2017 News

Columbia, Broad Institute to Identify More Effective Therapies for Gastric and Esophageal Cancers

Broad, Columbia collaborators
Three of the investigators in new Columbia, Broad Institute research collaboration aimed at gastric and esophageal cancer; L to R: Dr. Andrea Califano, Dr. Cory Johannessen, and Dr. Adam Bass (Johannessen image: Martin Adolfsson; Bass image: Sam Ogden/Dana-Farber Cancer Institute)

A research collaboration underway between Columbia’s Department of Systems Biology, the Broad Institute of MIT and Harvard, and Columbia University Medical Center (CUMC) is working to accelerate the discovery of new cancer drug combinations targeted at gastric and esophageal cancer. These tumors have not yet attracted prominent research focus and attention, and yet the general outcome for patients with these diseases is poor. According to the American Cancer Society, survival rates are only 20% at five years after diagnosis.

The newly formed research alliance between research teams at Columbia and at the Broad Institute came about thanks to a four-year gift by the Price Family Foundation, known for its philanthropic support of education, health, and biomedical research.

The Columbia-Broad team includes Dr. Andrea Califano , cofounder and chair of the Department of Systems Biology; Dr. Adam Bass , associate member of the Broad Institute; Dr. Cory Johannessen, senior research scientist at the Broad Institute; Dr. Josh Sonnett , the director of The Price Family Center for Comprehensive Chest Care, Lung and Esophageal Center at Columbia; and Dr. Naiyer A. Rizvi , the Price Chair in Clinical Translational Research at Columbia.

In 2016, the Price Family Foundation suggested that a team of scientists at the Broad Institute meet with researchers from CUMC. At the time, the Foundation was eager to leverage the project at the Broad—where researchers had uncovered an interesting finding for gastric and esophageal cancer—with innovative cancer systems biology work it was supporting at CUMC, focusing on the same diseases.

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Low-Cost Sequencing Technique Helps Advance Personalized Cancer Treatment

HTS
Research scientist Hai Li holds up a 384-well plate, pictured in front of Columbia Genome Center's Hamilton Star automation system for HTS; Image credit: Systems Biology

Drug screening and analysis is critical in advancing research and discovery of cancer therapeutics. To this end, a Systems Biology-led team of investigators has recently developed PLATE-Seq, a new technique for low-cost, bulk mRNA sequencing. Coupled with genome-wide regulatory network analysis, the novel PLATE-Seq method advances the goal of providing cancer patients with personalized treatment.

Developed by the labs of Peter Sims and Andrea Califano , PLATE-Seq stands for “pooled library amplification for transcriptome expression” sequencing, and enables genome-wide mRNA profiling specifically designed to complement high-throughput screening assays. High-throughput screening, or HTS, represents a key component of drug discovery and technology used widely in biomedical research. Due to cost or complexity, most screens are still performed using low-complexity reporters, such as cell viability, protein-protein interactions and cell growth, for example, but there is a growing need to couple this screening protocol with genome-wide reporters, to measure the activity of many proteins across the genome.

“Our PLATE-Seq method helps us generate a more comprehensive portrait of drug activity,” said Dr. Sims, assistant professor of systems biology, known for his innovative work in single-cell RNA sequencing. “We’ve been able to show that our technique cuts the cost for gene expression profiling considerably, by incorporating a method we devised for ‘barcoding’ cDNA samples and combining this with computational methods from the Califano Lab that are highly effective on low-coverage sequencing data. This method allows us to sequence 96 samples per plate and 768 samples per sequencing run.”

On average, PLATE-Seq reduces the cost of genome-wide screening from around $400 per sample down to approximately $25 per sample. Genome-wide sequencing is important in advancing our understanding and prediction of disease and in identifying potential treatments.

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World's Smallest Tape Recorder is Built from Microbes

TRACE cell recorders Wang Lab

Columbia University Medical Center reports on a new study in Science   led by Harris Wang, assistant professor of systems biology. Wang and collaborators, which include researchers at the Department of Pathology & Cell Biology, have converted a natural bacterial immune system into a microscopic data recorder, an innovative framework that can lead to advances in biological applications utilizing bacterial cells for everything from disease diagnosis to environmental monitoring.

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At the Intersection of Math and Genomics

Topology data analysis of cancer samples

Shown here, topology data analysis of cancer samples; Image credit: The Rabadan Lab

The new Program for Mathematical Genomics (PMG) is aiming to address a growing—and much-needed—area of research. Launched in the fall of 2017 by Raul Rabadan , a theoretical physicist in the Department of Systems Biology, the new program will serve as a research hub at Columbia University where computer scientists, mathematicians, evolutionary biologists and physicists can come together to uncover new quantitative techniques to tackle fundamental biomedical problems.

"Genomic approaches are changing our understanding of many biological processes, including many diseases, such as cancer," said Dr. Rabadan, professor of systems biology and of biomedical informatics. "To uncover the complexity behind genomic data, we need quantitative approaches, including data science techniques, mathematical modeling, statistical techniques, among many others, that can extract meaningful information in a systematic way from large-scale biological systems." 

This new program is being built upon collaborative research opportunities to explore and develop mathematical techniques for biomedical research, leading to a deeper understanding of areas such as disease evolution, drug resistance and innovative therapies. Inaugural members of the new program include faculty across several disciplines: statistics, computer science, engineering and pathology, to name a few. The program also will provide education and outreach to support and promote members' work, including joint discussion groups, the development of cross-campus courses and scientific meetings. 

In honor of its launch, PMG will co-host a two-day symposium February 7 to 8 on cancer genomics and mathematical data analysis. Guest speakers from Columbia University, Memorial Sloan Kettering and Cornell University will present a comprehensive overview of quantitative methods for the study of cancer through genomic approaches. 

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Systems Biology Faculty Nab Chan Zuckerberg Initiative Grants to Advance Human Cell Atlas

Peter Sims Lab Wins CZI Award

Assistant Professor Peter Sims and postdoctoral research scientist Jinzhou Yuan displaying their platform for automated single-cell RNA sequencing. (Photo: Lynn Saville)

Assistant Professor Peter Sims, PhD , has been awarded an inaugural Chan Zuckerberg Initiative (CZI) award for gene sequencing research that will help advance the Human Cell Atlas project. Launched in 2016 by a cohort of world-leading scientists, the Human Cell Atlas is a high-profile endeavor whose goal is to identify and define every cell type of the human body and create a collection of maps that will describe the cellular basis of health and disease.

With the support of CZI, founded by Facebook CEO Mark Zuckerberg and his wife, Priscilla Chan, Dr. Sims and his group in the Department of Systems Biology will receive grant funding to pilot a revolutionary technique for high throughput single-cell sequencing. Called SCOPE-Seq, the novel, economical method conducts RNA sequencing coupled with live imaging of the same individual cell on a large scale.

“We hope that our approach will provide functional insights into the novel cell types that will be discovered by the Human Cell Atlas effort that cannot be obtained from genomic analysis alone,” said Dr. Sims.

Raul Rabadan
Raul Rabadan

Fellow Systems Biology Professor Raul Rabadan, PhD , who directs the Center for Topology of Cancer Evolution and Heterogeneity, also is gaining support from CZI in a collaboration led by Tom Maniatis, PhD, who won the grant for their research to construct an atlas of gene activity of all cells in the human spinal cord. Dr. Maniatis chairs the Department of Biochemistry and Molecular Biophysics, directs Columbia's Precision Medicine Initiative and is a principal investigator at Columbia's Mortimer B. Zuckerman Mind Brain Behavior Institute.

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Department Honors Outstanding Young Investigators at Annual Retreat

Poster winners with Department Chair Andrea Califano (far right), left to right: Sebastien Weyn-Vanhentenryck, Yun Hao and Jinzhou Yuan

Research diversity and innovation were the key themes at the Department of Systems Biology’s annual retreat. Held Sept. 18 in Tarrytown, N.Y., the retreat was attended by 145 guests and included a mix of faculty, students, post-docs, research scientists and department guests. A series of presentations showcased the collaborative projects underway in the Center for Cancer Systems Therapeutics (CaST), along with sessions by faculty about their ongoing research, for example, in the areas of computational genetics, complex predictive methods and cancer-related genomics. The all-day event also included a poster session and competition, highlighting the department’s pool of talented students and researchers.

Department chair Andrea Califano said his hope is that the annual retreat gives everyone a chance to “reflect on the various different studies and diverse approaches currently going on in the department.” 

Faculty judges named three winners of the poster competition, recognizing the work of students Yun Hao and Sebastien Weyn-Vanhentenryck and post-doctoral research scientist, Jinzhou Yuan.

Yun Hao, a PhD student in Nicholas Tatonetti's lab, looked into targeted therapy, an emerging treatment that uses chemicals to block cancer growth and metastasis by interfering with specific molecular targets. Current agents used in cancer treatment such as epidermal growth factor receptor inhibitors are limited by low efficacy and high toxicity to normal tissues. Hao focused on G-protein coupled receptors (GPCRs), the largest family of membrane receptors, which have not yet been used in target therapy. Hao built a computational workflow to identify GPCRs for cancer therapy, and in his research, showed that predicted GPCRs exhibit both high efficacy and low toxicity levels, offering a new direction for the development of cancer drugs.

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Systems Biology PhD Student Wins Best Poster at SEED (Synthetic Biology, Engineering, Evolution & Design) Symposium

Sway Chen, a PhD student in the Harris Wang Lab,  won the Best Poster Award at one of the premiere international conferences, the 2017 Synthetic Biology: Engineering, Evolution & Design (SEED) in Vancouver, British Columbia, Canada on June 23rd. Sway’s poster was titled “In Situ Metagenomic Perturbation of Mammalian Gut Microbiomes Through Engineered Horizontal Gene Transfer”.  Carlotta Ronda, a postdoc in the Wang Lab, and Vitor Cabral, a former postdoc in the Wang Lab, contributed to Sway’s project as well. 

‘SEED 2017 is focused on advances in the science and technology emerging from the field of synthetic biology. This is broadly defined as technologies that accelerate the process of genetic engineering. The conference highlighted new tool development, as well as the application of these tools to diverse problems in biotechnology, including therapeutics, industrial chemicals and fuels, natural products, and agriculture. This year's theme is "building foundations of synthetic biology, scaling it up, and applying it to critical problems.”’  

Congratulations, Sway! 

Pictured in the photo are Sway Chen and David Lemberger of Molecular Systems Biology 

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It’s All In the Math: New Tool Provides Roadmap for Cell Development

Researchers at Columbia University Medical Center have created a new tool to describe the many possible ways in which a cell may develop. Rooted in the mathematical field of topology, the tool provides a roadmap that offers detailed insight into how stem cells give rise to specialized cells. 

The study was published May 1st in Nature Biotechnology. 

Every organism begins with one cell. As that cell divides, its copies branch off to become specialized cells—such as heart, bone, or brain cells—in a process known as differentiation. To understand the internal and external cues that move cells along this path, scientists can sequence their RNA—the molecular messenger that translates DNA into proteins and other products. 

Sequencing RNA from a batch of cells is not ideal, however, because the cells are usually in different states of development. To address this problem, scientists have developed single-cell RNA sequencing. “It’s like a new microscope, giving us the ability to study many biological phenomena at once,” said Raul Rabadan, PhD, associate professor of systems biology and biomedical informatics at Columbia and co-author of the paper. “However, researchers are still left with the problem of understanding the relationships between different cell states, which drive the process of development.” 

To study cellular development, scientists use mathematical tools to analyze massive amounts of sequencing data. But these tools rely on underlying assumptions that narrow the possible results. “Due to the complexity involved in cellular development, models that make assumptions actually limit your ability to make new discoveries,” said Abbas Rizvi, PhD, a postdoctoral research scientist in Columbia’s Department of Biochemistry & Molecular Biophysics and the lead author of the paper. 

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Sex May Not Have Evolved Without Changes in Immune System

Sexual reproduction may have never become possible if organisms hadn’t evolved a way to restrain the immune system during fertilization, according to a new study from the lab of Sagi Shapira, PhD, assistant professor of systems biology.

The study, published today in Immunity, took an in-depth look at how vertebrate eggs are fertilized.

To fight invading pathogens, all organisms (including vertebrate cells) are programmed to detect and attack any DNA and foreign RNA found outside of the nucleus in the cell’s cytoplasm. It’s usually a safe bet that any DNA found in the cytoplasm is from a foreign microbe, because the cell’s own DNA is safely sequestered in the nucleus. But during fertilization, DNA and RNA from sperm may be briefly exposed to the cytoplasm of an egg—and to the danger of being recognized and attacked.

For fertilization to succeed, Dr. Shapira reasoned that something must prevent the immune system from attacking DNA during fertilization and searched for candidates in the genome.

The search revealed a gene called NLRP14, which encodes a protein that Dr. Shapira’s laboratory demonstrated to play a role in the innate immune system. Without NLRP14, the immune system induces a strong inflammatory response to DNA and RNA found in the cytoplasm, and the fertilization process comes to a halt.

The finding could lead to new ways to treat infertility or develop novel contraceptives.
NLRP14 and related genes are found in many other organisms, Dr. Shapira says, “and safeguarding the genetic material is hardwired into every organism. So, evolving machinery to inhibit that process in gametes may have been a prerequisite for the evolution of sexual reproduction.”

The finding could lead to new ways to treat infertility (about 2 percent of people carry a NLRP14 mutation) or, conversely, to develop novel contraceptives.

In addition, since NLRP14 suppresses a critical arm of the immune system, it may serve as a viable therapeutic target for tuning immune responses in various disease states (i.e., to dampen in the case of autoimmune diseases like IBD, asthma, and lupus, and enhance in the case of cancer).

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Erin Bush Receives College of Physicians & Surgeons Officer of Research Award

Erin Bush Receives Award

Erin Bush with Department of Systems Biology Assistant Professor Peter Sims and College of Physicians & Sciences Dean Lee Goldman. (Photo: Amelia Panico)

The Department of Systems Biology is proud to congratulate Erin Bush on being selected for the Columbia University College of Physicians & Surgeons 2016 Officer of Research Award. The award is one of six given annually to recognize select staff members for their outstanding contributions in the workplace. Recipients of the 2016 were recognized in a ceremony that took place at Columbia University Medical Center on January 12, 2017.

Erin is a staff associate in the JP Sulzberger Columbia Genome Center and a sequencing specialist working in the laboratories of Peter Sims and Andrea Califano. She has been helping to develop new next-generation sequencing techniques, focusing on low input and single cell DNA and RNA library preparation and testing. As the CUMC Newsroom reports:

Noted for her technical skill and professionalism, Ms. Bush was honored for her work in the Department of Systems Biology, where her time and expertise are split among three laboratories. At the Sulzberger Columbia Genome Center, her efforts boosted efficiency at the sequencing core facility and enabled the core’s expansion. More recently, she helped develop an RNA-sequencing technology with the Califano and Sims labs that allows researchers to screen drugs for genetic effects at low cost and high throughput. The new technology is a promising tool for disease research and precision medicine and has led to multimillion-dollar federal grants within the department.

The P&S Annual Awards recognize one employee each in the categories of Management, Administration, Research, Clerical & Technical, Diversity, and Community Service.

Congratulations, Erin!

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Harris Wang Named Recipient of Presidential Early Career Award for Scientists and Engineers

Harris WangHarris Wang

Harris Wang has been named a recipient of the prestigious Presidential Early Career Award for Scientists and Engineers (PECASE). Dr. Wang is among 102 researchers recognized today by President Barack Obama as the newest recipients of this honor.

The PECASE is considered the United States’ highest award for young scientists and engineers, conferred annually at the White House at the recommendation of participating federal agencies. The award celebrates young researchers at the beginning of their independent research careers who show exceptional promise to lead at the frontiers of twenty-first century science and technology.

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Columbia Scientists Receive Grant to Integrate Clinical and Molecular Data

Integrating data sources

Clinical and molecular data are currently stored in many different databases using different semantics and different formats. A new project called DeepLink aims to develop a framework that would make it possible to compare and analyze data across platforms not originally intended to intersect. (Image courtesy of Nicholas Tatonetti.)

Medical doctors and basic biological scientists tend to speak about human health in different languages. Whereas doctors in the clinic focus on phenomena such as symptoms, drug effects, and treatment outcomes, basic scientists often concentrate on activity at the molecular and cellular levels such as genetic alterations, gene expression changes, or protein profiles. Although these various layers are all related physiologically, there is no standard terminology or framework for storing and organizing the different kinds of data that describe them, making it difficult for scientists to systematically integrate and analyze data across different biological scales. Being able to do so, many investigators now believe, could provide a more efficient and comprehensive way to understand and fight disease.

A new project recently launched by Nicholas Tatonetti (Assistant Professor in the Columbia University Departments of Systems Biology and Biomedical Informatics) along with co-principal investigators Chunhua Weng (Department of Biomedical Informatics) and Michel Dumontier (Stanford University), aims to bridge this divide. With the support of a $1.1 million grant from the National Center for Advancing Translational Science (NCATS) the scientists have begun to develop a tool they call DeepLink, a data translator that will integrate health-related findings at multiple scales.

As Dr. Tatonetti explains, “We want to close what we call the interoperability gap, a fundamental difference in the language and semantics used to describe the models and knowledge between the clinical and molecular domains. Our goal is to develop a scalable electronic architecture for integrating the enormous multiscale knowledge that is now available.”

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