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. 

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.”

Department of Systems Biology bioengineer Harris Wang describes the goals of the Human Genome Project - Write (HGP-write), an international initiative to develop new technologies for synthesizing very large genomes from scratch. 

In June 2016, a consortium of synthetic biologists, industry leaders, ethicists, and others  published a proposal in Science calling for a coordinated effort to synthesize large genomes, including a complete human genome in cell lines. The organizers of the project, called GP-write (for work in model organisms and plants) or sometimes HGP-write (for work in human cell lines), envision it as a successor to the Human Genome Project (retroactively termed HGP-read), which 25 years ago promoted rapid advances in DNA sequencing technology. As the ability to read the genome became more efficient and less expensive, it in turn enabled a revolution in how we study biology and attempt to improve human health. Now, by coordinating the development of new technologies for writing DNA on a whole-genome scale, GP-write aims to have a similarly transformative impact.

Among the paper’s authors were Virginia Cornish and Harris Wang, two members of the Columbia University Department of Systems Biology whose contributions to the field of engineering biology have in part made the idea of writing large-scale DNA sequences imaginable. We spoke with them to learn more about what GP-write hopes to accomplish, its potential benefits, and how the effort is evolving.

The Columbia University 2015 iGEM Team (l-r): Hudson Lee, Suppawat Kongthong, Jacky Cheung, Kenya Velez, Samuel Magaziner, and faculty moderator Harris Wang.

A team of undergraduate students based at Columbia University for the first time participated in this year’s International Genetically Engineered Machine Foundation (iGEM) competition. Supervised by Department of Systems Biology Assistant Professor Harris Wang, the team spent this past summer developing a project that used synthetic biology methods to engineer an edible, probiotic consortium of bacteria that could regulate hunger and digestion. In September they presented their results at the iGEM Giant Jamboree in Boston, MA, where they received a silver medal for their efforts. (For more informtion about their project, see the Columbia iGEM Team website.)

“I think it’s fantastic that this ambitious group of undergraduates worked so hard to represent Columbia University on this international stage,” says Dr. Wang. “Columbia has one of the great undergraduate colleges, and now that we have a critical mass of interested students and faculty laboratories with expertise in synthetic biology, we think iGEM offers a valuable opportunity to compete with and learn from teams at other leading institutions.”

Photo by David Gregory and Debbie Marshall, Wellcome Images. 

Recent deep sequencing studies are providing an increasingly detailed picture of the genetic composition of the human microbiome, the diverse collection of bacterial species that inhabit the gut. At the same time, however, little is known about the dynamics of these colonies, particularly why certain microbial strains outcompete others in the same environment. In a new paper published in the journal Molecular Systems Biology, Department of Systems Biology Assistant Professor Harris Wang, in collaboration with Georg Gerber and researchers at Harvard University, report on their development of the first method for using functional metagenomics to identify genes within commensal bacterial genomes that give them an evolutionary fitness advantage.

As a graduate student in George Church’s lab at Harvard University, Harris Wang developed MAGE, a revolutionary tool for the field of synthetic biology that made it possible to introduce genomic mutations into E. coli cells in a highly specific and targeted way. Now an Assistant Professor in the Columbia University Department of Systems Biology, Dr. Wang recently published a paper in ACS Synthetic Biology that introduces an important advance in the MAGE technology. The new technique, called (MO)-MAGE, uses microarrays to engineer pools of oligonucleotides that, once amplified and integrated into a genome, can generate thousands or even millions of highly controlled mutations simultaneously. This new method offers a cost-effective way for designing and producing large numbers of genomic variants and provides an efficient platform for experimentally exploring genome-wide landscapes of mutations in bacteria and optimizing the organisms’ biochemical capabilities.

In the following interview, Dr. Wang explains the origins of the new technology, and discusses what he sees as the remarkable potential it holds for both basic biological research and industrial applications of synthetic biology.

How are MAGE and (MO)-MAGE different from more traditional methods in genome engineering?

In traditional genome engineering, researchers would induce genome perturbations randomly. For example, you might use ultraviolet radiation or a mutagen to generate mutations and then do a selection experiment to compare and isolate cells with different genotypes based on how they respond to specific stimuli. The problem with this approach, though, is that you have no way to control what mutations occur, even if you know the mutation you are interested in investigating.

(MO)-MAGE offers a cost-effective and efficient way to simultaneously mutate large numbers of genes in a targeted way.