Videos of flies (5x speed) using FlyWalker, a program that enables scientists to label and track the position of each of the fly’s footfalls, thereby building a high-resolution picture of it’s walking gait. Top: normal fly walking at around 25 mm/s. Bottom: fly with its VNC serotonin neurons stimulated, which slows its speed to 15 mm/s (Credit: Clare Howard/Mann lab/Columbia's Zuckerman Institute)

A Columbia University study in fruit flies has identified serotonin as a chemical that triggers the body’s startle response, the automatic deer-in-the-headlights reflex that freezes the body momentarily in response to a potential threat. Today’s study reveals that when a fly experiences an unexpected change to its surroundings, such as a sudden vibration, release of serotonin helps to literally — and temporarily — stop the fly in its tracks.

These findings, recently published in Current Biology , offer broad insight into the biology of the startle response, a ubiquitous, yet mysterious, phenomenon that has been observed in virtually every animal studied to date, from flies to fish to people.

“Imagine sitting in your living room with your family and — all of a sudden — the lights go out, or the ground begins to shake,” said Richard Mann , PhD, a principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute and the paper’s senior author. “Your response, and that of your family, will be the same: You will stop, freeze and then move to safety. With this study, we show in flies that a rapid release of the chemical serotonin in their nervous system drives that initial freeze. And because serotonin also exists in people, these findings shed light on what may be going on when we get startled as well.”

In the brain, serotonin is most closely associated with regulating mood and emotion. But previous research on flies and vertebrates has shown it can also affect the speed of an animal’s movement. The Columbia researchers’ initial goal was to more fully understand how the chemical accomplished this.

Nicholas Tatonetti, Phd

Nicholas Tatonetti , PhD, solves problems. He has always enjoyed it, and as the informatics community has discovered, he is both creative and proficient in his methods.

Dr. Tatonetti, who was recently awarded tenure and promoted to the rank of Associate Professor in the Columbia Department of Biomedical Informatics (DBMI) and Department of Systems Biology , focuses on the use of advanced data science methods, including artificial intelligence and machine learning, to investigate medicine safety. Using emerging resources, such as electronic health records (EHR) and genomics databases, his lab is working to identify for whom these drugs will be safe and effective and for whom they will not.

His path to Columbia wasn’t a traditional one, but that fits his work. Since joining in 2012, Dr. Tatonetti has used non-traditional thinking to benefit both health and healthcare.

Utilizing both data mining of medical records and prospective lab experiments, Dr. Tatonetti created a methodology for both finding and validating adverse drug reactions and drug-drug interactions. During a two-year collaboration with Pulitzer Prize-winning journalist Sam Roe of the Chicago Tribune , Dr. Tatonetti discovered that the drugs ceftriaxone and lansoprazole, when taken together, induces an arrhythmia in the heart.

The data mining identified adverse effects, while the lab experiments established causality. Dr. Tatonetti wasn’t specifically looking for a negative reaction of those particular drugs; he had no reason to suspect them.

“We are able to find things that nobody expects to happen because the world of hypotheses we consider is basically everything,” he said. “We consider every possible combination, a type of analysis that would be impossible without a huge data set and significant computational power.”

A wide range of research topics, from studies related to pediatric cancer and glioblastoma to soil microbial communities and electronic health records analysis—were presented and discussed at this year’s Department of Systems Biology (DSB) retreat. 

Eugene Douglass, postdoctoral research scientist in the Andrea Califano lab, was one of the featured presenters at the two-day retreat. For a photo gallery, view the DSB Retreat Photo Album.

Held over two days for the first time, October 3 to 4 in Ellenville, NY, the retreat gave DSB faculty, post-docs, and students a chance to get away from the bustle of New York City, learn about their peers’ research, both from Morningside labs and CUIMC labs, and network. The department this year expanded its annual program over two days, encouraging more peer-to-peer connecting and devoted the spotlight specifically to research by young investigators. 

DSB researchers and graduate students participated in a poster competition held the first evening, and reviewed by Systems Biology faculty judges. At the end of the second day’s program, three Best Poster winners were announced by Andrea Califano, Dr, chair of the department. Poster competition winners this year were: Dafni Glinos , PhD, postdoctoral researcher in the lab of Dr. Tuuli Lappalainen at New York Genome Center/Systems Biology; Alexander Kitaygorodsky , a graduate student in the lab of Dr. Yufeng Shen; and Jordan Metz , an MD/PhD graduate student in the lab of Dr. Peter Sims. The poster winners gave presentations on the final day of the retreat and received a cash prize and an award certificate. 

Winning Research:

Dafni Glinos

Long-Read Sequencing to Study Allelic Effects on Transcriptome Structure

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.

Dr. Tal Korem

Tal Korem, PhD, has been named a CIFAR Azrieli Global Scholar, a fellowship that supports leading early-career researchers in science and technology. 

Dr. Korem is an assistant professor of systems biology with a joint appointment in obstetrics and gynecology at Columbia University Vagelos College of Physicians & Surgeons, and a faculty member of the Program for Mathematical Genomics . As a global scholar, he is joining CIFAR’s Humans and the Microbiome research program, where his work will focus on harnessing human microbial communities to identify and develop novel diagnostic and therapeutic tools.

CIFAR’s  Azrieli Global Scholars program supports its fellows through funding and mentorship, emphasizing essential network and professional skills development. The scholars join CIFAR research programs for a two-year period where they collaborate with fellows and brainstorm new approaches to pressing science and technology problems. Research topics are diverse, ranging from bio-solar energy and visual consciousness to engineered proteins and the immune system. 

Dr. Korem is one of 14 researchers out of an applicant pool of 217 selected by the Canadian-based nonprofit organization. This year’s cohort represents citizenship in eight countries and appointments in institutions from Canada, the U.S.,  Israel, Australia, the Netherlands, and Spain.

-Melanie A. Farmer

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.”

Awarded tenure this year in the Department of Systems Biology, left to right: Dr. Nicholas Tatonetti, Dr. Yufeng Shen, and Dr. Chaolin Zhang.

Congratulations to Drs. Yufeng Shen, Nicholas Tatonetti, and Chaolin Zhang of the Department of Systems Biology, who have been awarded tenure and promoted to associate professor. Their new appointments are effective July 1, 2019. 

Yufeng Shen, PhD

Dr. Shen joined Columbia University Irving Medical Center in 2011 as an Assistant Professor in Systems Biology and Biomedical Informatics. He directs a research group focused on studies of human biology and diseases using genomic and computational approaches. They are developing new methods to interpret genomic variations by machine learning based on biological mechanisms, and using these methods in large-scale genome sequencing studies to identify new genetic causes of human diseases, such as autism, birth defects, and cancer. His group also works on modeling of clonal and transcriptional dynamics of immune cells to improve our understanding of human adaptive immune system under normal and clinical conditions. Dr. Shen serves as an Associate Director of the JP Sulzberger Columbia Genome Center, a member of the Program in Mathematical Genomics, and an adjunct member of Columbia Center for Translational Immunology. 

Nicholas Tatonetti, PhD

Dr. Tatonetti, whose primary appointment is in the Department of Bioinformatics, has an interdisciplinary appointment with both the Departments of Systems Biology and Medicine. Dr. Tatonetti’s lab specializes in advancing the application of data science in biology and health science. His group integrates their medical observations with systems and chemical biology models to not only explain drug effects, but also to gain further understanding of basic biology and human disease.

Columbia investigators win Chan Zuckerberg Initiative grants to accelerate development of cellular roadmap of the human body.

In two groundbreaking research projects contributing to the Human Cell Atlas, Columbia University scientists are tasked with mapping complete cells in the immune system and the human spine. The global effort is aiming to identify and define every cell type of the human body and create a collection of maps for navigating the cellular basis of human health and disease.

Peter Sims, PhD, assistant professor of systems biology

The Columbia teams, which include co-principal investigators from the Department of Systems Biology Drs. Peter Sims and Raul Rabadan , are among the 38 collaborative science teams launching the Chan Zuckerberg Initiative’s (CZI) Seed Networks for the Human Cell Atlas project announced today. The three-year projects, receiving a total of $68 million in award funding by Seed Networks, are collaborative groups that are bringing together expertise in science, computational biology, software engineering, and medicine to support the ongoing progress of the Human Cell Atlas .

Investigating the Immune System + Aging

Dr. Sims, part of an international team including close collaborator Dr. Donna Farber of the Department of Surgery , is combining single-cell sequencing technologies, data analysis, and immunology expertise to better understand how the immune system ages and gain new insights into how human diseases occur. 

Dr. Andrea Califano sits down with BioTechniques at AACR. Video: Courtesy of BioTechniques.

At the 2019 annual meeting of the American Association for Cancer Research (AACR), Dr. Andrea Califano sat down with BioTechniques News for an overview on the field of systems biology and its impact in cancer research and in precision medicine. Dr. Califano is a pioneering researcher in the fast-growing field of systems biology whose expertise is in developing innovative, systematic approaches to identify the molecular factors that lead to cancer progression and to the emergence of drug resistance at the single-cell level. A physicist by training, Dr. Califano is the Clyde and Helen Wu Professor of Chemical and Systems Biology, founding chair of the Department of Systems Biology at Columbia University Irving Medical Center, director of the Columbia Genome Center and a program leader at the Herbert Irving Comprehensive Cancer Center.

The video interview is part of the series, Behind the Technqiue by BioTechniques News. 

Tuuli Lappalainen, PhD, was honored with the Lamport Research faculty award at the 2019 Commencement ceremony. Dr. Lappalainen is pictured here with Columbia University Trustee Andrew Barth (left) and Dean Lee Goldman of Columbia University Irving Medical Center. (Courtesy of CUIMC Communications)

Tuuli Lappalainen , PhD, assistant professor of systems biology at Columbia University and core faculty member at the New York Genome Center (NYGC) , has received the Harold and Golden Lamport Research award, presented on May 22 at the Vagelos College of Physicians and Surgeons Commencement Ceremony. 

The Lamport Research award is an annual prize given to junior faculty members that show promise in basic science or clinical science research. This year it recognizes Dr. Lappalainen’s ongoing research in functional genetic variation in human populations, and her work in elucidating the cellular mechanisms linked to genetic risk for various diseases and traits. Dr. Lappalainen and her lab combine computational analysis of high-throughput sequencing data, human population genetics approaches and experimental work. 

Her group at NYGC and Columbia is highly collaborative and has made important contributions to several international research consortia in human genomics, including the Genotype Tissue Expression (GTEx) Project and the TOPMed Consortium. 

Dr. Lappalainen joined the faculty at Columbia University in 2014 as part of the Department of Systems Biology and NYGC. In 2018, she received the annual Leena Peltonen Prize for Excellence in Human Genetics, which was presented to her in Milan, Italy, at the 52nd European Society of Human Genetics meeting. 

Phyllis Thangaraj, MD/PhD student (Tatonetti lab)

Aspiring physician-scientists from Columbia's Vagelos College of Physicians and Surgeons presented their research posters at the 14th annual MD-PhD Student Research Symposium on April 25. Their research delved into a range of topics, including Alzheimer’s disease, stroke, and stem cells. The event included a guest lecture by an alumna about her own career path as a physician-scientist, and culminated in the poster session judged by MD-PhD alumni who currently work at the University. Department of Systems Biology’s Phyllis Thangaraj, an MD/PhD student in the Nicholas Tatonetti lab , was named one of five poster winners at the event. 

She presented work on applying machine learning methods to phenotype acute ischemic stroke patients in the electronic health records. In cohort research studies, it is essential to identify a large number of subjects in an accurate and efficient manner, but often this requires time-consuming manual review of patient charts. 

“We applied machine learning methods to data within a patient’s electronic health records to develop a high-throughput way to define research cohorts,” explains Thangaraj. “Our test case is in acute ischemic stroke. We extracted clues within a person’s medical record that required minimal data processing to classify those who have had a stroke. In a separate cohort, the UK Biobank, we were able to use our model to identify patients with self-reported stroke but no mention in their medical data with 65-fold better precision than random selection of patients.” Although stroke was the test case in this particular work, she explained that their workflow could be applied to identify patients for cohorts of other diseases, particularly when the dataset has missing data. 

One of the structural variations detected in Anaerostipes hadrus, which is deleted in ~40% of the population (top), and associated with higher disease risk. Genes in this region (bottom) code a composite inositol catabolism - butyrate production pathway, potentially supplying the microbe with additional energy while supplying the host with butyrate, previously shown to have positive metabolic and anti-inflammatory effects. (Credit: Korem lab)

Our gut microbiome has been linked to everything from obesity and diabetes to heart disease and even neurological disorders and cancer. In recent years, researchers have been sorting through the multiple bacterial species that populate the microbiome, asking which of them can be implicated in specific disorders. But a paper recently published in Nature addressed a new question: "What if the same microbe is different in different people?" The study was co-led by Dr. Tal Korem , assistant professor of systems biology and core faculty member in the Program for Mathematical Genomics at Columbia University Irving Medical Center . 

It has been long known that the genomes of microbes are not fixed from birth, as ours are. They are able to lose some of their genes, exchange genes with other microorganisms, or gain new ones from their environment. Thus, a detailed comparison of the genomes of seemingly identical bacteria will reveal sequences of DNA that occur in one genome and not others, or possibly sequences that appear just once in one and several times over in others. These differences are called structural variants. Structural variants - even tiny ones - can translate into huge differences in the ways that microbes interact with their human hosts. A variant might be the difference between a benign presence and a pathogenic one, or it could give bacteria resistance to antibiotics.

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. 

Principal investigators on the PCF Challenge Award grant, from left to right: Andrea Califano, Michael Shen and Charles Drake.

Columbia University Irving Medical Center experts in prostate cancer will lead a new team research project that tests a novel approach for personalized cancer treatment. 

The two-year project, funded by a $1 million Challenge Award from the Prostate Cancer Foundation (PCF) , combines cutting-edge techniques that include computational methods for targeted drug therapy, single-cell RNA sequencing and novel cancer immunotherapy. The combined approaches are behind a proof-of-concept clinical trial for patients with lethal metastatic prostate cancer.  

PCF Challenge Awards fund projects that bring together experts from a number of related fields to form a team focused on the creation of innovative, effective therapies for advanced prostate cancer. As part of Columbia’s grant, the new clinical trial will take place at the James J. Peters VA Medical Center (also known as the Bronx VA), a partner of Columbia University Irving Medical Center (CUIMC) and New York-Presbyterian .

PCF is recognized as the leading philanthropic organization for prostate cancer research. For the team at Columbia’s Herbert Irving Comprehensive Cancer Center (HICCC ), receiving a Challenge Award from the foundation was more than just an exciting achievement. It underscores CUIMC’s continued commitment to strengthen and expand its expertise in prostate cancer research and care through investments in faculty recruitment, enhanced emphases on bolstering basic science research and clinical trials centered on the disease and direct engagement with PCF.