel Blood TestJanuary 7, 2011

Novel Blood Test May Improve Diagnosis of Many Diseases

While simple blood tests can accurately and efficiently screen for some diseases, such as diabetes, the lack of blood tests for the majority of diseases can result in delayed or incorrect diagnoses. To overcome this diagnostic obstacle, Dr. Thomas Kodadek, a researcher at The Scripps Research Institute and funded in part by an NIH Director’s Pioneer Award, has developed a novel screening method that could detect disease-associated proteins in the blood of patients with a variety of conditions. In the January 7, 2011 edition of the journal Cell, Dr. Kodadek and colleagues describe their technique for using a collection of synthetic molecules to detect the presence of unique proteins in the blood of diseased individuals that do not appear in the blood of healthy individuals. By screening blood samples from mice with multiple sclerosis, the researchers identified several molecules in their synthetic collection that would only bind to proteins in the blood of the diseased mice, and could distinguish between “patient” mice and normal, healthy mice. Importantly, the researchers went on to demonstrate that in samples from humans, they could use the same technique to identify different molecules that bound to proteins uniquely present in the blood of patients with Alzheimer’s disease. This same binding did not occur in samples from healthy people of similar ages or in patients with another neurodegenerative disorder, Parkinson’s disease. These promising results suggest that this type of blood test has the potential to screen for a wide variety of different diseases, including diseases that currently lack a reliable diagnostic test.

Reference:

Reddy MM, Wilson R, Wilson J, Connell S, Gocke A, Hynan L, German D, Kodadek T. Identification of candidate IgG biomarkers for Alzheimer’s disease via combinatorial library screening. Cell, 2011 Jan 7; 144(1): 132-42. PMID: 21215375.




 

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