Columbia investigators win Chan Zuckerberg Initiative grants to accelerate development of cellular roadmap of the human body.

In two groundbreaking research projects contributing to the Human Cell Atlas, Columbia University scientists are tasked with mapping complete cells in the immune system and the human spine. The global effort is aiming to identify and define every cell type of the human body and create a collection of maps for navigating the cellular basis of human health and disease.

Peter Sims, PhD, assistant professor of systems biology

The Columbia teams, which include co-principal investigators from the Department of Systems Biology Drs. Peter Sims and Raul Rabadan , are among the 38 collaborative science teams launching the Chan Zuckerberg Initiative’s (CZI) Seed Networks for the Human Cell Atlas project announced today. The three-year projects, receiving a total of $68 million in award funding by Seed Networks, are collaborative groups that are bringing together expertise in science, computational biology, software engineering, and medicine to support the ongoing progress of the Human Cell Atlas .

Investigating the Immune System + Aging

Dr. Sims, part of an international team including close collaborator Dr. Donna Farber of the Department of Surgery , is combining single-cell sequencing technologies, data analysis, and immunology expertise to better understand how the immune system ages and gain new insights into how human diseases occur. 

Dr. Raul Rabadan is leading a global research project as part of a new grant from the Pancreatic Cancer Collective to identify high-risk factors of pancreatic cancer. (Courtesy of Stand Up to Cancer)

A global team of researchers led by theoretical physicist Raul Rabadan, PhD, professor of systems biology at Columbia’s Vagelos School of Physicians and Surgeons, and Núria Malats, MD, PhD, head of the Genetic and Molecular Epidemiology Group of the Spanish National Cancer Research Centre (CNIO), are working to develop a comprehensive computational framework that will identify high-risk factors for pancreatic cancer.  

Armed with a new two-year, $1 million grant from the Pancreatic Cancer Collective, the team intends to attack pancreatic cancer research from multiple disciplines—genomics, mathematics and medicine—to provide an integrated, computational approach to studying genomic, environmental and immune factors that could identify populations at high risk of pancreatic cancer. The need for deeper understanding of the contributing factors to this lethal disease is pressing, as pancreatic cancer is projected to become the second leading cause of cancer-related mortality within the next decade. 

Drs. Raul Rabadan and Nuria Malats

Peter Sims, PhD

The Mark Foundation for Cancer Research has awarded Peter Sims , PhD, an Emerging Leader Award and will support his work to advance a novel use of single-cell RNA sequencing to develop brain cancer treatments. Dr. Sims, assistant professor of systems biology at Columbia University Irving Medical Center, is one of just eight recipients of the inaugural grant, given to promising early career scientists for projects aimed at substantially unmet needs in cancer risk prediction, prevention, detection and treatment. 

Dr. Sims is an early contributor to the emerging field of large-scale single-cell RNA sequencing, which has made it possible to analyze tens of thousands of cells while simultaneously obtaining imaging and genomic data from each individual cell. He will be using this approach to improve patient-derived models of glioblastoma multiforme (GBM), an aggressive form of cancer that invades the brain, making complete resection difficult. In other words, making it extremely difficult in surgery to remove all cancerous cells from the brain. To date, drug therapies for this type of aggressive brain cancer have had limited success, partly because of the heterogeneity of these tumors. Furthermore,  current patient-derived models for researching glioblastoma do not fully recapitulate the cellular diversity of tumor cells that are present in the tumor, so it is extremely challenging to classify those cells in order to match them with the drug therapies that work. 

Indeed, there is a critical need to better characterize and understand GBM. Dr. Sims has collaborated with several brain tumor experts in the Herbert Irving Comprehensive Cancer Center , including Drs. Peter Canoll, Jeffrey Bruce, Antonio Iavarone and Anna Lasorella to advance single-cell genomic approaches to characterizing this disease. Approaching this problem at the single cell level could result in development of novel treatments that  prioritize and identify the specific drug therapies that may actually work on diminishing these tumor cells. The ultimate goal is to attain better predictions of therapeutic efficacy. 

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. 

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.

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. 

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.”

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!

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.”