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.

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:

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.

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.”

Regulators of mesenchymal GBM subtype

An example of tumor oncotecture. Transcription factors involved in the activation of mesenchymal glioblastoma subtype are shown in purple. Together, they comprise a tightly knit tumor checkpoint, controlling 74% of the genes in the mesenchymal signature of high-grade glioma. CEBP (both β and δ subunits) and STAT3 regulate the other three transcription factors in the tumour checkpoint, synergistically regulating the state of mesenchymal GBM cells. (Image: Nature Reviews Cancer)

In a detailed Perspective article published in Nature Reviews Cancer, Department of Systems Biology chair Andrea Califano and research scientist Mariano Alvarez (DarwinHealth) summarize more than a decade of work to propose the existence of a universal, tumor independent “oncotecture” that consistently defines cancer at the molecular level. Their findings, they argue, indicate that identifying and targeting highly conserved, essential proteins called master regulators — instead of the widely diverse genetic and epigenetic alterations that initiate cancer and have been the focus of much cancer research — could offer an effective way to classify and treat disease.

As coverage of the paper in The Economist reports:

ONE of the most important medical insights of recent decades is that cancers are triggered by genetic mutations. Cashing that insight in clinically, to improve treatments, has, however, been hard. A recent study of 2,600 patients at the M.D. Anderson Cancer Centre in Houston, Texas, showed that genetic analysis permitted only 6.4% of those suffering to be paired with a drug aimed specifically at the mutation deemed responsible. The reason is that there are only a few common cancer-triggering mutations, and drugs to deal with them. Other triggering mutations are numerous, but rare—so rare that no treatment is known nor, given the economics of drug discovery, is one likely to be sought. 

Facts such as these have led many cancer biologists to question how useful the gene-led approach to understanding and treating cancer actually is. And some have gone further than mere questioning. One such is Andrea Califano of Columbia University, in New York. He observes that, regardless of the triggering mutation, the pattern of gene expression—and associated protein activity—that sustains a tumour is, for a given type of cancer, almost identical from patient to patient. That insight provides the starting-point for a different approach to looking for targets for drug development. In principle, it should be simpler to interfere with the small number of proteins that direct a cancer cell’s behaviour than with the myriad ways in which that cancer can be triggered in the first place. (Read full article.)