Colleagues: Recently Tenured

KAPIL BHARTI, PH.D., NEI

Senior Investigator, Unit on Ocular and Stem Cell Translational Research, National Eye Institute

Education: Panjab University, Chandigarh, India (B.Sc. in biophysics); Maharaja Sayaji Rao University, Baroda, India (M.Sc. in biotechnology); Johann Wolfgang Goethe University, Frankfurt, Germany (Ph.D. in molecular cell biology)

Training: Research fellow, National Institute of Neurological Disorders and Stroke (NINDS)

Came to NIH: In 2004 for training; became staff scientist in NINDS in 2009; became Earl Stadtman Investigator in 2012

Selected professional activities: Scientific advisory board member for nonprofit patient-advocacy organizations: The Regenerative Outcomes Foundation (Nashville, Tennessee) and Choroideremia Research Foundation, (Springfield, Massachusetts)

Outside interests: Hiking; running

Website: https://irp.nih.gov/pi/kapil-bharti

Research interests: My lab is using induced pluripotent stem-cell (iPSC) technology to perform translational research on degenerative eye diseases. We are using this technology to develop in vitro disease models to study patient-specific disease processes, set up high-throughput drug screens, and develop cell-based therapy for retinal degenerative diseases.

In particular, we are focused on the retinal pigment epithelium (RPE), a monolayer of highly polarized cells located in the back of the eye adjacent to retinal photoreceptors. The RPE performs several functions that are critical for the health and integrity of photoreceptors—regulating nutrient and metabolite flow, maintaining ionic homeostasis in the subretinal space, regenerating visual pigment, and phagocytizing shed photoreceptor outer segments. Dysfunctions in the RPE are thought to be the initiating events that lead to degenerative eye diseases. Therefore, a better understanding of the disease-initiating pathways in RPE will provide a basis for therapeutic interventions.

By culturing iPSC-derived RPE cells on biodegradable scaffolds, we are able to develop functional RPE tissue. We have modified the existing stem-cell-to-RPE-differentiation protocols to make them more compliant with current Good Manufacturing Practices. We are collaborating with the NIH Clinical Center’s Department of Transfusion Medicine to develop iPSC-derived RPE tissue for cell-based therapy. Later this year, we plan to launch a clinical trial that uses this autologous iPS-cell-derived RPE tissue to treat patients with retinal degenerative diseases.

In collaboration with the NEI clinic, we are obtaining blood samples from patients who have clinically diagnosed degenerative eye diseases. These samples are being used to derive iPSCs. RPE cells differentiated from such iPSCs are used to study events that have led to disease initiation and progression. In collaboration with the National Center for Advancing Translational Sciences, we are combining a patient-specific iPSC approach with high-throughput screening assays to identify novel compounds that could act as potential therapeutic agents. Our work uses the most cutting-edge technologies in the field and aims to translate these technologies to a clinical use.

ASHISH LAL, PH.D., NCI-CCR

Senior Investigator and Head, Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute

Education: Banaras Hindu University, Varanasi, India (B.S. in chemistry; M.S. in biochemistry; Ph.D. in biotechnology)

Training: Research Associate, Center for Cellular and Molecular Biology (Hyderabad, India); postdoctoral fellow, Laboratory of Cellular and Molecular Biology, National Institute on Aging; instructor of pediatrics, Immune Disease Institute, Harvard Medical School (Boston)

Came to NIH: From 2003 to 2007 for training; returned in 2010 as tenure-track investigator and head, Regulatory RNAs and Cancer Section, Genetics Branch, NCI-CCR

Selected professional activities: Editorial board member Molecular and Cellular Biology; associate editor RNA Biology; ad hoc reviewer for NIH and National Science Foundation study sections

Outside interests: Hiking; playing basketball, soccer, and ping pong

Website: https://irp.nih.gov/pi/ashish-lal

Research interests: Most of the eukaryotic genome is noncoding; only two percent represents protein-coding sequences. Among the several types of noncoding RNAs, microRNAs (miRNAs) and long noncoding (lncRNAs) have gained significant attention due to emerging evidence demonstrating critical roles of some miRNAs and lncRNAs in regulation of vital cellular processes.

Our goals are to define the molecular mechanisms by which noncoding RNAs such as lncRNAs function in the control of proliferation, apoptosis, and differentiation in the context of colorectal cancer, to gain insights into RNA biology, and to lay the foundation for future translational research.

Unlike miRNAs, which have been studied for more than two decades, the lncRNA field lags far behind. The lncRNAs were recently discovered. Their expression is often altered in cancer; they act via diverse mechanisms, are expressed at low concentrations, and are not well-conserved. The lncRNAs are therefore a source of investigation and debate.

To discover lncRNAs that may have a function, we use two approaches. The first approach involves identification and functional integration of lncRNAs regulated by TP53, the most frequently mutated gene in human cancer. We expect that this approach will enable us to better understand how TP53 and its regulated lncRNAs mediate tumor suppression.

The second approach relies on altered lncRNA expression in colorectal cancer and tissue specificity. We identify lncRNAs that are downregulated in colorectal cancer and select those that are expressed in an intestine-specific manner. We believe that a subset of these intestine-specific lncRNAs are expressed only in intestinal tissue because they have an important role to play in its biology. A deeper understanding of what restricts their expression in the intestine and the biology of these lncRNAs is critical in determining their potential in cancer therapy.

Using cell and molecular biological approaches to investigate lncRNA function and mode of action, combined with analysis of lncRNA expression in patient samples and in vivo studies in mice, we hope to better understand their role in cancer pathogenesis.

SHALINI OBERDOERFFER, PH.D., NCI-CCR

Senior Investigator, head, RNA Processing in Cellular Development Section, Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute

Education: Bryn Mawr College, Bryn Mawr, Pennsylvania (A.B. in biology); Harvard University, Cambridge, Massachusetts (Ph.D. in immunology)

Training: Postdoctoral fellow, Immune Disease Institute, Harvard Medical School (Boston)

Came to NIH: In 2010 as tenure-track investigator, Center for Cancer Research, Frederick National Laboratory for Cancer Research (Frederick, Maryland); in 2012 became tenure-track investigator in NCI-CCR

Outside interests: Traveling; reading books; enjoying spicy foods

Website: https://irp.nih.gov/pi/shalini-oberdoerffer

Research interests: In my laboratory, we examine how DNA and RNA epigenetics dynamically regulate gene expression. The protein-coding capacity of human genes is diversified at essentially every step, ranging from the copying of DNA into pre-messenger RNA (pre-mRNA), to processing of pre-mRNA into protein-coding mRNA, to the translation of mRNA into proteins. The net result is a staggering expansion in the coding potential of the human genome, wherein some 20,000 genes serve as a template for more than 1,000,000 proteins. Much of this diversity is achieved through epigenetic regulation (changes in gene expression that are unrelated to DNA sequence, but rather occur through nucleic acid modifications that alter the biochemical properties of DNA or RNA). In mammals, the “epigenome” is principally formed through methylation of the nucleobase cytosine in DNA. In contrast, in mRNA, modifications occur in all four nucleobases to generate the “epitranscriptome.”

To understand the archetype for epigenetic control within DNA, we examine how nucleic-acid modifications of cytosine influence gene expression at unexpected stages in the lifecycle of an mRNA. We specifically ask how methylation of cytosine in DNA affects pre-mRNA splicing decisions, and how subsequent acetylation of cytidine in processed mRNA affects translation. We use a variety of tools to investigate the enzymatic regulation of cytosine modifications and their net impact genome-wide and at target genes. We are also developing methods to achieve base-resolution analysis of the modification landscape in single cells. Overall, we aim to uncover connections between the epigenome, epitranscriptome, and mRNA metabolism. Ultimately, we hope to understand how cytosine modifications contribute to the etiology of disease and to potentially identify avenues for novel therapeutic interventions.

MADHAV THAMBISETTY, M.D., PH.D., NIA

Senior Investigator and Chief, Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging

Education: Government Medical College, University of Calicut, Kerala, India (Bachelor of Medicine and Surgery); University of Oxford, Green College, Oxford, England (D.Phil. in clinical pharmacology)

Training: Residency in in neurology, Emory University School of Medicine (Atlanta); fellow and clinical associate in cognitive neurology and sleep disorders, Emory University School of Medicine

Before coming to NIH: Clinical Research Fellow, Alzheimer’s Society Institute of Psychiatry, Kings College London (London)

Came to NIH: In 2007 as a staff clinician, Clinical Research Branch, NIA; in 2012 became investigator and chief, Unit of Clinical and Translational Neuroscience, Laboratory of Behavioral Neuroscience, NIA

Selected professional activities: Adjunct professor of Neurology, Johns Hopkins University School of Medicine (Baltimore); elected member of the American Neurological Association; board of trustees, McKnight Brain Research Foundation; associate editor, Journal of Alzheimer’s Disease

Outside interests: He is an aspiring gourmand; enjoys cooking for his two boys aged 4 and 9 who have yet to provide informed consent to being unwitting consumers of his culinary experiments; enjoys writing and often rues a career path not taken—that of a cricket journalist.

Website: https://www.nia.nih.gov/about/staff/thambisetty-madhav

Research interests: I explore the disease mechanisms that operate in Alzheimer disease and am trying to identify novel biomarkers that can predict the disease before the onset of clinical symptoms. I am also a practicing neurologist and care for patients with memory disorders at the Johns Hopkins Bayview Memory and Alzheimer’s Treatment Center (Baltimore).

My research team uses multiple “OMICs” methods (metabolomics/proteomics/transcriptomics) to understand mechanisms underlying Alzheimer disease. We are also interested in relating genetic and environmental risk factors to changes in brain structure, function, and pathology during aging. The repeated failures of clinical trials of treatments for Alzheimer disease have highlighted the urgent need to identify novel targets for effective interventions.

Our work has added to growing evidence that Alzheimer disease is a pervasive metabolic disorder with abnormalities in many interacting biochemical pathways. These studies are leading to an emerging hypothesis that there may be multiple routes to Alzheimer pathology in the brain and the eventual expression of disease symptoms. This hypothesis in turn suggests that interventions targeting these metabolic abnormalities may be promising treatments. We are now testing whether commonly used medications for other illnesses may target metabolic abnormalities in Alzheimer disease.

I lead the Drug Repurposing for Effective Alzheimer’s Medicines (DREAM) Study, which will test whether older individuals exposed to such drugs may be subsequently protected against Alzheimer disease. The DREAM study will analyze large real-world clinical datasets covering millions of older individuals to test this hypothesis. If we identify such drugs, they could then be rapidly tested in clinical trials. This is an exciting juncture in our work as we are beginning to translate enhanced knowledge about disease mechanisms into effective treatments for patients.

JOHN S. TSANG, PH.D., NIAID

Senior Investigator and Chief, Multiscale Systems Biology Section, Laboratory of Immune System Biology; Co-director, Center for Human Immunology (CHI), National Institute of Allergy and Infectious Diseases

Education: University of Waterloo, Waterloo, Ontario, Canada (B.A.Sc. computer engineering; M.Math. computer science); Harvard University, Cambridge, Massachusetts (Ph.D. in biophysics)

Before coming to NIH: From 2008 to 2010, senior research scientist, Rosetta Inpharmatics, Merck Research Laboratories (Seattle and Boston)

Came to NIH: In 2010 as a tenure-track investigator and chief, Systems Genomics and Bioinformatics Unit in NIAID’s Laboratory of Immune System Biology and CHI’s Director of Computational Systems Biology

Selected professional activities: Member, steering committee, Human Immunology Project Consortium; member, steering committee, Human Vaccines Project; Co-organizer, Cold Spring Harbor Laboratory Inaugural Meeting on Systems Immunology (2019)

Outside interests: Enjoying jazz and classical music; playing tennis; traveling; hiking

Website: https://www.niaid.nih.gov/research/john-tsang-phd

Research interests: My laboratory works on systems and quantitative immunology. Immune responses involve complex molecular and cellular events occurring across space and time. They have been productively studied for decades at the level of individual molecules (such as major-histocompatibility-complex-encoded proteins), cells (regulatory T cells), or interactions (T cell–B cell cooperation). What is largely missing is a more quantitative and integrated understanding of how multiple interacting elements at several biological scales give rise to immune responses. Attaining such a quantitative, predictive understanding of immunity has positive implications for furthering basic immunological understanding and advancing translational applications.

Toward these goals, my lab develops and applies systems-biology approaches—combining computation, modeling, and experiments—to study the immune system at and across the organismal, cellular, and molecular levels. One area of focus is human immunology. We use multiplexed technologies to assess the state of the immune system before and after both natural (disease and genetic variation) and experimental (particularly via vaccination) perturbations. We analyze and model the resulting multimodal datasets to 1) uncover biomarkers of immune responsiveness and health; 2) infer connectivities among components of the immune system; and ultimately, 3) understand how immune responses are orchestrated across spatial and time scales.

At the cellular level, we are particularly interested in understanding how immune cells adapt to the environment and in studying the functional consequences of cell-to-cell variations at both the network and cellular levels. We also aim to develop or turn internal toolkits into broadly distributed tools when it is apparent that they are useful in more-general settings. For example, we developed a free platform called Omics Compendia Commons, or OMiCC (https://omicc.niaid.nih.gov/). OMiCC uses a crowdsourcing approach to empower the broader biomedical research community to generate and test hypotheses using large, complex datasets.