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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.

 

Dr. Harris Wang of Systems Biology
Dr. Harris Wang is lead PI on a new DARPA-funded project developing novel therapies to counter effects of high-dose ionizing radiation.

Harris Wang, PhD, assistant professor of systems biology at Columbia University Irving Medical Center , is leading a team of experts in radiation research, CRISPR-Cas technologies, and drug delivery on an innovative new project announced June 27 funded by the Defense Advanced Research Projects Agency (DARPA) . The up to $9.5M project focuses on pursuing a therapy to protect the body from the effects of high-dose ionizing radiation, and is part of DARPA's initiative to fund research into new strategies to combat public health and national security threats.

In humans, acute radiation syndrome primarily affects stem cells in the blood and gut, yet existing treatments only help to regenerate blood cells, and only with limited effect. There is no possibility for prophylactic administration of these drugs, and most must be delivered immediately following radiation exposure to provide any benefit. There are no existing medical countermeasures for radiation damage to the gut.

The Columbia team aims to develop an orally delivered programmable gene modulator therapeutic. The multimodal treatment the team envisions would take hold in both the gut and liver, triggering protection and regeneration of intestinal cells, while also inducing liver cells to produce protective cues that trigger the regeneration of blood cells in bone marrow.

Cory Abate-Shen, PhD, a distinguished scientist whose multidisciplinary research has advanced our understanding of the molecular basis of cancer initiation and progression, has been named chair of the Department of Pharmacology at Columbia University Vagelos College of Physicians and Surgeons. Her appointment will be effective April 1, 2019.

Recruited to Columbia in 2007, Dr. Abate-Shen is currently the Michael and Stella Chernow Professor of Urologic Sciences and professor of pathology & cell biology, medicine, and systems biology. She has served as the leader of the prostate program, associate director, and twice as interim director of the Herbert Irving Comprehensive Cancer Center (HICCC) at Columbia University Irving Medical Center and NewYork-Presbyterian.

An internationally recognized leader in genitourinary malignancies, Dr. Abate-Shen is particularly interested in advancing our understanding of the mechanisms and modeling of prostate and bladder tumors. An innovator in the generation of novel mouse models for these cancers, her work has led to the discovery of new biomarkers for early detection, as well as key advances in cancer prevention and treatment.

In the fall of 2018, Dr. Abate-Shen was elected a fellow of the American Association for the Advancement of Science (AAAS). She is an American Cancer Society Professor, the first faculty member at Columbia University Vagelos College of Physicians and Surgeons to have received this honor. Previously, she served as a member of the National Cancer Institute’s Board of Scientific Counselors, and she currently is a member of the board of directors of the American Association of Cancer Research. 

Dr. Abate-Shen will succeed Robert S. Kass, PhD, the Hosack Professor of Pharmacology, Alumni Professor of Pharmacology, and chair of pharmacology since 1995.

Visit the CUIMC Newsroom for the full announcement

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. 

 

Cory Abate-Shen
Cory Abate-Shen, PhD

Cory Abate-Shen , PhD, who is known for her leading work in the development of innovative mouse models for translational research in prostate and bladder cancers, has been elected a fellow of the American Association for the Advancement of Science (AAAS) . The AAAS is honoring Dr. Abate-Shen for her work in mouse models to better understand how basic cellular mechanisms are co-opted in cancer and for her contributions to the field of cancer biology. 

She joins a class of 416 new fellows, including two additional Columbia University faculty members, Drs. Richard Axel and Upmanu Lall, who also were elected today to the prestigious group. 

Dr. Abate-Shen, the Michael and Stella Chernow Professor of Urologic Sciences at Columbia University Irving Medical Center (CUIMC) , holds joint appointments in the Departments of Systems Biology , Medicine and Pathology & Cell Biology , and is a member and former interim director of the Herbert Irving Comprehensive Cancer Center (HICCC) . An internationally recognized leader in genitourinary malignancies, Dr. Abate-Shen is particularly interested in advancing our understanding of the mechanisms and modeling of prostate and bladder tumors. An innovator in the generation of novel mouse models for these cancers, her work has led to the discovery of new biomarkers for early detection, as well as key advances in cancer prevention and treatment. Dr. Abate-Shen has been the recipient of numerous awards, including a Sinsheimer Scholar Award, an NSF Young Investigator Award, a Bladder Cancer Advocacy Network Innovator Award and the Women in Cell Biology Junior Award from the American Society for Cell Biology. Currently, she is an American Cancer Society Research Professor, the first to be awarded at CUIMC. 

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.

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.

Faculty

Hynek Wichterle

Associate Director, Columbia Genome Center
Co-director, Columbia Stem Cell Initiative
Vice-Chief, Division of Regenerative Medicine
Associate Professor, Departments of Pathology & Cell Biology, and Neuroscience (in Neurology)

Associate Director

Faculty

Harris Wang

Assistant Professor, Department of Systems Biology

Assistant Professor, Department of Systems Biology

Faculty

Adolfo Ferrando

Associate Professor, Departments of Pathology and Pediatrics

Associate Professor, Departments of Pathology and Pediatrics

Faculty

Cory Abate-Shen

Michael and Stella Chernow Professor of Urological Oncology
Michael and Stella Chernow Professor of Urological Oncology