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MAGIC - Wang Lab

Illustrated here: (a) In contrast to traditional approaches to cultivate microbes first and then test for genetic accessibility, MAGIC harnesses horizontal gene transfer in the native environment to genetically modify bacteria in situ. (b) MAGIC implementation to transfer replicative or integrative pGT vectors from an engineered donor strain into amenable recipients in a complex microbiome. Replicative vectors feature a broad-host range origin of replication (oriR), while integrative vectors contain a transposable Himar cassette and transposase. The donor E. coli strain contains genomically integrated conjugative transfer genes (tra) and a mCherry gene. Transconjugant bacteria are detectable based on expression of an engineered payload that includes GFP and an antibiotic resistance gene (abr).

A team of researchers, led by Dr. Harris Wang of the Department of Systems Biology , has engineered bacteria to benefit and improve the overall health of our gut microbiome. In a proof-of-concept paper published in Nature Methods , Dr. Wang and his team demonstrate MAGIC, an innovative gene delivery system that ‘hacks’ the gut microbiome to perform any desired function, from harvesting energy from food and protecting against pathogen invasion to bolstering anti-inflammatory properties and regulating immune responses.

“The MAGIC system allows us to insert new gene functions directly into an existing microbiome without permanently altering the composition of the microbiome as a whole,” says Sway Chen , an MD/PhD student in the Wang lab and co-author of the study.

Time lapse of a developing drosophila embryo. (Credit: Carlos Sanchez-Higueras/Hombría lab/CABD)

Every animal, from an ant to a human, contains in their genome pieces of DNA called Hox genes. Architects of the body, these genes are keepers of the body’s blueprints; they dictate how embryos grow into adults, including where a developing animal puts its head, legs and other body parts. Scientists have long searched for ways to decipher how Hox genes create this body map; a key to decoding how we build our bodies.

Now an international group of researchers from Columbia University and the Spanish National Research Council (CSIC) based at the Universidad Pablo de Olavide in Seville, Spain have found one such key: a method that can systematically identify the role each Hox gene plays in a developing fruit fly. Their results, reported recently in Nature Communications , offer a new path forward for researchers hoping to make sense of a process that is equal parts chaotic and precise, and that is critical to understanding not only growth and development but also aging and disease.

“The genome, which contains thousands of genes and millions of letters of DNA, is the most complicated code ever written,” said study co-senior author Richard Mann , PhD, principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute and a faculty member in the Department of Systems Biology . “Deciphering this code has proven so difficult because evolution wrote it in fits and starts over hundreds of millions of years. Today’s study offers a key to cracking that code, bringing us closer than ever to understanding how Hox genes build a healthy body, or how this process gets disrupted in disease.”

Read the full article at the Zuckerman Institute

Sagi Shaipra PHIPSTer Cell Paper
Researchers implement P-HIPSTer, an in silico computational framework that leverages protein structure information to identify approximately 282,000 protein-protein interactions across all fully-sequenced human-infecting viruses (1001 in all). This image highlights that in addition to rediscovering known biology, P-HIPSTer has yielded a series of new findings and enables discovery of a previously unappreciated universe of cellular circuits and biological principles that act on human-infecting viruses. (Image Courtesy of Dr. Sagi Shapira)

Researchers at Columbia University Irving Medical Center have leveraged a computational method to map protein-protein interactions between all known human-infecting viruses and the cells they infect. The method, along with the data that it generated, has spawned a wealth of information toward improving our understanding of how viruses manipulate the cells that they infect and cause disease. Among its findings, the work uncovered a role for estrogen receptor in regulating Zika Virus (ZIKV) infection, as well as links between cancer and the human papillomavirus (HPV).

The research, led by Sagi Shapira , PhD, Assistant Professor in the Department of Systems Biology and the Department of Microbiology & Immunology at Columbia University Vagelos College of Physicians and Surgeons , appears today in the journal, Cell . Dr. Shapira’s collaborators include Professors Barry Honig , PhD, of Systems Biology and of Biochemistry and Molecular Biophysics and Raul Rabadan , PhD, of Systems Biology and of Biomedical Informatics. 

Protein engineering is a relatively young field that creates new proteins never seen before in nature. Today’s protein engineers usually create synthetic proteins by making small changes to the gene that encodes a naturally occurring protein. The variety of synthetic proteins range from stain-removing enzymes that have improved detergents to a long-acting insulin that’s used by millions of people with diabetes.

But two big unsolved challenges for protein engineers remain: The gene encoding the synthetic protein needs to be contained to prevent escape into other organisms and the gene needs to resist mutating over time so the protein doesn’t lose its function.

By merging two genes into a single DNA sequence, Columbia University synthetic biologists have created a method that could prevent human-engineered proteins from spreading into the wild, as well as stabilize synthetic proteins so they don’t change over time. The work, recently published in Science, was developed by Harris Wang, PhD, assistant professor of systems biology, with graduate student, Tomasz Blazejewski and postdoctoral scientist, Hsing-I Ho, PhD. 

In devising the method, the researchers were inspired by overlapping genes in viruses. When two different genes overlap, they occupy the same sequence of DNA. But the genes are read in different frames so that two different proteins are produced.

In overlapping genes, a random mutation in the sequence may not affect one gene, but it’s likely that it will harm the second gene.

“Overlapping genes essentially lock in a specific DNA sequence, and we thought we could exploit this idea for synthetic biology ...Ten years ago, we didn’t have the technology that would make this possible,” says Dr. Wang. “We didn’t have enough sequences in the database to make informed predictions and we didn’t have a way to synthesize long DNA sequences for testing our predictions.”

The gut microbiome–composed of hundreds of different species of bacteria–is a complex community and a challenge for scientists to unravel. One specific challenge is the spatial distribution of different microbes, which are not evenly distributed throughout the gut. A new method developed by the lab of Dr. Harris Wang should help scientists locate and characterize these neighborhoods, which could shed light on how microbes influence the health of their hosts.

Techniques that can identify all species in the gut microbiome only work with homogenized samples (like stool), but methods that preserve spatial information can only cope with a handful of species.

Dr. Wang, assistant professor of systems biology and of pathology & cell biology, and graduate student Ravi Sheth in the Department of Systems Biology, tested the new technique with mice who switched from a low-fat to a high-fat diet. Diet is known to change the abundance of specific bacteria in the gut within days, but the new technique also revealed that the switch caused wholesale changes of microbial neighborhoods.

“Specific regions of bacteria were entirely lost with a switch in diet,” Sheth says. “This was exciting to us as it will give us clues to understanding how that change happens and how the change may impact health.”

Read the full article in the CUIMC Newsroom

The research, titled “Spatial metagenomic characterization of microbial biogeography in the gut,” was published July 22 in Nature Biotechnology.

 

Wang Lab
Ravi Sheth (left) and Harris Wang, PhD

Dr. Harris Wang , PhD, and systems biology graduate student, Ravi Sheth , have been awarded a new grant from the Bill and Melinda Gates Foundation to help advance a global health project aimed at reducing childhood mortality in sub-Saharan Africa. The project incorporates Dr. Wang’s innovative microbiome research techniques and applies them to study the antibiotic, Azithromycin, towards understanding its role as an intervention for improving childhood survival rates in rural low-income, low-resource settings.

The study supported by the Gates grant expands on breakthrough research conducted in the MORDOR study , a cluster-randomized trial in which communities in Malawi, Niger and Tanzania were assigned to four twice-yearly mass distributions of either oral Azithromycin or placebo. Children, as young as 12 months of age, participated, and results indicated that the all-cause mortality rate was significantly lower for communities receiving the antibiotic versus placebo. 

“This is an extremely exciting and, in many ways, very surprising result for such an underserved population,” says Sheth, who is a fourth-year PhD student in the systems biology track at Columbia University Irving Medical Center (CUIMC) . “Now it is crucial to understand how Azithromycin is acting to increase survival in such a profound way – to aid scale-up of the intervention and to help optimize the treatment regime and minimize any unintended consequences.” 

The researchers will focus on developing a mechanistic understanding of how Azithromycin reshapes the gut microbiome, and how this altered microbiome state affects the host. The effect of the antibiotic will be studied over space and time to understand the perturbation to the gut ecosystem and resulting community re-configuration and re-assembly, and this information will be utilized to predict and test optimal dosing strategies. 

Yufeng Shen Episcore

The epigenomic profile of RBFOX2, a haploinsufficient gene recently identified as a risk gene of congenital heart disease. Each small box represents 100 bp region around transcription start sites (TSSs) and the shade of the color reflect the strength of the histone mark signal in tissues under normal conditions. RBFOX2 has large expansion of active histone marks (H3K4me3 and H3K9ac), especially in heart and epithelial tissues (purple and gray rows), and tissue-specific suppression mark (H3K27me3) in blood samples.(Credit: Shen lab)

The genetics of developmental disorders, such as congenital heart disease and autism, are highly complex. There are roughly 500 to 1,000 risk genes that can lead to each of these diseases, and to date, only about a few dozen have been identified. Scientists have ramped up efforts to develop computational approaches to address challenges in accurately identifying genetic risk factors in ongoing genetic studies, and the availability of such tools would greatly assist researchers in gaining a deeper understanding of the root causes of these diseases. 

Focusing on haploinsufficiency, a key biological mechanism of genetic risk in developmental disorders, Yufeng Shen , PhD, and his lab have developed a novel computational method that enables researchers to find new risk genes in these diseases. Their key idea is that the expression of haploinsufficient genes must be precisely regulated during normal development, and such regulation can be manifested in distinct patterns of genomic regulatory elements. Using data from the NIH Roadmap Epigenomics Project, they showed there is a strong correlation of certain histone marks and known haploinsufficient genes. Then based on supervised machine learning algorithms, they developed a new method, which they call Episcore , to predict haploinsufficiency from epigenomic data representing a broad range of tissue and cell types. Finally, they demonstrate the utility of Episcore in identification of novel risk variants in studies of congenital heart disease and intellectual disability.  

A research team from Columbia University Irving Medical Center has received a 2018 PCF Challenge Award from the Prostate Cancer Foundation (PCF) to advance prostate cancer research. The interdisciplinary team at Columbia includes leading experts in systems biology, cancer research and medicine from Columbia’s Department of Systems Biology and the Herbert Irving Comprehensive Cancer Center (HICCC)

Announced today, PCF is awarding more than $5.5 million in funding to a total of six teams to conduct research with the highest potential for accelerating new and improved treatments for advanced prostate cancer. PCF is one of the largest non-governmental organizations dedicated solely to funding prostate cancer research, and its annual Challenge Awards are highly coveted in the scientific and medical fields. 

In the United States, prostate cancer is the most common non-skin cancer, and 1 out of every 9 men in the U.S. will be diagnosed with the disease in his lifetime. To date, treatment of the most aggressive forms of prostate cancer represents a clinical challenge. After treatment failure with anti-androgen drugs, which are part of the standard of care for advanced metastatic prostate cancer, only few current therapeutic options remain and the impact on patient survival is limited. Indeed, the field needs major innovative, out-of-the-box approaches to new therapies to combat advanced prostate cancer. 

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. 

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.