Roy and Diana Vagelos Precision Medicine Pilot Awards Announcement

We are pleased to announce the winners of the inaugural Roy and Diana Vagelos Precision Medicine Pilot Awards. We were impressed with the response and with the broad range of proposals from Columbia faculty.

March 02, 2018

The standard of the 56 applications we received was very high, and investigators came from all Columbia campuses. Thanks to all who submitted proposals and to those who participated in the review process.

The three winning proposals reflect the high standard, the broad base, and the collaborative nature of precision medicine basic science research being conducted and conceived at Columbia:

Two proposals are a collaboration between junior and senior faculty;

Two feature collaboration between investigators on different campuses;

One, a collaboration between basic and clinical researchers.

 

The winning proposals are:

1. Programmable probiotics for personalized cancer immunotherapy.

Nicholas Arpaia, PhD, Assistant Professor, Dept. of Microbiology & Immunology;

Tal Danino, PhD, Assistant Professor, Dept. of Biomedical Engineering

 

2. Elucidating the tissue-specific molecular mechanisms underlying disease associations through integrative analysis of genetic variation and molecular network data.

Tuuli Lappalainen, PhD, Assistant Professor, Dept. of Systems Biology; Junior investigator and Core Member, New York Genome Center

Harmen J Bussemaker, PhD, Professor, Dept. of Biological sciences; Dept. of Systems Biology

 

3. Notch2 polymorphisms as predictors of low β-cell mass and increased type 2-diabetes risk.

Utpal Pajvani, MD, PhD, Herbert Irving Assistant Professor of Medicine, Dept. of Medicine, Endocrinology;

Dieter Egli, PhD, Maimonides Assistant Professor of Developmental Cell Biology, Dept. of Pediatrics;

Domenico Accili, MD, Russell Berrie Foundation Professor of Diabetes, Dept. of Medicine; Chief of Endocrinology Division; Director of the Columbia University Diabetes and Endocrinology Research Center.


Programmable probiotics for personalized cancer immunotherapy

Nicholas Arpaia, PhD, Assistant Professor, Dept. of Microbiology & Immunology;

  • Expert in mucosal immunity, understanding how mucosal immune responses are coordinated to maintain homeostasis and respond to infection, injury or alterations in commensal microbial diversity
  • Studies focus on discovering pathways with the potential for therapeutic manipulation, specifically signals driving pro- and anti-inflammatory immune responses

Selected publications

  • Green, J.A.*, Arpaia, N.*, et al. (2017) A nonimmune function of T cells in promoting lung tumor progression. J. Exp. Med. 214: 3565-3575.
  • Arpaia, N., et al. (2015) A distinct function of regulatory T cells in tissue protection. Cell 162: 1078-1089.
  • Sivick, K.E., et al. (2014) Toll-like receptor deficient mice reveal how innate immune signaling influences Salmonella virulence strategies. Cell Host and Microbe 15: 203-213.
  • Arpaia, N. and Rudensky, A.Y. (2014) Microbial metabolites control gut inflammatory responses. Proc. Natl. Acad. Sci. U.S.A. 111: 2058-2059.
  • Arpaia, N., et al. (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504: 451-455.
  • Arpaia, N., et al. (2011) TLR signaling is required for Salmonella typhimurium virulence. Cell 144: 675-688.

Tal Danino, PhD, Assistant Professor, Dept. of Biomedical Engineering

  • Expert in synthetic biology, engineering gene circuits in microbes.
  • Studies focus on cancer therapeutics and diagnostics, mathematical modeling of gene network dynamics, microfluidics and biosensor applications.

Selected publications

  • Din, O., et al.  (2016) Synchronized cycles of bacterial lysis for in vivo delivery. Nature 536: 81-85.
  • Luna, J., et al. (2015) Hepatitis C virus RNA functionally sequesters miR-122. Cell 160: 1099–1110.
  • Danino, T.*, et al. (2015) Programmable probiotics for detection of cancer in urine. Sci. Transl. Med. 7: 289ra84.
  • Danino, T., et al. (2012) In vivo gene expression dynamics from tumor-targeted bacteria. ACS Synthetic biology 1: 465-470.
  • Prindle, A., et al. (2011) Sensing array of radically coupled genetic biopixels. Nature 481: 39-44.
  • Danino, T.*, et al. (2010) A synchronized quorum of genetic clocks. Nature 463: 326-330

Background:

In 1891, William Coley demonstrated that injection of live cultures of Streptococcus could stimulate the immune system and prompt complete remission in some patients with cancer, thus heralding the promise of immunotherapy. In recent years, several therapies using antibodies that target immune checkpoints and reactivate anti-cancer immune responses have been approved for use in the clinic. The connection from Coley to modern immunotherapy is the ability to reactivate anti-tumor T cells. Many of these T cells recognize tumor-specific antigens, known as neoantigens; thus the identification of a patient’s unique neoantigen repertoire is critical to promote personalized, systemic anti-tumor immunity.

Objectives:

First, engineer probiotic strains that locally release immunotherapeutics along with tumor-specific antigenic peptides within the tumor microenvironment. Investigators will use synthetic biology approaches to engineer genetic circuits using a strain of E. Coli, which will permit selective growth and synchronized lysis within the hypoxic core of a solid tumor, thus allowing for localized release of plasmid-encoded immunotherapeutics and tumor-specific antigens.

Second, characterize anti-tumor immune responses following delivery of engineered immunotherapeutic bacteria encoding tumor-specific antigenic peptides, or reported neoantigens. Investigators will quantify antigen specific anti-tumor T cell responses in an animal model and characterize cytokine production, and hypothesize that bacterial co-delivery will enhance anti-tumor immunity.

Third, assess the durability and systemic efficacy of anti-tumor responses elicited by engineered bacterial strains. Investigators hypothesize that the locally primed anti-tumor immunity will lead to durable antigen specific immune responses with long lasting eradication of systemic metastases.

Future work:

This proposal leverages expertise in synthetic biology and immunology to engineer probiotic strains of bacteria that selectively colonize tumors and elicit systemic, neoantigen-guided anti-tumor immunity. In future studies, investigators will develop methodologies for identifying patient-specific tumor neoantigen repertoires to create personalized bacterial strains for patient- and tumor-specific immunotherapy.


Elucidating the tissue-specific molecular mechanisms underlying disease associations through integrative analysis of genetic variation and molecular network data

Tuuli Lappalainen, PhD, Assistant Professor, Dept. of Systems Biology; Assistant investigator and Core Member, New York Genome Center

  • Expert in characterizing functional genetic variation in human populations, based on integration of human population-scale genome and transcriptome sequencing data sets.
  • Leading role in the Genome Tissue Expression (GTEx) project
  • Key role in several other consortia
  • Experimental work used CRISPR-Cas9 genome editing to validate cellular effects of genetic variants
  • Lab website: http://tllab.org/

Selected publications

  • Genetic effects on gene expression across human tissues. GTEx Consortium. Nature 2017 PMID 29022597
  • Quantifying the regulatory effect size of cis-acting genetic variation using allelic fold change. Mohammadi, P. et al. Genome Res. 2017 PMID 29021289
  • Associating cellular epigenetic models with phenotypes. Lappalainen, T. & Greally, J.M. Nat.Rev.Genet. 2017 PMID 28555657
  • Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations. Kim-Hellmuth S., et al. Nature Communications. 2017 PMID 28814792
  • The Genotype-Tissue Expression (GTEx) pilot analysis of multi-tissue gene regulation in humans. GTEx Consortium. Science 2015 PMID 25954001
  • Transcriptome and genome sequencing uncovers human functional variation. Lappalainen T., et al. Nature. 2013 PMID 24037378

Harmen J Bussemaker, PhD, Professor, Dept. of Biological sciences; Dept. of Systems Biology

  • Expert in modeling gene regulatory network function based on integrative analysis of high-throughput functional genomics data
  • Leader in the field of motif discovery and quantitative prediction of protein-DNA interaction
  • Pioneer of methods that explain changes in global gene expression pattern in terms of modulation of protein-level activity of transcription factors
  • Pioneer of network-based methods for mapping trans-acting variants in model organisms based on knowledge of the DNA binding specificity of transcription factors
  • Lab website: bussemakerlab.org

Selected publications

  • Identifying genetic modulators of the connectivity between transcription factors and their transcriptional targets. Fazlollahi M. et al. Proc Natl Acad Sci USA. 2016 PMID: 26966232
  • Identifying regulatory mechanisms underlying tumorigenesis using locus expression signature analysis. Lee E. et al. Proc Natl Acad Sci USA. 2014 PMID: 24706889
  • Identifying the genetic determinants of transcription factor activity. Lee E. et al. Mol Syst Biol 2010 PMID: 20865005
  • Quantitative Analysis of the DNA Methylation Sensitivity of Transcription Factor Complexes. Kribelbauer J.F. et al. Cell Rep. 2017 PMID: 28614722
  • Genome-wide mapping of autonomous promoter activity in human cells. Van Arensbergen J. et al. Nat Biotechnol. 2017. PMID: 28024146
  • Regulatory element detection using correlation with expression. Bussemaker, H.J. et al. Nature Genet. 2001. PMID: 11175784

Background:

Over the past decade, genome-wide association studies (GWAS) have discovered thousands of loci associated with diverse human traits and diseases. However, it is usually difficult to reconstruct the chain of causal interactions that mediates the association between small genetic perturbations and complex disease phenotypes because the majority of GWAS associations are in non-coding regions. A detailed mechanistic understanding of how cellular machinery interprets non-coding variants is required in order to deliver on the promise of GWAS to pinpoint potential drug targets and elucidate causal molecular mechanism of disease risk. One approach that has been used to address this gap is to map genetic associations with gene expression levels (so-called expression quantitative trait loci or ‘eQTLs’). Most work in this area so far has focused on cis-acting eQTLs that influence the expression of nearby genes. While there is evidence that trans-acting eQTL associations are biologically important, mapping them has proven very difficult in humans.

Thanks to recent technical advances, accurate modeling of protein-DNA interaction, and sequence-based inference of protein-level transcription factor (TF) activity based on these binding models, has become feasible. Along these lines, the investigators propose to bridge the fields of quantitative genetics and mechanistic biology to obtain a mechanistic understanding of regulatory effects of genetic variants in humans.

Objectives:

The first goal is to dissect the molecular mechanisms underlying tissue-specificity of genetic regulatory variants. Using extensive data produced by the Genome Tissue Expression (GTEx) project, which catalogued thousands of genetic associations with gene expression across hundreds of individuals and dozens of human tissues, the investigators will analyze how the cellular environment modifies the effect size of genetic cis-regulatory variants in the human genome. They will also investigate to what extent these regulatory effects can be rationalized in terms of allelic variation in the binding affinity of transcription factors as predicted from the DNA sequence.

The second goal is to map network-level regulatory variants that cause protein-level transcription factor activity to vary between individuals. The investigators will infer TF activity based on DNA binding specificity models of human TFs, and use it as a tissue-specific parameter of the cellular environment. They will also map trans-acting genetic variants that affect TF activity (coined ‘aQTLs’ by one of the investigators) in each tissue. It is anticipated that the trans-acting loci identified by this analysis will be of major interest to basic biology researchers, and will also help explain GWAS associations to complex disease.

Future work:

This proposal hopes to elucidate which transcription factors are driving the functional impact and tissue specificity of any particular eQTL. Identifying the transcription factors that are upstream regulators of genetic regulatory variants provides a starting point for mapping the environmental stimuli or drugs that modify these transcription factors. Interactions with disease associations can be studied and validated in available large-scale ‘phenome’ data sets. Furthermore, any aQTLs that colocalize with GWAS loci provide important starting points for further mechanistic study.


Notch2 polymorphisms as predictors of low β-cell mass and increased type 2-diabetes risk

  Utpal Pajvani, MD, PhD, Herbert Irving Assistant Professor of Medicine, Dept. of Endocrinology;

  • Expert in field of diabetes
  • Studies the reactivation of developmental pathways in obesity
  • Winner of 2014 David L. Williams Lecture and Scholarship award, given annually to an early career investigator working in the general area of lipid and lipoprotein metabolism and atherosclerosis.
  • Named a Louis Gerstner, Jr. Scholar (2009-2012)

Selected publications

  • Degradation of PHLPP2 by KCTD17, via a glucagon-dependent pathway, promotes hepatic steatosis. Kim K, et al. Gastroenterology. 2017 Dec;153(6):1568-80. PMID: 28859855
  • Hepatic Notch signaling correlates with insulin resistance and nonalcoholic fatty liver disease. Valenti L, et alDiabetes. 2013 Dec;62(12):4051-62. doi: 10.2337/db13-0769. PMID: 23990360
  • Inhibition of Notch signaling ameliorates obesity–induced insulin resistance in a FoxO1-dependent manner. Pajvani U, et al. Nature Medicine. 2011 July 31;17(8):961-7. PMID: 21804540

Dieter Egli PhD, Maimonides Assistant Professor of Developmental Cell Biology, Dept. of Pediatrics; Dept. of Ob/Gyn; Research Fellow, New York Stem Cell Foundation Research Institute

  • Expert on the study of pluripotent stem cells
  • Studies stem cell derived human beta cells which enables the study of genes and pathways involved in beta cell failure, while also providing a source of cells that will likely be useful for cell replacement.
  • Harold and Golden Lamport Award for Excellence in Clinical Science Research, 2017

Selected publications

  • β-Cell Replacement in Mice Using Human Type 1 Diabetes Nuclear Transfer Embryonic Stem Cells. Sui L, et al. Diabetes. 2018 Jan;67(1):26-35. PMID: 28931519
  • Tying genetic stability to cell identity. Georgieva D, & Egli D. Cell Cycle. 2017 Jun 18;16(12):1139-1140. PMID: 28548589
  • Genomic instability during reprogramming by nuclear transfer is DNA replication dependent. Chia G, et al. Nat Cell Biol. 2017 Apr;19(4):282-291. PMID: 28263958

Domenico Accili, MD, Russell Berrie Foundation Professor of Diabetes, Dept. of Medicine; Chief of Endocrinology Division; Director of the Columbia University Diabetes and Endocrinology Research Center.

  • Expert on islet biology
  • Identified a family of DNA-binding proteins that regulate diverse processes, including food intake, insulin production and adipogenesis.
  • Awarded American Diabetes Association Banting Medal for 2017, recognizing outstanding, long-term contributions to the field of diabetes.
  • Awarded 2004 Lilly Award for outstanding scientific achievement

Selected publications

  • Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling. Langlet F, et al. Cell. 2017 Nov 2;171(4):824-835.e18. PMID: 29056338
  • Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice. Kim-Muller JY, et al . Nat Comm. 2016 Aug 30;7:12631. doi: 10.1038/ncomms12631. PMID: 27572106
  • Pancreatic β cell dedifferentiation as a mechanism of β cell failure. Talchai C, et al . Cell. 2012 Sep 14;150(6):1223-34. doi: 10.1016/j.cell.2012.07.029. PMID: 22980982

Background:

Over the past decade, GWAS have successfully identified common variants at genomic loci associated with increased risk of T2D development. One risk locus is a relatively common intronic SNP in the NOTCH2 gene (rs10923931), consistently found in a wide variety of populations. NOTCH2 is part of a family of receptors critical for cell-fate decisions in normal development. Recently, it was found that the signaling is reactivated in response to obesity in several insulin-sensitive tissues. The role of Notch signaling in β-cell proliferation and maturation is unclear. Investigators will look at the role of NOTCH2, and the particular risk variant, on β-cell development and function.

Objectives:

First, use CRISPR to generate null NOTCH2 alleles, on the background of a reporter IPS line encoding GFP in the insulin locus to allow tracking of the cells in vitro and in vivo. After differentiation to β-cells in vitro and in vivo, test the repercussions of loss of NOTCH2 on β-cell biology.

Second, determine the mechanism of reduced NOTCH2 expression and other possible molecular repercussions of the rs10923931 SNP, and determine effects on β-cell Notch activity and downstream effects on β-cell proliferation and maturation.

Future Work:

Investigators predict that NOTCH2 T2D risk variants decrease proliferation of pancreatic progenitors and/or fully developed cells due to reduced β-cell NOTCH2 expression, which in turn reduces β-cell Notch activity. Future work will focus on translational studies, to cross-reference individual genomic information to β-cell mass data from PET imaging. In addition, investigators will test whether the NOTCH2 variant is associated with lower insulin/C-peptide in T2D patients, and whether the NOTCH2 variant will predict early need for insulin therapy in susceptible patients.