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Personalized Gene Delivery to the Gut

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.

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Designer Proteins Come with Built-In Safeguards

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.”

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Harris Wang’s Lab Receives Funding from the Gates Foundation to Study Childhood Mortality in Sub-Saharan Africa

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. 

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New Resource for Controlling Gene Expression in Bacteria

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." 

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Harris Wang Named 2018 Schaefer Scholar

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.”

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Harris Wang Named Recipient of Presidential Early Career Award for Scientists and Engineers

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.

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A Grand Challenge for Genome Engineering: Virginia Cornish and Harris Wang on the GP-write Project

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.

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Graduate Students Invent Technique for Reprogramming Translation

Andrew Anzalone and Sakellarios ZairisMD/PhD students Andrew Anzalone and Sakellarios Zairis combined approaches based in chemical biology, synthetic biology, and computational biology to develop a new method for protein engineering.

The ribosome is a reliable machine in the cell, precisely translating the nucleotide code carried by messenger RNAs (mRNAs) into the polypeptide chains that form proteins. But although the ribosome typically reads this code with uncanny accuracy, translation has some unusual quirks. One is a phenomenon called -1 programmed ribosomal frameshifting (-1 PRF), in which the ribosome begins reading an mRNA one nucleotide before it should. This hiccup bumps translation “out of frame,” creating a different sequence of three-nucleotide-long codons. In essence, -1 PRF thus gives a single gene the unexpected ability to code for two completely different proteins.

Recently Andrew Anzalone, an MD/PhD student in the laboratory of Virginia Cornish, set out to explore whether he could take advantage of -1 PRF to engineer cells capable of producing alternate proteins. Together with Sakellarios Zairis, another MD/PhD student in the Columbia University Department of Systems Biology, the two developed a pipeline for identifying RNA motifs capable of producing this effect, as well as a method for rationally designing -1 PRF “switches.” These switches, made up of carefully tuned strands of RNA bound to ligand-sensing aptamers, can react to the presence of a specific small molecule and reliably modulate the ratio in the production of two distinct proteins from a single mRNA. The technology, they anticipate, could offer a variety of exciting new applications for synthetic biology. A paper describing their approach and findings has been published in Nature Methods.

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Columbia Launches Undergraduate Synthetic Biology Team

Columbia University iGEM Team 2015

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.”

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Harris Wang Named Office of Naval Research Young Investigator

Gut-Brain Microbiota
A grant from the Office of Naval Research will support the development of three foundational synthetic biology technologies for engineering the human gut microbiota.

Harris Wang, an assistant professor in the Columbia University Department of Systems Biology, has been selected for the Office of Naval Research 2015 Young Investigators Program. This highly selective program promotes the development of early-career academic scientists whose research shows exceptional promise and creativity. With the support of this award, Dr. Wang will extend his research in the field of synthetic biology to develop new technologies for engineering the gut microbiome, the ecosystem of bacteria that inhabit the human digestive system. These new methods, Wang anticipates, could provide new ways of designing communities of different microbial species and ultimately modulating interactions between the gut, the immune system, and the brain.

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Functional Metagenomics Enables First Study of Bacterial Fitness in the Gut Microbiome

Gut bacteria

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.

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Harris Wang Named Winner of Sloan Research Fellowship

Harris Wang

Harris Wang, an assistant professor in the Columbia University Department of Systems Biology and Department of Pathology and Cell Biology, has been selected to receive a 2015 Alfred P. Sloan Foundation Research Fellowship in computational and evolutionary molecular biology. This two-year, $50,000 grant will support work that combines methods from synthetic biology and computational biology to study how horizontal gene transfer contributes to microbial evolution.

Since 1955, the Sloan Research Fellowship program has supported outstanding early-career scientists in recognition of their achievements and their potential to make important contribution to their fields. This year’s fellows included 126 investigators, with 12 awardees in the field of computational and evolutionary molecular biology. Other disciplines represented in the awards include chemistry, computer science, economics, mathematics, neuroscience, ocean sciences, and physics.

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New Directions in Genome Engineering: An Interview with Harris Wang

Harris Wang

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.

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Synthetic and Systems Biology: Reinventing the Code of Life

A panel at the Helix Center, titled "Synthetic and Systems Biology: Reinventing the Code of Life included Columbia University professors Saeed Tavazoie and Andrea Califano, as well as Michael Hecht (Professor of Chemistry, Princeton University), Mark Fishman (President, Novartis Institutes for BioMedical Research), Christopher Mason (Assistant Professor of Physiology and Biophysics, Institute for Computational Biology, Weill Cornell Medical College), and Michael Waldholz (Medical Science Writer and Media Consultant).

Advances in genomics and the development of new technologies over the past decade have given biologists the ability to engineer DNA to perform specific functions. This emerging science, called synthetic biology, holds great potential for a number of applications, and experiments have already been done to reprogram algae to produce biofuels, design bacteria that can sense and consume toxic substances, and use living cells to manufacture compounds that can be used as drugs.

Synthetic biology has emerged in parallel with systems biology, but in many ways the two sciences are closely intertwined. As systems biology improves our mechanistic understanding of how biology functions at the molecular level, synthetic biology is taking this knowledge to push biology in new directions, from synthesizing molecules using biology all the way to synthesizing new forms of biological life.

In a public roundtable discussion at the Helix Center in New York City, Columbia University Department of Systems Biology professors Saeed Tavazoie  and Andrea Califano  joined a panel of experts in discussing the intersection of systems and synthetic biology, and the role that these two disciplines will play in the development of the biological and biomedical sciences in the coming years.

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