2018 News

Brian Ji Vitkup Lab
Brian Ji won Best Oral Presentation at Biennial Integrated Program Retreat; Visit the gallery for photos from the event.

Brian Ji , a combined MD/PhD student in Columbia’s Department of Systems Biology, delivered the winning oral presentation at the recent Biennial Integrated Program Retreat. Ji, who is a member of the Vitkup Lab, presented “Quantification of Human Gut Microbiota Variability Using Replicate Sampling,” and was one of six systems biology graduate students who delivered research presentations at the conference. 

Ji discussed a novel experimental and computational method he has developed to understand spatiotemporal dynamics of the human gut microbiome, as well as the technical noise tied to current human microbiome sequencing techniques. In addition to the human gut, the method, he says, is broadly applicable to other bacterial ecosystems and other sequencing-based studies. In the Vitkup Lab , Ji works on developing and utilizing quantitative approaches to reveal novel biological insights into bacterial ecology as well as cell physiology. His research interests also include exploring computational models and tools to study cancer metabolism at a global scale. In 2011, Ji received a prestigious Barry Goldwater Scholarship for his work on mathematical modeling to study impaired brain connectivity in epilepsy.  

composite image of the scientists and research figure
Tuuli Lappalainen (top photo) and Stephane Castel co-led the new study. The hypothesis of the study is illustrated here with an example in which an individual is heterozygous for both a regulatory variant and a pathogenic coding variant. The two possible haplotype configurations would result in either decreased penetrance of the coding variant, if it was on the lower-expressed haplotype, or increased penetrance of the coding variant, if it was on the higher-expressed haplotype. (Composite image courtesy of NYGC)

Researchers at the New York Genome Center (NYGC) and Columbia University's Department of Systems Biology have uncovered a molecular mechanism behind one of biology’s long-standing mysteries: why individuals carrying identical gene mutations for a disease end up having varying severity or symptoms of the disease. In this widely acknowledged but not well understood phenomenon, called variable penetrance, the severity of the effect of disease-causing variants differs among individuals who carry them. 

Reporting in the Aug. 20 issue of Nature Genetics, the researchers provide evidence for modified penetrance, in which genetic variants that regulate gene activity modify the disease risk caused by protein-coding gene variants. The study links modified penetrance to specific diseases at the genome-wide level, which has exciting implications for future prediction of the severity of serious diseases such as cancer and autism spectrum disorder.

NYGC Core Faculty Member and Systems Biology Assistant Professor Dr. Tuuli Lappalainen, PhD, led the study alongside post-doctoral research fellow Dr. Stephane Castel.

Suying Bao, PhD
Suying Bao, PhD

Suying Bao, a postdoctoral research scientist in the Chaolin Zhang lab , has been named an inaugural Precision Medicine Research fellow by Columbia’s Irving Institute of Clinical and Translational Research . The two-year fellowship aims to train postdocs to use genomics and complex clinical data to improve personalized and tailored clinical care and clinical outcomes. 

This fellowship “will provide me with more opportunities to translate my findings from basic science research into clinical application,” says Bao, “and pave my way towards an independent researcher in this field.” 

Bao’s expertise lies in RNA regulation at the interface of systems biology, ranging from the specificity of protein-RNA interaction to function of specific splice variants. RNA regulation is critical in proper cellular function; gaining deeper insights into this complex molecular mechanism will promote the development of precision medicine therapies. 

In this project, Bao is aiming to develop new approaches to identify causal noncoding regulatory variants (RVs) modulating post-transcriptional gene expression regulation, such as RNA splicing and stability.  “A majority of genetic variants associated with human diseases reside in noncoding genomic regions with regulatory roles,” notes Bao. “Thus, elucidating how these noncoding regulatory variants contribute to gene expression variation is a crucial step towards unraveling genotype-phenotype relationships and advancing precision medicine for common and complex diseases.”

To identify these RVs, she will leverage massive datasets of high-throughput profiles of gene expression and protein-RNA interactions generated from large cohorts of normal and disease human tissues and cell lines by multiple consortia, such as ENCODE, GTEx and CommonMind, and develop innovative computational methods of data mining. 

Hyundai $2.5M Grant to Columbia
Julia Glade Bender, MD, (center) at the Hyundai Hope on Wheels announcement Mar. 29 during the New York International Auto Show at the Jacob Javitz Center. (Photo courtesy of HHOW)

A team of researchers at Columbia University Irving Medical Center (CUIMC) has recently been awarded a five-year $2.5 million grant from Hyundai Hope on Wheels (HHOW) to fund innovative pediatric cancer research. 

The team at Columbia is being led by principal investigator (PI), Julia Glade Bender , MD, associate professor of pediatrics at CUIMC, with co-PIs Andrea Califano , Dr, chair of Columbia’s Department of Systems Biology and Darrell Yamashiro , MD, PhD, director of pediatric hematology, oncology and stem cell transplantation, along with researchers from Memorial Sloan Kettering, University of San Francisco Children’s and Dana-Farber Cancer Center. 

The Quantum Collaboration award from HHOW is aimed at funding research focused on childhood cancers with poor prognosis. At Columbia, the team will target osteosarcoma, the most commonly diagnosed bone tumor in children and adolescents. No new treatment approaches have successfully been introduced for osteosarcoma in nearly 40 years, and patients with the disease have not benefited from recent breakthroughs like immunotherapy or DNA sequencing and require a shift in the understanding and approach to therapy. 

Michael Shen, PhD
Michael Shen, PhD (Image Courtesy of the Shen Lab)

The Bladder Cancer Advocacy Network (BCAN) has awarded Professor Michael Shen, PhD, the 2018 Bladder Cancer Research Innovation Award. The honor is given to scientists whose novel, creative research has great potential to produce breakthroughs in the management of bladder cancer.  

Dr. Shen, who is professor of medicine, genetics & development, urology and systems biology at Columbia University, has used new techniques of 3D cell culture to establish “organoids” from primary bladder tumors obtained from patients. These personalized laboratory models, which the Shen lab can create in a matter of weeks, provide a new, innovative way to study the molecular mechanisms associated with drug response and drug resistance in bladder cancer patients. 

The BCAN award supports the Shen lab’s efforts in furthering their work in patient-derived bladder tumor organoids

“We will employ these organoid lines to examine how specific oncogenic drivers may regulate the invasiveness and metastatic ability of muscle-invasive bladder cancer (MIBC), both in cell culture and in mouse models,” says Dr. Shen. “Our goal is to use these new experimental approaches to provide molecular insights into the lethal properties of human MIBC, which will hopefully lead to improved therapeutic approaches.”

Bladder cancer is the fifth most common cancer in the United States, and the primary treatment of the disease is surgery. Overall, this new project will examine central questions of bladder cancer biology using Dr. Shen’s innovative approach involving patient-derived tumor organoids, and may provide the basis for future therapies for metastatic bladder cancer.

LIN28 Selectively Modulates Subclass Let-7 miRNAs
The proposed model of selective Let-7 microRNA suppression modulated by the bipartite LIN28 binding.(Image courtesy of Zhang Lab)

A new study led by Chaolin Zhang, PhD , assistant professor of systems biology , published today as the cover story of  Molecular Cell , sheds light on a critical RNA-binding protein that is widely researched for its role in stem cell biology and its ties to cancer progression in multiple tissues.

The LIN28 RNA-binding protein, initially found in worms about 15 years ago, is specifically expressed in stem cells.  It became well known because the protein is one of the four factors that were used to “reprogram” skin cells to induced pluripotent stem cells, or iPSCs, a breakthrough that was awarded the Nobel Prize in 2012. More recently, it was determined that the LIN28 RNA-binding protein can also be reactivated in cancer to drive tumor growth and progression. Due to its critical importance in developmental and cancer biology, scientists want to understand the role LIN28 plays at the molecular level. This new study provides some understanding of how the LIN28 protein suppresses a specific family of microRNAs, called Let-7, which are selectively lost in cancer.

“Let-7 microRNAs are the major downstream targets controlled by LIN28 identified so far. While LIN28 is mostly found in stem cells, Let-7 is only detected in differentiated cells because of stem cell-specific suppression by LIN28. However, the interplay between the two is still not well understood,” says Dr. Zhang, who is also a member of Columbia University’s Center for Motor Neuron Biology and Disease . “This study contributes to our understanding of how LIN28 suppresses Let-7, as well as provides a refined model for this important, rather complex molecular pathway.”

Califano-Cancer Bottleneck
The N of 1 trial leverages systems biology techniques to analyze genomic information from a patient’s tumor. The goal is to identify key genes, called master regulators (green circles), which, while not mutated, are necessary for cancer cell survival. Master regulators are aberrantly activated by patient-specific mutations (X symbols) in driver genes (yellow circles), which are mutated in large cancer cohorts. Passenger mutations (blue circles) that are not upstream of master regulators have no effect on the tumor. (Image: Courtesy of the Califano Lab)

A novel N of 1 clinical trial led by the Califano Lab at Columbia University Irving Medical Center is focusing on rare or untreatable malignancies that have progressed on multiple lines of therapy, with the goal of identifying and providing more effective, customized therapies for patients. The approach is grounded in a computational platform developed over the last 14 years by the Califano Lab to allow accurate identification of a novel class of proteins that represent critical tumor vulnerabilities and of the drug or drug combination that can most effectively disarm these proteins, thus killing the tumor. Platform predictions are then validated in direct tumor transplants in mice, also known as Patient-Derived Xenografts (PDX). 

“We call these proteins master regulators and have developed innovative methodologies that allow their discovery on an individual patient basis,” said Dr. Andrea Califano , Clyde and Helen Wu Professor of Chemical and Systems Biology and chair of the Department of Systems Biology at Columbia. 

Califano OncoTreat
Schematic diagram for the OncoTreat clinical pipeline. The pipeline consists of a series of pre-computed components, including a reference set of more than 13,000 tumor expression profiles representing 35 different tumor types, a collection of 28 tissue context-specific interactomes and a database of context-specific mechanism of action (MoA) for >400 FDA-approved drugs and investigational compounds in oncology. The transcriptome of the perturbed cell lines is profiled at low cost by PLATE-Seq. The process begins with the expression profile of a single patient sample, which is compared against the tumor databank to generate a tumor gene expression signature. This signature is interpreted by VIPER using a context-matched interactome to identify the set of most dysregulated proteins, which constitute the regulators of the tumor cell state – tumor checkpoint. These proteins are then aligned against the drugs’ and compounds’ MoA database, to prioritize compounds able to invert the activity pattern of the tumor checkpoint. (Image courtesy of Califano Lab)

Researchers at Columbia University Irving Medical Center (CUIMC) have developed a highly innovative computational framework that can support personalized cancer treatment by matching individual tumors with the drugs or drug combinations that are most likely to kill them. 

The study, online today in Nature Genetics , by Dr. Andrea Califano of Columbia University Irving Medical Center and Dr. Irvin Modlin of Yale University and Wren Laboratories LLC, co-senior author on the study, with collaborators from 17 research centers worldwide, details a proof of concept for a novel analytical platform applicable to any cancer type and validates its predictions on gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The latter represent a rare class of tumors of the digestive system that, when metastatic, are associated with poor survival. 

Tuuli Lappalainen , PhD assistant professor of systems biology and core faculty member at New York Genome Center (NYGC) is the recipient of the 2018 Leena Peltonen Prize for Excellence in Human Genetics.  The award was presented to Dr. Lappalainen on June 16, 2018, in Milan, Italy, at the 52nd Annual European Society of Human Genetics meeting, the largest human genetics conference in Europe.  The award is funded by the Leena Peltonen Memorial Fund in the Paulo Foundation.

Dr. Lappalainen's research focus is on functional genetic variation in human populations. She and her research group at NYGC study regulatory variation affecting the transcriptome, as well as cellular mechanisms underlying genetic associations to diseases.  The work of her research group links computational and population genomics to experimental molecular biology.  Widely published in her field, Dr. Lappalainen has made important contributions to several international research consortia in human genomics, including the Genotype Tissue Expression (GTEx) Project, the 1000 Genomes Project and the Geuvadis Consortium. 

The prize Dr. Lappalainen received honors the memory of Dr. Leena Peltonen, a world-renowned human geneticist from Finland who passed away in 2009. A visionary in medical genetics, Dr. Peltonen contributed to the identification of disease genes for human diseases in the Finnish and other populations. Her outstanding achievements inspired many young researchers in the field of medical genetics, including Dr. Lappalainen, who grew up in Finland, earning her PhD in Genetics at the University of Helsinki in 2009, followed by postdoctoral research at the University of Geneva and Stanford University.

"Tuuli's commitment to international collaboration as well as her philosophy of empowering and inspiring the next generation of genomic researchers mirrors Leena Peltonen's values and vision for advancing the field," said a member of the award's nominating committee, Samuli Ripatti, PhD, professor of Biometry Public Health, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Broad Institute of MIT and Harvard.

Project GENIE
Richard Carvajal (left) and Raul Rabadan are lead PIs on Project GENIE

Columbia University Irving Medical Center (CUIMC) has recently joined 11 new institutions to collaborate on Project GENIE, an ambitious consortium organized by the  American Association for Cancer Research . An international cancer registry built through data sharing,  Project GENIE , which stands for Genomics Evidence Neoplasia Information Exchange, brings together leading institutions in cancer research and treatment in order to provide the statistical power needed to improve clinical decision-making, particularly in the case of rare cancers and rare genetic variants in common cancers. Additionally, the registry, established in 2016, is powering novel clinical and translational research. In its first two years, Project GENIE has been able to accumulate and make public more than 39,000 cancer genomic records, de-identified to maintain patient privacy. 

Molly Przeworski Distinguished Columbia Faculty Award
Molly Przeworski

Molly Przeworski, PhD , professor of  biological sciences and of systems biology , has received the Distinguished Columbia Faculty Award for exceptional teaching. A leading population geneticist, Dr. Przeworski is one of eight recipients of the annual award, which recognizes faculty across a range of academic activities, including scholarship, University citizenship and professional involvement, with an emphasis on the instruction and mentoring of undergraduate and graduate students. 

The recipients this year were presented with the award at an April 11 event held at Columbia’s Italian Academy.

“It is wonderful to see the work we do teaching and mentoring graduate students recognized,” says Dr. Przeworski. “I have been really lucky to attract phenomenal students and postdocs, and find that interacting with them is one of the most rewarding aspects of what I do.”

According to one undergraduate referred to in the award citation, Dr. Przeworski “is definitely one of the best teachers I have ever been taught by.” The student also described her lectures as “well-designed” to build a keen understanding of and active engagement with the material. Columbia also lauded her for helping to launch the first annual New York area meeting in population genetics, successfully connecting researchers of varying career stages.

Dr. Przeworski's work aims to understand how natural selection has shaped patterns of genetic variation, and to identify the causes and consequences of variation in recombination and mutation rates, in humans and other organisms. She is the recipient of the Howard Hughes Medical Institute Early Career Scientist award, the Rosalind Franklin Young Investigator award, the Friedrich Wilhelm Bessel Research award and an Alfred P. Sloan fellowship. 

Tatonetti Heritability Image

Each subgraph in this image is a family reconstructed from EHR data: Each node represents an individual and the colors represent different health conditions. (Figure: Nicholas Tatonetti, PhD, Columbia University Vagelos College of Physicians and Surgeons).

Acne is highly heritable, passed down through families via genes, but anxiety appears more strongly linked to environmental causes, according to a new study that analyzed data from millions of electronic health records to estimate the heritability of hundreds of different traits and conditions. 

As reported by the Columbia Newsroom, the findings, published in Cell by researchers at Columbia University Irving Medical Center and NewYork-Presbyterian could streamline efforts to understand and mitigate disease risk—especially for diseases with no known disease-associated genes.

“Knowledge of a condition’s heritability—how much the condition’s variability can be attributed to genes—is essential for understanding the biological causes of the disease and for precision medicine,” says study co-leader Nicholas Tatonetti, PhD , the Herbert Irving Assistant Professor of Biomedical Informatics at Columbia University Vagelos College of Physicians and Surgeons and an assistant professor of systems biology. “It is clinically useful for estimating disease risk, customizing treatment, and tailoring patient care.”

Judith in the lab
Judith Kribelbauer

As a child growing up in a small town in Germany, Judith Kribelbauer excelled in science, counting chemistry and mathematics as her two favorite subjects from grade school through high school. After high school graduation, she attended the Ruprecht-Karls University in Heidelberg to pursue a bachelor’s degree in chemistry, which she completed in 2012. 

Becoming more serious about pursuing scientific research, Kribelbauer, who is graduating this May with a PhD in the Systems Biology Integrated Program, moved to the U.S. to work as a graduate exchange student at the University of North Carolina-Chapel Hill (UNC) before enrolling at Columbia University in 2013. At UNC, using SHAPE-MaP sequencing technology, she researched the structural basis of the HIV-1 RNA frame-shift element, a sequence that causes ribosomes to shift reading frames, therefore producing truncated proteins.  

Columbia’s collaborative environment—the chance to work with researchers spanning areas from biology to chemistry and physics to computer science—is what drew her to the University and ultimately to concentrating in systems biology. 

“Thanks to this unique environment, I could realize my dream research project—combining both experimental and computational approaches,” says Kribelbauer. “This comprehensive training allowed me to conduct my thesis research in two labs, with both PhD advisers having appointments in Systems Biology.”

Sebastien Weyn

Sebastien Weyn, a graduating PhD student in the Chaolin Zhang lab, has been awarded the Titus M. Coan Prize for Excellence in Research. Weyn, who intends to participate in the May 13 Hooding Ceremony at the Vagelos College of Physicians and Surgeons (P&S), is one of two graduates who has received the award, bestowed annually by P&S. Weyn is being recognized in the area of outstanding basic cell and molecular research. 

“I am happy to represent Systems Biology for the award, which together with previous DSB winners, showcase the important biological contributions coming from the department,” says Weyn. “Winning this award also speaks greatly to my mentor, Chaolin, and his vision and insight in the field.”

Work in the Zhang lab concentrates on the study of the nervous system and its underlying molecular mechanisms. The group focuses on the function of post-transcriptional gene regulation, in particular a level of molecular regulation called alternative RNA splicing, in the nervous system.

“The regulation of RNA splicing is surprisingly mysterious despite the fact that it is critical for proper cellular function, and there are several genetic diseases that result from improper splicing,” notes Weyn. “Understanding splicing can lead to breakthrough therapies.” 

For his dissertation project, Weyn dissected the regulatory mechanisms underlying dynamic alternative splicing switches during neurodevelopment. His work led to insights into the role that Rbfox proteins have in promoting mature splicing patterns, including in a number of autism candidate risk genes. The Rbfox family of proteins are important regulators of alternative splicing and mutations of these genes have been linked to several neurodevelopmental disorders. 

2018 Graduating Students
From left to right: Judith Krilbelbauer, Jonathan Chang, Sebastien Weyn.

Congratulations to our systems biology PhD students and lab members who are set to graduate this Commencement season. 

The following graduate students are expected to attend the May 13, 2018, Hooding Ceremony at the Vagelos College of Physicians and Surgeons. We wish them all the best!

Jonathan Chang

Biomedical Informatics

The Vitkup Lab

 

Judith Krilbelbauer 

Integrated Program

The labs of Harmen Bussemaker and Richard Mann

 

Sebastien Weyn

Integrated Program

The Zhang Lab

For more details about University Commencement, visit the official Commencement 2018 page. 

May 7, 2018

From Code to Cure

Columbia Magazine

Published Spring 2018 cover story , Columbia Magazine

As reported by David J. Craig, senior editor at Columbia Magazine , we are living in the age of big data, and with every link we click, every message we send, and every movement we make, we generate torrents of information. In the past two years, the world has produced more than 90 percent of all the digital data that has ever been created. New technologies churn out an estimated 2.5 quintillion bytes per day. 

Today, researchers at Columbia University Irving Medical Center (CUIMC) are using the power of data to identify previously unrecognized drug side effects; they are predicting outbreaks of infectious diseases by monitoring Google search queries and social-media activity; and they are developing novel cancer treatments by using predictive analytics to model the internal dynamics of diseased cells. These ambitious projects, many of which involve large interdisciplinary teams of computer scientists, engineers, statisticians, and physicians, represent the future of academic research.

Craig covers Dr. Nicholas Tatonetti's work involving prescription drug safety and his innovative use of digital health and clinical records and Dr. Andrea Califano's unconventional computational approaches in advancing cancer research.

To read the full article , visit the online issue of Columbia Magazine

Raul Rabadan
Raul Rabadan

Systems Biology Professor Raul Rabadan, Phd , has been awarded a Philip A. Sharp Innovation in Collaboration award from Stand Up to Cancer (SU2C) , a group established by film and media leaders to fund cancer research projects that have the potential to quickly deliver new therapies to patients. Dr. Rabadan has received the award jointly with collaborator Dan A. Landau, MD, PhD, of Weill Cornell Medicine.

A theoretical physicist whose expertise lies in the cross section of mathematical genomics, tumor evolution, and cancer research, Dr. Rabadan will work together with Dr. Landau on their winning project, “Cupid-seq—high throughput transcriptomic spatial mapping of immune-tumor interactions in the micro-environment.”  The investigators will devise a novel sequencing technique and computational method for better understanding immune recognition mechanism in glioblastoma. Dr. Rabadan is currently a principal investigator on the SU2C-National Science Foundation Drug Combination Convergence Team and Dr. Lau is a 2016 recipient of a SU2C Innovative Research Grant.

The idea behind the Sharp Awards is to fund projects that involved SU2C researchers who have not yet worked together, including collaborations between members of Dream Teams, Research Teams, and Convergence teams, and between SU2C members and recipients of its innovative research grants. The latter are typically early-career investigators. The Sharp Awards are named after Sharp, Nobel laureate and institute professor at MIT and the Koch Institute for Integrated Cancer Research, to honor the emphasis he has placed on the importance of collaborative research. 

Dr. Rabadan, who also is professor of biomedical informatics at Columbia University, is one of 10 recipients of this year’s Sharp Awards; investigators hail from the U.S., Canada, and the Netherlands, and projects are being funded from a pool of $1.25 million. 

No Read Left Behind

Gradually eliminating low-affinity binding sites identified by NRLB (from left to right) results in a gradual reduction of gene expression (white); Credit: Mann Lab/Columbia’s Zuckerman Institute

As reported  by the Zuckerman Mind Brain Behavior Institute, Columbia University researchers have developed a new computational method for deciphering DNA’s most well-kept secrets, and this new algorithm may help find the links between genes and disease. 

The researchers included lead PI at Zuckerman  Richard Mann , PhD, with collaborator, Harmen Bussemaker , PhD, both faculty members of the Department of Systems Biology. They recently published their findings in the Proceedings of the National Academy of Sciences .

“The genomes of even simple organisms such as the fruit fly contain 120 million letters worth of DNA, much of which has yet to be decoded because the cues it provides have been too subtle for existing tools to pick up,” said Mann, who is also Higgins Professor of Biochemistry and Molecular Biophysics and senior author of the paper. “But our new algorithm lets us sweep through these millions of lines of genetic code and pick up even the faintest signals, resulting in a much more complete picture what DNA encodes.”

A few years ago, the two labs--Mann and Bussemaker--developed a genetic sequencing method called SELEX-seq to systematically characterize all Hox binding sites. Hox genes are known as the drivers of some of the body's earliest and most critical aspects of growth and differentiation. Still, SELEX-seq had limitations: It required the same DNA fragment to be sequenced over and over again. With each new round, more pieces of the puzzle were revealed, but information about those critical low-affinity binding sites remained hidden.

Andrea Califano
Andrea Califano, Dr, chair of Columbia's Department of Systems Biology

The Chan Zuckerberg Initiative (CZI) has awarded Andrea Califano, Dr, a new grant in support of his work to develop a comprehensive library of regulatory interactions within molecularly defined cellular populations and molecular determinants (master regulators) of individual cells’ state. This will arm scientists with a unique resource to study biology at the individual cell level and to gain further insight into the fundamental understanding of molecularly distinct cell types.

With the support of CZI, founded by Facebook CEO Mark Zuckerberg and his wife, Priscilla Chan, Dr. Califano, chair of Columbia’s Department of Systems Biology, and his group will apply their computational methods that accurately and systematically measure and analyze regulatory interaction at the single cell level to elucidate distinct cellular states and to establish both cell-state markers, as well as the proteins that are causally responsible for implementing that state. 

A critical advantage offered by the approaches that the Califano Lab brings to the CZI community is that of addressing one of the most critical issues in single cell biology characterization. Specifically, since the depth of transcriptional sequencing of single cells is generally a very small fraction of what can be achieved from bulk tissue, most of the genes are actually lost and only the 20% to 30% of the genes that are most highly expressed can be detected. This has been dubbed the gene dropout problem. By using the recently published metaVIPER algorithm, this problem is eliminated as regulatory networks are used to accurately infer the activity of 6,000 proteins that include all the critical players in cell state implementation and modulation, even if their RNA cannot be detected, thus fully addressing gene dropout and allowing much deeper investigation of single cell biology. 

Harmen and Tuuli
Harmen Bussemaker (left) and Tuuli Lappalainen

Harmen Bussemaker, PhD, and Tuuli Lappalainen, PhD, have received an inaugural Roy and Diana Vagelos Precision Medicine Pilot Award for a collaboration that will bridge quantitative genetics and mechanistic biology to obtain a mechanistic understanding of regulatory effects of genetic variants in humans.

Drs. Bussemaker and Lappalainen, both faculty in Columbia’s Department of Systems Biology, represent one of three winning proposals out of a pool of 56 applications. Their project titled, “Elucidating the tissue-specific molecular mechanisms underlying disease associations through integrative analysis of genetic variation and molecular network data”, will help to advance Columbia University’s efforts in precision medicine basic science research. 

As reported by Columbia Precision Medicine, the investigators’ research objectives include: to dissect the molecular mechanisms underlying tissue-specificity of genetic regulatory variants and to map network-level regulatory variants that cause protein-level transcription factor (TF) 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. The investigators hope to elucidate which transcription factors are driving the functional impact and tissue specificity of any particular eQTL, genomic loci that contribute to variation in gene expression levels. 

Organoids bladder cancer

Organoids created from the bladder cancers of patients mimic the characteristics of each patient’s tumor and may be used in the future to identify the best treatment for each patient. Images: Michael Shen

Columbia University Irving Medical Center (CUIMC) and NewYork-Presbyterian researchers have created patient-specific bladder cancer organoids that mimic many of the characteristics of actual tumors. As reported by CUIMC, the use of organoids, tiny 3-D spheres derived from a patient’s own tumor, may be useful in the future to guide treatment of patients.

The study was published April 5 in the online edition of Cell.

Coauthors
Study lead coauthors Nathan Johns (left), systems biology graduate student in the Wang Lab, and Antonio Gomes, former member of the Wang Lab, now at Memorial Sloan Kettering Cancer Center.

Advances in synthetic biology have already spurred innovation in the areas of drug development, chemical production and health diagnostics. To help push the field even further, and potentially at a more rapid pace, a new, comprehensive resource devised by Columbia University investigators will help synthetic biologists better engineer designs for complex biological systems.

A team of researchers, led by Harris Wang, PhD, assistant professor of systems biology and of pathology and cell biology, report the characterization and analysis of thousands of bacterial regulatory elements in different species of bacteria. The paper , published March 19, appears in Nature Methods .

Synthetic biology employs well-characterized genetic parts to assemble gene circuits with specific functions, such as producing chemicals or sensing the environment. The toolbox of genetic parts to make functioning genetic circuits, however, has been limiting. A key shortfall is the availability of precisely measured regulatory sequences-segments of DNA responsible for dialing up or dialing down the expression of proteins within an organism. For many commercially useful bacteria, tuning gene expression has been challenging because of a lack of reliable regulatory sequences. 

"Synthetic biology is now at a precipice where we are not just demonstrating proof-of-concept in the laboratory but we're moving toward real-world applications," says Nathan Johns , lead coauthor of the paper, a member of the Wang Lab and a graduate student in the Department of Systems Biology at Columbia. "To facilitate this, having a wide array of useful genetic components and measurement techniques-in our case, regulatory sequences-are extremely helpful." 

Harris Wang in Lab

Harris Wang, PhD, assistant professor of systems biology, has been named a 2018 Schaefer Research Scholar for his novel approach to explore the role that bacteria cells in our gastrointestinal tract play on the efficacy of drug therapies.

Dr. Wang, who has a joint appointment in the Department of Pathology and Cell Biology, develops new tools and platforms to determine how genomes in microbial populations form, maintain themselves, and change over time, across many environments. His goal is to use synthetic biology approaches to engineer ecologies of microbial populations, such as those found in the gut and elsewhere in the human body, in ways that could improve human health.

The project that won the support of the Schaefer Scholars Research program centers on developing a platform approach to systematically determine new mechanisms by which specific members of the human microbiome metabolize and alter drugs and pharmaceuticals. Dr. Wang and his group intend to evaluate the impact of the microbiome on drug efficacies using cellular and animal models, focusing on the gut microbiome—an important and underexplored area of research.

“There have been studies that suggest a key link between microbes and their role altering the efficacy of drug treatments,” says Dr. Wang, “but this area of research is unchartered territory, and there is more knowledge to be gained by pinpointing how a person’s microbiome could metabolize specific therapeutics by inactivation, degradation, or alteration of its chemical structures. The large-scale data generated from our project could improve drug prescriptions and clinical trials by reducing failures and classifying patients based on otherwise unknown yet important microbiome-drug interactions.”

Two new precision medicine tests, born out of research from the Califano Lab, that look beyond cancer genes to identify novel therapeutic targets have just received New York State Department of Health approval and are now available to both oncologists and cancer researchers for use at the front lines of patient care. As reported by Columbia University Irving Medical Center (CUIMC), the tests are based on research conducted by CUIMC investigators—and could pave the way for a more precise approach to cancer therapy and help find effective drugs when conventional approaches to precision medicine have failed.

“This means that the vast majority of cancer patients who do not have actionable mutations, or have not responded to, or have relapsed after chemotherapy or targeted therapy, now have access to additional tests that can help their oncologist select the treatment best suited to their specific tumor,” says the tests’ lead developer, Andrea Califano, Dr., chair of systems biology at Columbia University Vagelos College of Physicians and Surgeons.

The two tests, DarwinOncoTreat and DarwinOncoTarget, are available exclusively through the Laboratory of Personalized Genomic Medicine in the Department of Pathology and Cell Biology at Columbia University Vagelos College of Physicians and Surgeons. The tests were developed by DarwinHealth, a Manhattan-based biotech firm founded in 2015 by Dr. Califano and colleague, Gideon Bosker, MD.

For the complete article, visit the CUIMC Newsroom.

 

In neurons lacking Rbfox, the AIS is disrupted, impairing neuron’s ability to fire action potentials.
The Rbfox protein is a master regulator of neuronal RNA splicing that is demonstrated to be pivotal to establish the mature RNA splicing program in neurons. In neurons lacking this protein, an axonal cytoskeletal structure called “axon initial segment” is disrupted, impairing neuron’s ability to fire action potentials. (Image courtesy of Zhang Lab).

Neurons, or nerve cells, in the brain communicate with each other by transmitting electric signals, or firing action potentials, through long processes named axons (which send out signals) and dendrites (which receive signals). The capability of firing action potentials, among other functions of mature neurons, has to be acquired during development and neuronal maturation. However, the molecular mechanisms governing this complex process are so far poorly understood.

To peel away at the intricate layers that govern the development of neurons, a research team led by Chaolin Zhang, PhD, Assistant Professor in Systems Biology and Biochemistry and Molecular Biophysics and Hynek Wichterle, PhD, Associate Professor in Pathology & Cell Biology, Neuroscience, and Neurology , at the Center for Motor Neuron Biology and Disease , Columbia University Medical Center, focuses on a level of molecular regulation called alternative splicing. Alternative splicing is a process of generating multiple transcripts and protein variants by joining different combinations of coding segments. This process is highly dynamic during neural development with dramatic switches of splicing patterns in thousands of genes, which produce a repertoire of protein products required at specific developmental stages.

A key regulator of alternative splicing is the Rbfox family of proteins, which are enriched in neurons and previously were linked to neurodevelopmental disorders, including autism, schizophrenia, and epilepsy.

Feb 7-8 Cancer Genomics Symposium

Pictured above, Adolfo Ferrando (left), professor of pediatrics and of pathology and cell biology at Columbia, with Luis Arnes, associate research scientist and first-place winner of the symposium's poster competition; For photos from the symposium, visit the gallery page . Credit: Lydia Lee Photography

A multidisciplinary team of researchers across Columbia University have been busy addressing the complex challenges in basic and translational cancer research. Faculty and investigators are bridging their expertise in fields ranging from mathematics, biology, and engineering to physics, genomics, and chemistry to develop innovative approaches to better understand, for instance, cancer disease progression, drug resistance, and the systems-wide network of tumor evolution.

Central to this ongoing work is research grounded in cancer genomics and mathematical data analysis explored during a two-day conference Feb. 7-8 co-hosted by the National Cancer Institute (NCI) centers at Columbia University Medical Center, Cornell University, and Memorial Sloan Kettering Cancer Center. (Visit the Rabadan Lab YouTube Channel for video of the symposium).

"Genomics is becoming an important tool for the quantitative study of biological systems,” says Raul Rabadan, PhD , professor of systems biology at Columbia and director of the Center for Topology of Cancer Evolution and Heterogeneity and of the Program for Mathematical Genomics . “This meeting organized by four different NCI centers addressed some of the important challenges and new perspectives on the quantitative understanding of cancer using genomics tools.”

New NIH Grant to Accelerate Commercialization of Single-Cell Analysis Platform

fluorescently-labeled live cells
Microwell array flow cell device loaded with fluorescently-labeled live cells. (Image provided by the Sims Lab.)

The field of single-cell RNA sequencing is moving at a fast clip. Adding to its rapid advance is a novel platform for linking optical imaging with high-throughput single-cell sequencing devised by researchers in the Sims Lab at Columbia’s Department of Systems Biology.

The new technology, developed by Peter Sims, PhD , assistant professor of systems biology, and postdoctoral research scientist, Jinzhou Yuan, PhD , enables live cell imaging and RNA sequencing simultaneously of the same individual cell on a large scale and at low cost. Jointly awarded a $1.5 million grant funded by the National Institutes of Health’s SBIR program, the Sims Lab and Cell Microsystems are collaborating to build and test the device, with the goal of bringing to market a fully-integrated system capable of imaging thousands of single cells and preparing them for genomic analysis.

The proposed system will integrate Cell Microsystems’ proprietary CellRaft Technology with the Sims Lab’s novel approaches to tracking single cells with so-called optical barcodes.

In single-cell RNA sequencing, “State-of-the-art technology now allows us to routinely process thousands of individual cells and obtain their genome-wide mRNA expression profiles,” notes Dr. Yuan. “However, cells that share similar expression profiles at the mRNA level may be distinct from each other based on features obtainable by optical microscopy, such as morphology, motility, and fluorescent labels. A more comprehensive description of each cell obtained by both imaging and sequencing may help us further refine cell type and state.”

Courtesy of The Olive Lab

Shown here, a human pancreatic tumor stained with Masson's trichrome; Image credit: Dr. Kenneth Olive

The Lustgarten Foundation has awarded Columbia University’s Herbert Irving Comprehensive Cancer Center (HICCC) a three-year grant, as part of its Translational Clinical Program, to test a new precision medicine approach to the treatment of metastatic pancreatic cancer.

“The prevailing model in personalized cancer treatment is to attack the DNA mutations that are believed to be driving an individual patient’s tumor,” says principal investigator Kenneth P. Olive, PhD , assistant professor of medicine and pathology & cell biology at HICCC. “While this approach has been astonishingly effective for a handful of rare cancers, we expect it will only work for a very small fraction of patients with the most common types of cancer.”

Pancreatic ductal carcinoma (PDA)—the most common form of pancreatic cancer—is a case in point. Researchers have identified few genetic drivers in pancreatic tumors, and the most common driver ( KRAS ) is not easily targeted. Conservatively, only about 15 percent of PDA patients are likely to benefit from conventional DNA mutation-based precision medicine therapies and most of these will either not respond or will relapse with a drug-resistant form of the disease.

“Our study takes an entirely new approach,” says Dr. Olive. “Instead of looking at the mutations encoded in a tumor’s DNA, we analyze the tumor’s RNA. Since RNA is the tissue-specific ‘working copy’ of a cancer cell’s DNA, it’s a more accurate reflection of the genetic programs that are active in a tumor and critical for its survival. We can then match the patient to approved and investigational drugs that inhibit those programs.”

Nicholas P. Tatonetti, PhD, has recently been named director of clinical informatics at the Institute for Genomic Medicine (IGM) at Columbia University Medical Center. In this new role, he is charged with planning, organizing, directing and evaluating all clinical informatics efforts across the Institute. In particular, he will focus on the integration of electronic health record data for use in genetics and genomics studies.

Dr. Tatonetti, who is Herbert Irving Assistant Professor of Biomedical informatics with an interdisciplinary appointment in the Department of Systems Biology, specializes in advancing the application of data science in biology and health science. Researchers in his lab integrate their medical observations with systems and chemical biology models to not only explain drug effects, but also further understanding of basic biology and human disease. They focus also on integration of high throughput data capture technologies, such as next-generation genome and transcriptome sequencing, metabolomics, and proteomics, with the electronic medical record to study the complex interplay between genetics, environment, and disease.

At the Institute for Genomic Medicine, researchers are focused on innovative approaches to genomic medicine. Their multi-tiered approach to genomic medicine utilizes large scale genomic sequencing and analysis, paired with functional biology to advance the diagnosis, characterization, and treatment of genetic diseases. IGM is playing a critical role in Columbia’s overall Precision Medicine Initiative, a major University-wide effort to provide medical diagnosis, prevention and treatment based on an individual’s variation in genes, environment, and lifestyle. 

Dr. Tatonetti, who joined Columbia in 2012, is also affiliated with the Center for Computational Biology and Bioinformatics, the Department of Medicine, the Department of Biomedical Informatics, and the Center for Cancer Systems Therapeutics.