systemsbiology.columbia.edu

Department of Systems Biology Irving Medical Center

Research Highlights Addressing the Global Pandemic New Tumor-Specific Molecular Interaction Maps 2019-2020 Capture Complexity of Cancer Networks Dynamics of Gut Bacteria Follow Ecological Laws Ancient Part of Immune System May Underpin Severe COVID COLUMBIA UNIVERSITY DEPARTMENT OF SYSTEMS BIOLOGY

Table of Contents

Inside this issue, learn about the latest research, noteworthy grants and milestones from the Department of Systems Biology.

Systems Biology Faculty Address the Global Pandemic Q+A: Raul Rabadan, PhD Find out how several faculty in the department are rapidly As the author of Understanding Coronavirus, Dr. Rabadan has addressing the novel SARS-CoV-2 virus...... Page 3 set out to provide readers an accessible overview that quells misinformation about the novel virus, its origin, causes, and spread. Page 10 Systems Biology COVID Volunteers ...... During the spring COVID-19 outbreak in , four New Faculty: Mohammed AlQuraishi, PhD members of the systems biology department were especially active in a volunteer effort called Columbia Researchers A warm welcome to Dr. Mohammed AlQuraishi, who Against Coronavirus...... Page 4 joined the department as an assistant professor and as a member of Columbia’s Program for Mathematical . Page 11 New Tumor-Specific Molecular Interaction Maps ...... Capture Complexity of Cancer Networks Method Detects Genetic Expression Disruptors, Novel representations called SigMaps capture the full Improves Diagnosis of Rare Disease complexity of protein signaling and regulatory pathways in tissue-specific context...... Page 5 A new computational method from the lab of Tuuli Lappalainen can identify genes where genetic variants disrupt gene expression in patients and improve the diagnosis of rare Dynamics of Gut Bacteria Follow Ecological Laws genetic disease...... Page 12 The gut microbiome is more organized than it first appears and follows some of the same ecological laws that apply to Pew-Stewart Scholar Dr. Xuebing Wu Focuses on birds, fish, tropical rainforests, and even complex economic Therapeutic Targets in Breast Cancer and financial markets...... Page 6 Xuebing Wu, PhD, has been selected as a Pew-Stewart Scholar Network-based Approach for Predicting Response for his innovative approaches to cancer research...... Page 13 to Cancer Treatment Molly Przeworski, PhD, Elected to the National Researchers use algorithm to predict individual patient Academy of Sciences response to inhibition of HDAC6, a master regulator of inflammatory breast cancer...... Page 7 Congratulations to Molly Przeworski, PhD, elected to the National Academy of Sciences, and recognized for her Gene Signature Predicts Whether Localized distinguished achievements in original research. ....Page 13 Prostate Cancer is Likely to Spread Around the Department Researchers have identified a genetic signature in localized prostate cancer that can predict whether the cancer is Grants, awards, and more...... Page 14 likely to spread, or metastasize, early in the course of the disease...... Page 8 Newly Tenured Faculty Three new faculty in the Department of Systems Biology Ancient Part of Immune System May Underpin have been awarded tenure and promoted to associate Severe COVID professor...... Page 15 One of the immune system’s oldest branches, called complement, may be influencing the severity of COVID disease...... Page 9

2 systemsbiology.columbia.edu Systems Biology Faculty Address the Global Pandemic

study published in Cell Systems, Drs. Sha- pira and Honig applied similar methods to map virus-encoded mimics of host protein structures across thousands of viruses and hosts that are part of Earth’s virome. They identified, among their findings, over 150 human proteins that are mimicked by coro- naviruses, providing clues about cellular processes driving the pathogenesis of the ongoing COVID-19 pandemic. In a study published in Nature Medicine, Dr. Shapira collaborated with Nicholas Tatonetti, PhD, associate professor of systems biology and of biomedical informatics, to leverage these clues in an analytical and computational framework to demonstrate that genetic and Raul Rabadan, PhD, (standing) with Francesco Brundu, postdoctoral research scientist in the functional dysregulation in immune com- Rabadan lab (Credit: Jeffrey Schifman) plement and coagulation pathways are risk factors of morbidity and mortality associat- y early spring, the highly contagious is part of a family of viruses that include ed with COVID-19. Their ongoing efforts Bnovel coronavirus ripped through com- SARS and MERS—two devastating infec- are extending these approaches to identify munities and challenged medical resources, tious diseases that surfaced in the last 20 key genetic and functional determinants of particularly in epicenters like New York years. Xuebing Wu, PhD, assistant profes- disease susceptibility in the context of oth- City. The surge in positive cases at the time sor of systems biology, is an expert in RNA er emerging pathogens. (See related article summoned clinical communities to the front research and studies RNA-centric gene reg- on page 9) lines of the pandemic, and simultaneously ulation in mammalian cells. He is working Andrea Califano, Dr, is a pioneer in the it galvanized the scientific community to on developing a CRISPR-based approach field of systems biology and founding chair quickly collaborate across multiple disci- for killing the SARS-CoV-2 virus, and po- of Columbia’s Department of Systems Bi- plines and problem-solve a cure. tentially also the infected surrounding cells. ology. He has developed sophisticated al- Several faculty in the Department of Sys- CRISPR is a natural bacterial immune gorithms to identify key master regulator tems Biology rapidly came together to ad- system that scientists have begun to use as proteins in tumors and enable the prioriti- dress the novel SARS-CoV-2 virus. There a revolutionary tool to alter genomes. Dr. zation of FDA-approved drugs that could has since been an incredible outpouring of Wu and his collaborators have already de- treat and kill cancer in various tumor types. rapid response by academic researchers to veloped a similar CRISPR-based technique He is now applying these validated meth- aid in a cure or uncover the fundamental bi- to eliminate cancer cells, and intend to apply ods to study the biology of coronaviruses ology driving the novel coronavirus. this method to target COVID-19. The hope and their ability to hijack the machinery of “This is an unprecedented time in history, is that this research can aid in the speedier human host cells. when scientists from all fields who are not development of a therapeutic, not just for Dr. Califano and his collaborators have necessarily experts in virology are forming this novel strain but for future variants of already analyzed gene expression profile teams with exceptional complementary tal- SARS-CoV-2. data generated from SARS-CoV-infected ent to address one of the greatest challenges Data-driven Solutions and mock-infected epithelial cells to iden- our society has ever faced,” said Systems In a study published in Cell, Sagi Shapira, tify the proteins responsible for maintain- Biology Department Chair Andrea Califa- PhD, and Barry Honig, PhD, faculty in the ing the transcriptional state of infection no, Dr. at the time. “The current situation Department of Systems Biology, developed response. (SARS-CoV is closely related creates a unique and unprecedented commit- P-HIPSTer, a computational method that to the current novel coronavirus SARS- ment to a shared goal without institutional, leverages the supercomputing infrastruc- CoV-2 and produces a similar response in geographic, or expertise boundaries.” ture at Columbia to identify key interac- patients.) They’ve applied the computation- A sample of COVID-19 research from tions between all human-infecting viruses al method, OncoTreat, developed by the systems biology faculty: (including coronaviruses) and the cells Califano lab, to identify several promising CRISPR-based Therapeutics they infect. In addition to studying vaccine drugs to potentially treat these infections, Coronavirus genomes comprise sin- design, they are using the information to including drugs used to treat rheumatoid gle-stranded RNA, and the novel coronavi- identify FDA-approved drugs that may be arthritis as well as several kinase and trans- rus, SARS-CoV-2 that leads to COVID-19, repurposed and immediately deployed. In a port protein inhibitors. Dr. Califano and his 3 COLUMBIA UNIVERSITY DEPARTMENT OF SYSTEMS BIOLOGY team have now generated gene expression tise and algorithms to analyze the UK profiles from nasopharyngeal cells of Biobank data (comprising 500,000 Systems Biology COVID-19 infected and negative con- individuals, with genetic and clinical trol and are repeating the analysis. They data) as well as transcriptomic data COVID Volunteers are also collaborating with Dr. Welling- from COVID-19 patients. “This effort ton Cardoso, professor of medicine at will help us to better understand the Columbia University, to screen a larger SARS-CoV-2 mechanism of action,” number of drugs in physiologically rel- says Dr. Rabadan, “and to define risk evant cells, beyond those selected for groups with greater precision, in par- oncology, and to validate their ability to ticular those with other conditions.” revert the effect of the virus on the host. Dr. Califano also is collaborating with Exploring Untapped Data Dr. Sagi Shapira to use these gene ex- Nicholas Tatonetti, PhD, associate pro- pression profiles to identify RNA-based fessor of systems biology, has teamed biomarkers from nasal swab tests that can up with colleagues Noemie Elhadad and predict the need for hospitalization and in- Lena Mamykina in biomedical informat- tensive care. The researchers will analyze ics, and collaborators in urban policy and patient cell samples from swab tests by affairs and infectious disease on a da- using rapid-turnaround, next-generation ta-collection app and website for tracking sequencing methods that capture both the the impact of the COVID-19 pandemic in infection status and complex immune re- New York City. sponse profiles. Using Dr. Califano’s com- CovidWatcher, which launched in putational methods, the researchers hope April works as a crowd-sourcing re- to identify master regulator-based mark- search platform that surveys users— ers to predict clinical outcomes based on both healthy and potentially exposed the transcriptional profiles of easily acces- to COVID-19—about their exposure sible samples. The hope is to be able to to the virus, symptoms, and access to rapidly inform doctors how to best triage medical care. The data will be used not COVID-19 patients upon diagnosis. Miles Richardson, DSB graduate student and early only as a decision tool to advise pa- CRAC team organizer COVID-19 Genomics tients if they should seek help but also to enable healthcare officials to deploy Raul Rabadan, PhD, professor of sys- At the peak of the COVID-19 pandem- resources at New York City “hot spots”, tems biology and director of the Program ic, four members of the Systems Biology or where they are needed most. The ul- for Mathematical Genomics at Colum- Department were especially active in the timate goal is to prevent future spread. bia, is an expert in uncovering patterns Columbia-wide volunteer project, Colum- of evolution in biological systems—in “There has been no ability yet to track bia Researchers Against Coronavirus or particular, RNA viruses and cancer. He and obtain this kind of data from New CRAC. They were graduate student Nick has developed computational methods Yorkers,” says Dr. Tatonetti, who also Giangreco, postdoctoral research scien- to study cancer genetics and to eluci- directs clinical informatics at Columbia’s tist Amir Momen-Roknabadi, postdoctor- date biological understanding of how tu- Institute for Genomic Medicine. “Our al research scientist Panos Oikonomou, mors evolve over time, in such complex live surveys, for instance, could help find and graduate student Miles Richardson. cancers as leukemia, pancreatic ductal out where New Yorkers are in the city Richardson says his main role as chief adenocarcinoma and glioblastoma. Dr. that are having symptoms, even before organizational officer of the group was Rabadan and his collaborators are now they may or not may not become infected searching for and finding problems, and applying these methods to assess indi- with the virus. Then, we can redistribute fixing them. “The progress we make as viduals’ predispositions to COVID-19. this data to hospital sites to help them scientists,” he says, “is often abstract and Why do some patients who test positive prepare for what’s coming their way.” indirect, divorced from the society that for COVID-19 experience severe symp- Dr. Tatonetti and other faculty across we serve. So I jumped at this opportunity toms and complications—in some cases Columbia have been quickly transform- to help—which ended up dominating the their illness results in death—whereas ing their research to address COVID-19. next three months of my life.” other COVID positive patients do not? The collaborative energy from the sci- Giangreco was the data and analytics Dr. Rabadan and his group are tak- entific community has been “incredible lead on a global effort to design an open- ing a deep dive into the genetics of to witness,” he says, underscoring that source tool to support people affected by COVID-19, with the hope of identify- right now, research is moving quickly COVID-19. “The project,” he says, “sym- ing biomarkers of COVID-19 severity but there is still very much a sense of a bolizes the connectedness of people and and that can lend to immediate man- shared vision and goals. shared experiences, the urge to help out our agement of patients at risk, including neighbors in need, and the amazing ability cancer patients. They are already le- —Originally published of smart people to put their talents and skills veraging their cancer genomics exper- by HICCC News together for the common good.”

4 systemsbiology.columbia.edu New Tumor-Specific Molecular Interaction Maps Capture Complexity of Cancer Networks

SigMap. Using lung adenocarcinoma as an example, of the 40 highest-scoring proteins predicted in the KRAS SigMap, 20 were already known, and 16 of the remaining 20 were experimentally vali- dated. “This is an extraordinary valida- tion rate,” says Dr. Califano. SigMaps might also be used to identify pharmacologically accessible candidate targets for many mutated oncoproteins, including KRAS, thus providing a valu- able tool for guiding hypothesis-based studies to validate their disease-related relevance. “This is fundamentally a new method- ology,” says Dr. Califano, “and its use- Barry Honig, PhD Andrea Califano, Dr fulness should extend well beyond can- cer. Pathways and networks are central hough cancer researchers have made text, i.e., a protein mechanism of action. to how cells recognize one another and Tconsiderable headway in elucidat- This novel representation is called a sig- communicate. One reason we are more ing signaling and regulatory pathways, naling map, or SigMap. advanced in dealing with cancer than current representations fail to capture The paper presents OncoSig, an inte- with, say, Alzheimer’s disease, is that the full complexity of the mechanisms grative machine learning (ML) frame- the cells of other diseases don’t prolif- that mediate the effects of both genet- work for the systematic protein-centric erate. It’s much easier to culture cancer ic and pharmacological perturbations. reconstruction of tumor-specific Sig- More specifically, prior efforts to iden- Maps. The SigMaps reported are cen- cells—proliferating is what they like to tify signaling and regulatory pathways tered on virtually all known oncopro- do. But SigMaps can also be constructed do not capture their cross-tissue differ- teins and contextualized to more than for proteins unrelated to cancer, greatly ences (context-dependence), are based 20 tumor contexts. OncoSig is trained expanding the value of the algorithm.” largely on interactions reported in the on integrated information derived from “Advances in ML methodology have literature, and do not effectively reflect predicted physical protein-protein in- enabled us to integrate these very dif- their role in mediating oncoprotein-spe- teractions, inferred from 3D structural ferent sources of input,” says Dr. Honig. cific signals. Some researchers have re- data; and transcriptional and post-tran- “The complexity of SigMaps is daunt- cently begun to incorporate cell line-, scriptional interactions, from gene-ex- ing, but biology is complex, and some- tumor-, or tissue-specific information in pression and mutational profiles in efforts to produce findings that are con- large-scale repositories such as The times it is important to embrace that text-specific, but comprehensive, pro- Cancer Genome Atlas (TCGA). complexity.” teome-wide depictions of human inter- The researchers first generated a actomes across different tissue contexts KRAS-specific SigMap for lung cancer remain elusive. (the KRAS oncogene is commonly mu- REFERENCE In a paper published in Nature Bio- tated in lung cancer). The SigMap not technology on Sept. 14, 2020, Andrea only included known KRAS interactors Broyde J, Simpson DR, Murray D, Califano, Dr, chair of Systems Biology; reported in published pathways, but also Paull EO, Chu BW, Tagore S, Jones SJ, Diana Murray, PhD, research scientist identified many novel synthetic lethal Griffin AT, Giorgi FM, Lachmann A, in Systems Biology; and Barry Honig, proteins that were subsequently validat- Jackson P, Sweet-Cordero EA, Honig PhD, professor of Systems Biology, and ed in 3D spheroid models at a validation B, Califano A. Oncoprotein-specific their co-authors propose a fundamental- rate exceeding 80%; it also identified ly different representation of the signal- crosstalk with Rab and Rho pathway molecular interaction maps (SigMaps) ing and regulatory machinery needed to proteins. OncoSig generates a single in- for cancer network analyses. Nature modulate the function of a specific pro- tegrated score that represents the proba- Biotechnology. 2020 Sept. doi: 10.1038/ tein of interest in a specific tissue con- bility that a protein belongs to a specific s41587-020-0652-7.

5 COLUMBIA UNIVERSITY DEPARTMENT OF SYSTEMS BIOLOGY Dynamics of Gut Bacteria Follow Ecological Laws

he seemingly cha- aspects of microbiome dynamics, such as tions. These wildly fluctuating bacteria Totic bacterial soup fluctuations and abundances of various were associated with documented periods of the gut microbiome bacteria over time, or the average times dif- of gut distress or travel to foreign countries is more organized than ferent microbes continuously reside in the in humans providing data for the study. it first appears and fol- human gut. “Up to now, it has been an open Thus, this approach may immediately al- lows some of the same question whether there are any natural laws low researchers to understand and identify ecological laws that ap- describing dynamics of these complex bac- which specific bacteria are out of line and ply to birds, fish, tropi- terial communities,” Dr. Vitkup says. behave in a potentially harmful fashion. cal rainforests, and even Chaotic fluctuations follow Using mice data, the researchers also ob- Dennis Vitkup, PhD complex economic and served that microbiomes associated with financial markets, according to a paper pub- statistical laws unhealthy high fat diets drift in time signifi- lished in Nature Microbiology by systems As expected, they discovered large fluctu- cantly faster compared with microbiomes biology researchers. ations in the composition and daily changes feeding on healthier high fiber diets. This One of the main challenges facing re- of the human and mouse gut microbiomes. demonstrates that ecological laws can be searchers who study the gut microbiome But strikingly, these apparently chaotic applied to understand how various dietary is its sheer size and amazing organization- fluctuations followed several elegant eco- changes may affect and perhaps alleviate al complexity. Many trillions of bacteria, logical laws. persistent microbiome instabilities. representing thousands of different species, “Similar to many animal ecologies and live in the human intestinal tract, interact- complex financial markets, a healthy gut Gut microbiome as miniature ing with each other and the environment in microbiome is never truly at equilibrium,” ecological laboratory countless and constantly changing ways. Dr. Vitkup says. “For example, the num- The study by Columbia researchers also The study’s discovery of multiple princi- ber of a particular bacterial species on day opens an exciting opportunity to use the ples of gut bacterial dynamics should help one is never the same on day two, and so gut microbial communities as a model researchers to understand what makes a gut on. It constantly fluctuates, like stocks in system for exploring general ecological microbiome healthy, how it may become a financial market or number of animals relationships. “Ecologists have debated for perturbed in disease and unhealthy diets, in a valley, but these fluctuations are not years why and how these natural ecologi- and also suggest ways we could alter mi- arbitrary. In fact, they follow predictable cal laws arise, without any clear answers,” crobiomes to improve health. patterns described by Taylor’s power law, says Dr. Vitkup. “Previous ecological re- a well-established principle in animal ecol- Gut microbiome dynamics search has been mostly limited to observa- ogy that describe how fluctuations are re- tional studies, which can take decades to remain poorly understood lated to the relative number of bacteria for perform for animals and plants. And some Although current DNA sequencing tech- different species.” key experiments, such as additions or re- nologies make it possible to identify and Other discovered laws of the gut micro- moval of particular species simply cannot track bacteria in the gut over time, “the biome also followed principles frequently biological processes governing the short- observed in animal ecologies and economic be performed.” and long-term changes in the gut’s micro- systems, including the tendency of gut bac- The gut microbiome, in contrast, provides biome remain very poorly understood,” teria abundances to slowly but predictably an ideal miniature laboratory, where re- says the study’s senior author, Dennis drift over time and the tendency of species searchers could easily manipulate different Vitkup, PhD, professor of systems biology to appear and disappear from the gut micro- variables, such as the number and compo- and of biomedical informatics at Columbia biome at predictable times. sition of microorganisms, and then explore University Vagelos College of Physicians “It is amazing that microscopic biolog- various aspects of environmental influenc- and Surgeons. ical communities—which are about six es. “One of our next goals is to understand As a first step in identifying the factors orders of magnitude smaller than macro- the origin of these general ecological laws that describe microbial communities in the scopic ecosystems analyzed previously— using gut microbiota,” Dr. Vitkup says. gut, Dr. Vitkup and his co-authors, graduate appear to be governed by a similar set of students Brian W. Ji and Ravi U. Sheth and mathematical and statistical principles,” —Reprinted with permission research scientists Purushottam Dixit and says Dr. Vitkup. by Columbia News Konstantine Tchourine, looked for math- Laws allow identification of ematical relationships describing dynami- REFERENCES cal changes of the gut microbiome of four abnormal bacterial behavior healthy people followed for a year. They These universal principles should help Ji BW, Sheth RU, Dixit PD, Tchourine also analyzed microbiome data obtained for researchers to better understand what pro- K, Vitkup D. Macroecological dynamics mice fed either high fiber or high fat diets cesses govern the microbial dynamics in the of gut microbiota. Nat Microbiol. 2020 every day for several weeks. gut. Using the statistical laws, the Columbia May;5(5):768-775. doi: 10.1038/s41564- With this data, the researchers explored researchers were able to identify particular 020-0685-1. Epub 2020 Apr 13. PMID: statistical connections between various bacterial species with abnormal fluctua- 32284567.

6 systemsbiology.columbia.edu Network-Based Approach for Predicting Response to Cancer Treatment

istone deacetylases (HDACs) play a lator modules whose activity is responsible Hcentral role in regulating gene expres- for the vast majority of cancers represented sion, by modulating how tightly histones in (TCGA). bind chromatin. In cancer, their aberrant “Oncologist still have to deal with the ex- activation can lead to the repression of tu- ceptionally large number of genetic muta- mor-suppressing genes. Thus, one strategy tion patterns that cause individual cancers,” for treating cancer is the use of HDAC in- says Dr. Califano, chair of the Department hibitors, which change the epigenetic state of Systems Biology. “These would poten- of the cell and re-enable tumor suppression tially require thousands of distinct drugs. programs. Clinical use of pan-HDAC inhib- But by specifically targeting the master itors has been limited, however, due to their regulator modules, you may need only a toxicity, and researchers have been seeking few dozen drugs.” Indeed, Dr. Califano’s Andrea Califano, Dr, (center) with collaborators to develop more selective inhibitors that methodology has the potential not only to Jose Silva, PhD (right) and Kevin Kalinsky, MD target individual HDACs. In addition, oth- identify master regulators but to identify (Credit: Timothy Lee) erwise promising inhibitors have had disap- potential treatments to target them. pointing clinical results for lack of predic- Prior to the clinical trial reported in this breast cancer treatment with ricolinostat in tive biomarkers to identify those patients in study, the Silva and Califano labs had iden- combination with nabpaclitaxel, Dr. Cali- a cancer cohort most likely to respond. tified HDAC6 as a master regulator of in- fano and his colleagues were also able to In a prior collaboration, Drs. Andrea flammatory breast cancer, a rare but highly determine that the HDAC6 score was high- Califano, Jose Silva, and Jiyang Yu pre- aggressive form of the disease, as well as of ly predictive of clinical response. dicted that the HDAC6-specific inhibitor an additional 30% of aggressive breast can- “When Drs. Silva and Yu expanded the ricolinostat would be effective in a subset cers. They did so using an algorithm that analysis to other cancers,” says Dr. Califa- of breast cancer patients identified by the can quantify the activity of proteins, in- no, “we found other types of tumors with aberrant activity of this protein (Putcha cluding HDAC6, in individual tumors. Fur- high HDAC6 scores, including common et al., 2015), as measured by VIPER, an thermore, HDAC6 inhibitors were found malignancies such as prostate and col- algorithm developed in the Califano lab to synergize with paclitaxel-based chemo- orectal cancer, as well as less common but (Alvarez et al, 2016). Now, in a paper pub- therapy. The algorithm can now be used to highly lethal ones such as melanoma and lished online on medRxiv on April 28, 2020 assign an HDAC6 score to each patient, to glioblastoma. Thus, our methodology may (Zeleke et al. 2020) and currently in review, determine the likelihood of their response help to extend the use of HDAC6 inhibitors Drs. Califano, Kevin Kalinsky, Yu, and to HDAC6 inhibitors—thus providing a to treat cancers other than breast.” Silva report the results of the first clinical much-needed predictive biomarker. study of ricolinostat in breast cancer, show- When analysis of approximately 3,000 REFERENCES ing remarkable agreement between patient primary human breast cancers showed clinical response and HDAC6 activity in that around 30% of them had high HDAC6 Putcha, P., Yu, J., Rodriguez-Barrueco, their tumors, as also measured by VIPER. scores, the researchers designed the phase R., Saucedo-Cuevas, L., Villagrasa, P., A focus of Dr. Califano’s research pro- 1b clinical trial reported in this study to Murga-Penas, E., Quayle, S.N., Yang, M., gram at Columbia University Irving Med- evaluate the safety of combining ricolinos- Castro, V., Llobet-Navas, D., et al. (2015). ical Center has been the identification and tat (an HDAC6 inhibitor) and nabpaclitaxel HDAC6 activity is a non-oncogene addic- characterization of master regulator pro- for treatment of patients with metastatic tion hub for inflammatory breast cancers. teins in cancer. These are proteins that coor- breast cancer. They found not only that the Breast Cancer Res 17, 149. dinate the regulatory programs that control two agents could be safely combined, but Alvarez, M.J., Shen, Y., Giorgi, F.M., cancer establishment and progression. As that the patient’s HDAC6 score was high- Lachmann, A., Ding, B.B., Ye, B.H., and such, they are ideal targets for pharmaco- ly effective in predicting progression-free Califano, A. (2016). Functional charac- logical intervention. Until recently, most survival following treatment with the two terization of somatic mutations in cancer cancer research has focused on mutations agents in HR+/HER2- cancers. Though using network-based inference of protein in individual cancer-causing genes. Be- the biomarker was available at the time activity. Nat Genet 48, 838-847. cause master regulators are rarely mutated, the study was designed, the FDA required Zeleke, T., Pan, Q., Chiuzan, C., Onishi, genomics is not an efficient way to identi- the study to be conducted across the entire M., Alvarez, M.J., Honan, E., Yang, M., fy them. Instead, the Califano lab develops spectrum of breast cancer, independent of Chia, P.L., Mukhopadhyay, P., Kelly, S., algorithms such as VIPER, which leverage HDAC6 activity. In this way, the potential et al. (2020). Network-based assessment the structure of regulatory networks to iden- value of the biomarker could be assessed of HDAC6 activity is highly predictive of tify master regulators. Using VIPER, Dr. retrospectively. Thus, though the aim of pre-clinical and clinical responses to the Califano’s lab has identified 24 master regu- the trial was to study the effectiveness of HDAC6 inhibitor ricolinostat. medRxiv.

7 COLUMBIA UNIVERSITY DEPARTMENT OF SYSTEMS BIOLOGY Gene Signature Predicts Whether Localized Prostate Cancer is Likely to Spread

prostate cancer metastases. Using this first-of-its-kind mouse model, the researchers discovered that bone metas- tases have a different molecular profile than that of primary tumors. “By focusing on those differences, we were able to identify 16 genes that drive localized prostate cancer to metastasize,” Dr. Abate-Shen says. 16 genes predict metastasis in patients The genetic signature, called META-16, Cory Abate-Shen, PhD was then tested on biopsies from several hundred patients with localized prostate esearchers have identified a genetic the prostate and can be successfully man- cancer. The outcomes of those patients Rsignature in localized prostate cancer aged by active surveillance or local therapy were blinded to the researchers. that can predict whether the cancer is likely (mainly surgery or radiotherapy), with five- The Columbia team found that META-16 to spread, or metastasize, early in the course year survival rates above 99%. But once was highly effective at predicting time to of the disease and whether it will respond prostate cancer spreads, it is considered in- metastasis and response to anti-androgen to anti-androgen therapy, a common treat- curable, and five-year survival rates drop to therapy (which is used to suppress andro- ment for advanced disease. The new gene approximately 30%. gen, the male hormone, which promotes signature may also be useful for evaluating “The problem is that with existing tumor progression). responses to treatment and for developing The team is currently refining the test, new therapies to prevent or treat advanced “If we could know in advance which they then hope to evaluate in a pro- prostate cancer. which patients will develop spective clinical trial. “If we could know in advance which pa- In theory, META-16 could also be used to tients will develop metastases, we could metastases, we could start develop therapies against metastatic pros- start treatments earlier and treat the cancer treatments earlier and treat tate cancer. more aggressively,” says the study’s senior the cancer more aggressively.” “The genes in our signature are not only author, Cory Abate-Shen, PhD, chair of the correlated with metastasis, they appear to Department of Molecular Pharmacology —Cory Abate-Shen, PhD be driving metastasis,” Dr. Arriaga says. and Therapeutics, the Michael and Stella “That means that if we can suppress the Chernow Professor of Urologic Sciences (in tests, it’s hard to know which cancers are activity of those genes, we might be able Urology), and professor of pathology & cell which,” says the study’s lead author, Juan to prevent the cancer from spreading or at biology (in the Herbert Irving Comprehen- M. Arriaga, PhD, associate research scien- least improve outcomes.” tist in molecular pharmacology and ther- sive Cancer Center), and professor of sys- --Reprinted with permission by apeutics at Columbia University Vagelos tems biology at Columbia University Vage- Columbia News los College of Physicians and Surgeons. College of Physicians and Surgeons. “Conversely, patients whose dis- “We miss a lot of aggressive cancers that ease is likely to remain confined to the should have been treated earlier, and we REFERENCE prostate could be spared from getting overtreat some slow-growing cancers that Arriaga, J.M., Panja, S., Alshalalfa, M., unnecessary therapy.” probably would not have spread.” Zhao J., Zou M, Giacobbe A, Madubata The study was published in Nature New gene signature first C, Kim JY, Rodriguez A, Coleman I, Virk Cancer. R, Hibshoosh H, Ertunc O, Ozbek B, identified in new mouse model Existing tests can’t identify Fountain J, Karnes RJ, Luo J, Antonarakis To identify a more accurate method E, Nelson P, Feng F, Rubin M, De Marzo aggressive cancers of predicting advanced prostate cancer, A, Rabadan R, Sims PA, Mitrofanova A, Prostate cancer is the second-leading the researchers first created a mouse Abate-Shen, C. A MYC and RAS co-ac- cause of cancer death among men in the model of prostate cancer that accurately tivation signature in localized prostate United States; about 33,330 men are ex- reflects the human form of the disease, cancer drives bone metastasis and castra- pected to die of the disease this year. including how the cancer spreads to the tion resistance. Nat Cancer (2020). doi. Most prostate cancers remain confined to bone, the tissue most often affected by org/10.1038/s43018-020-00125-0

8 systemsbiology.columbia.edu Ancient Part of Immune System May Underpin Severe COVID

Macular degeneration associated with greater COVID mortality If complement and coagulation influ- ence severity of COVID, people with pre-existing hyperactive complement or coagulation disorders should be more susceptible to the virus. That led Drs. Shapira and Tatonetti to look at COVID patients with macular degeneration, an eye disease caused by overactive complement, as well as com- mon coagulation disorders like throm- bosis and hemorrhage. Among 11,000 COVID patients Nicholas Tatonetti, PhD, Sagi Shapira, PhD who came to Columbia University Ir- ving Medical Center with suspected ne of the immune system’s oldest Findings stem from study of COVID-19, the researchers found that over 25% of those with age-related mac- Obranches, called complement, may coronavirus mimicry be influencing the severity of COVID ular degeneration died, compared to disease, according to a new study from The idea to investigate the role of co- the average mortality rate of 8.5%, and researchers at the Vagelos College of agulation and complement in COVID-19 roughly 20% required intubation. The greater mortality and intubation rates Physicians and Surgeons at Columbia began with a sweeping survey of viral could not be explained by differences in University Irving Medical Center. mimicry across all viruses on Earth— the age or sex of the patients. Among other findings linking comple- over 7,000 in all. “Viruses have proteins that can mim- “Complement is also more active in obe- ment to COVID, the researchers found ic certain host proteins to trick the host’s sity and diabetes,” Dr. Shapira says, “and that people with age-related macular de- cells into aiding the virus with completing may help explain, at least in part, why peo- generation—a disorder caused by over- its life cycle,” Dr. Shapira says. “Beyond ple with those conditions also have a great- active complement—are at greater risk the fundamental biological questions that er mortality risk from COVID.” of developing severe complications and we were interested in addressing, based on People with a history of coagulation dying from COVID. our previous work and the work of others, disorders also were at increased risk of The connection with complement sug- we suspected that identifying those mim- dying from SARS-CoV-2 infection. gests that existing drugs that inhibit the ics could provide clues about how viruses Coagulation and complement complement system could help treat pa- cause disease.” tients with severe COVID-19. The study, Coronaviruses, the survey found, are pathways activated led by systems biology faculty Sagi masters of mimicry, particularly with The researchers then examined how gene Shapira, PhD, MPH, with Nicholas Ta- proteins involved in coagulation and activity differed in people infected with the tonetti, PhD, was published in Nature proteins that make up complement, one coronavirus. Medicine. of the oldest branches of the human im- That analysis revealed a signature in The authors also found evidence that mune system. COVID-19 patients indicating that the vi- clotting activity is linked to COVID Complement proteins work a bit like rus engages and induces robust activation severity and that mutations in certain antibodies and help eliminate pathogens of the body’s complement and coagula- complement and coagulation genes by sticking to viruses and bacteria and tion systems. are associated with hospitalization of marking them for destruction. Comple- “We found that complement is one of the COVID patients. ment can also increase coagulation and most differentially expressed pathways in “Together, these results provide im- inflammation in the body. “Unchecked, SARS-CoV-2-infected patients,” says Dr. portant insights into the pathophysiolo- these systems can also be quite detri- Tatonetti, who also is an associate profes- gy of COVID-19 and paint a picture for mental,” says Dr. Shapira. sor of biomedical informatics. “As part of the role of complement and coagulation “The new coronavirus—by mimicking the immune system, you would expect to pathways in determining clinical out- complement or coagulation proteins— see complement activated, but it seems comes of patients infected with SARS- might drive both systems into a hyperac- over and above what you’d see in other CoV-2,” says Dr. Shapira. tive state.” infections like the flu.”

9 COLUMBIA UNIVERSITY DEPARTMENT OF SYSTEMS BIOLOGY

Some coagulation and complement genes associated Q+A: Raul Rabadan, PhD, and with hospitalization Understanding the Coronavirus More evidence linking severe COVID with coagulation and complement comes from a genetic analysis of thousands of COVID patients from the U.K. Biobank, which contains medical records and genetic data from half a million people. The authors found that variants of several genes that influence complement or coag- ulation activity are associated with more severe COVID-19 symptoms that required hospitalization. “These variants are not necessarily going to determine someone’s outcome,” Dr. Sha- pira says. “But this finding is another line of evidence that complement and coagulation pathways participate in the morbidity and mortality associated with COVID-19.” Targeting coagulation and complement Physicians treating COVID patients have noticed coagulation issues since the begin- Raul Rabadan, PhD, authors new book on the novel coronavirus (Credit: Jeffrey Schifman) ning of the pandemic, and several clinical tri- als are underway to determine the best way to aul Rabadan, PhD, is an expert in un- ing a treatment or vaccine. Scheduled to be use existing anti-coagulation treatments. Rcovering patterns of evolution in highly on sabbatical earlier this year, Dr. Rabadan Complement inhibitors are current- dynamic biological systems, including in instead remained quarantined with his family ly used in relatively rare diseases, but at complex diseases like cancer. As the author in New York City, shifting his attention to the least one clinical trial is testing the idea of Understanding Coronavirus, published new book and his own ongoing work in the with COVID patients. by Cambridge University Press in June, Dr. genomics of cancer and COVID-19 research. Rabadan, who originally began his academ- “I think our findings provide a stronger Q: You were early to pivot your cancer-fo- ic career in mathematical physics, has set foundation for the idea that coagulation and cused research to address SARS-CoV-2. out to provide readers an accessible over- complement play a role in COVID,” Dr. What motivated you to focus on the virus? Tatonetti says, “and will hopefully inspire view that quells misinformation about the others to evaluate this hypothesis and see if novel virus, its origin, causes, and spread. A: I have been working on viruses and it’s something that can be useful for fighting Dr. Rabadan is professor of systems biolo- cancers for the last 15 years. The relation the ongoing pandemic.” gy and of biomedical informatics. He directs between viruses and cancers is fascinating. Around 20% of all cancers in the world are --Reprinted with permission Columbia’s Program for Mathematical Ge- related to viruses, including some lympho- by Columbia News nomics and co-directs the Cancer Genom- ics and Epigenomics research program at mas, nasopharyngeal carcinomas, cervi- REFERENCES the Herbert Irving Comprehensive Cancer cal and liver cancers, among many others. Center (HICCC). He joined Columbia in Many fundamental discoveries about the Ramlall V, Thangaraj PM, Meydan C, Foox J, 2008 right before the novel influenza, H1N1 mechanisms of oncogenesis have been found Butler D, Kim J, May B, De Freitas JK, Glicks- or “swine flu,” emerged and quickly spread through their relation with viruses. berg BS, Mason CE, Tatonetti NP, Shapira SD. across the U.S. and the world. Coronaviruses have not been linked to Immune complement and coagulation dys- At the time, Dr. Rabadan’s work homed in cancers but cancers and viruses share fun- function in adverse outcomes of SARS-CoV-2 on understanding the genomic changes in a damental and abstract principles. They are infection. Nat Med. 2020 Oct;26(10):1609-1615. virus infecting a host and investigating how both very fast-evolving systems and this evo- doi: 10.1038/s41591-020-1021-2. Epub 2020 these changes contribute to the virus’ trans- lution can be read through changes in their Aug 3. PMID: 32747830. fer to a different species. He continues to be genomes. These changes follow certain rules Lasso G, Mayer SV, Winkelmann ER, Chu T, fascinated by what can be gleaned from ex- that can be uncovered and modeled with the Elliot O, Patino-Galindo JA, Park K, Rabadan amining disease evolution. right set of approaches. Understanding these R, Honig B, Shapira SD. A Structure-Informed When COVID-19 cases surged through rules can hopefully help us to develop better Atlas of Human-Virus Interactions. Cell. 2019 ways of combating the associated diseases. Sep 5;178(6):1526-1541.e16. doi: 10.1016/j. the U.S., particularly in New York City in the cell.2019.08.005. Epub 2019 Aug 29. PMID: spring, Dr. Rabadan—like many fellow scien- For instance, some of these genomic changes 31474372; PMCID: PMC6736651. tists—contributed his research toward develop- in cancers and viruses could be associated

10 systemsbiology.columbia.edu to resistance to therapy. Reading and inter- students with an interest in a quantitative preting these changes could help to optimize understanding of infectious diseases, and vi- DSB Welcomes Dr. therapeutic approaches. ruses in particular. Many of the notes used in Mohammed AlQuraishi Q: How does your expertise in cancer, the book came from this course: viruses and , and systems biology dove- their genomes, recent and past outbreaks tail with virology research? and pandemics, how genomic information could be used to learn about the viruses and A: When I came to Columbia in 2008 I was their hosts. These notes provided a frame- very active in trying to understand the origins work to conceptualize the current pandemic. of pandemic viruses, mostly influenza pandem- ics. These pandemics occur every 30 years or Q: What do you hope readers will take so, and the last one was the H1N1 influenza away from this book? of 2009. I was fascinated with understanding A: The main goal is to conceptualize the cur- the genomic changes of a virus. In 2009, I was rent events we are living. There are many refer- working on how influenza viruses infecting pigs ence points in the horizon of our experience that and birds could generate new genetic combina- can help to frame the current situation, and there tions that enable them to infect and propagate are many things that still need to be learned. in humans. We developed computational meth- Previous pandemics have taught us about ep- Mohammed AlQuraishi, PhD, joined DSB in ods to identify genetic changes in these rapidly idemiology and public health measures. The the fall of 2020 evolving systems. Many of these approaches outbreak propelled research into coronaviruses, The Department of Systems Biology is were the seeds of the genomic work I have car- about their origin, associated diseases, and even pleased to welcome Mohammed AlQurai- ried out with many colleagues at Columbia in therapies. Common circulating coronaviruses, shi, PhD, who joined Columbia University cancer evolution since 2010. viruses that are associated with mild respirato- Irving Medical Center in September as an My research is focused on understanding ry infections, are also very interesting, as they assistant professor and as a member of the fast evolving biological systems by reading have been with us for some time and they also Program for Mathematical Genomics. and modeling these changes in their genomes. have a zoonotic origin, meaning they can be Prior to joining Columbia, Dr. AlQuraishi Mathematical frameworks to identify relevant transmitted from animals to humans. Although served as a fellow of systems pharmacolo- changes could lead to understanding basic we can learn from these other outbreaks, the gy and systems biology at Harvard Medical mechanisms of evolution that can be applied comparisons between these episodes can also School. He completed his PhD in genetics to different biological systems. Learning from have some dangers. For instance, the compar- and master’s in statistics from Stanford Uni- one system can help develop approaches to ison with seasonal influenza has been quite versity. At Santa Clara University, he earned understand others. misused, and is a poor metaphor for the current two bachelor’s degrees in biology and in COVID-19 pandemic. I thought it could be use- Q: What compelled you to write the book? computer engineering. ful for some people to learn about all these top- Dr. AlQuraishi’s lab focuses on two bi- A: The first semester of 2020 was supposed ics to help conceptualize the current situation. to be my first sabbatical since I started at ological perspectives: the molecular and Columbia in 2008. With all sabbatical plans Q: What have you and your lab uncovered systems levels. On the molecular side, canceled I was absorbed in research related about the virus up to this point? What are the AlQuraishi lab is developing machine to the new coronavirus. As I was taking notes you currently working on? learning models for predicting protein on scientific results I realized that there was a A: We are working on several aspects of the structure and function, protein-ligand in- significant amount of confusing ideas, prob- virus. COVID-19 is a disease caused by the vi- teractions, and learned representations of ably due to the fast pace of events involving rus SARS-CoV-2, but while an infection in an proteins and proteomes. On the systems the outbreak. Last year, I published a book on individual could be asymptomatic in another it side, his group is applying these models in mathematical methods that we developed for could be deadly. In other words, COVID-19, a proteome-wide fashion to investigate the analyzing genomic data. Talking to the editors the infectious disease, is a product of the virus organization, combinatorial logic, and com- of that book at Cambridge University Press, and the individual. My work is mostly on ge- putational paradigms of signal transduction I was motivated to organize notes and ideas nomics, and in this case, we are characterizing networks, and investigate how these net- to provide a landscape of what we currently the genome of the virus and the genome of the works vary in human populations, and how know about the novel coronavirus: How is infected individuals. Some of the questions we they are dysregulated in human diseases, it related to other coronaviruses, including are trying to answer are related to the origins of particularly cancer. SARS; what do we know about its origins; the virus: Where is it coming from? How is it Dr. AlQuraishi’s expertise in the founda- how is it evolving; and how does it relate to evolving? Other sets of questions relate to the tions of biology; the principles, patterns, previous pandemics? severity of the disease: Why do some patients and mechanisms that underlie living organ- In some ways, this book is a natural ex- have mild cases and others severe outcomes? isms, as well as innovative computational tension of work that I began several years There is an increasing amount of data that could methods, position him uniquely as a PI in ago. Shortly after I joined Columbia, and help to address these questions. the Program for Mathematical Genomics. following the H1N1 flu pandemic, I orga- His expertise is essential for understand- nized a course on Mathematical Modeling ing the functional role of mutations across —Reprinted with permission of Infectious Diseases aimed at graduate many diseases, including cancer and herita- by HICCC News ble and infectious diseases.

11 COLUMBIA UNIVERSITY DEPARTMENT OF SYSTEMS BIOLOGY Method Detects Genetic Expression Disruptors, Improves Diagnosis of Rare Disease

Illustration depicts with an example of four genes, how knowing how variable genes are in the normal population helps to find candidate disease genes in a patient. (Courtesy of New York Genome Center) Top: Tuuli Lappalainen Bottom: Pejman Mohammadi or individuals with rare diseases, get- genetic variants disrupt gene expression in Fting a diagnosis is often a long and patients and improve the diagnosis of rare performance of their method and diag- complicated odyssey. Over the past few genetic disease. nosed additional patients where previous years, this has been greatly improved by The new method introduced in this methods of genome and RNA analysis had genome sequencing that can pinpoint the study, Analysis of Expression Variation or failed to find the broken genes. mutation that breaks a gene and leads to ANEVA, first takes allele-specific expres- The study was led by Pejman Moham- a severe disease. However, this approach sion data from a large reference sample madi, PhD, a former postdoctoral scien- is still unsuccessful in the majority of pa- of healthy individuals to understand how tist at the New York Genome Center and tients, largely because of our inability to much genetic regulatory variation each Columbia University and now an assistant read the genome to identify all mutations gene harbors in the normal population. professor at the Scripps Research Insti- that disrupt gene function. Then, using the ANEVA Dosage Outlier tute, and supervised by Tuuli Lappalainen, In a study published in Science, research- Test, researchers can analyze the transcrip- PhD, core faculty member at the New York ers from New York Genome Center, Co- tome of any individual – such as a patient Genome Center and an associate professor lumbia University, and Scripps Research – to find a handful of genes where he or she of systems biology at Columbia Universi- Institute propose a solution to this prob- carries a genetic variant with an unusually ty. Their method is implemented in soft- lem. Building a new computational meth- large effect compared to what healthy in- ware released with the paper and can be od for analyzing genomes together with dividuals have. By applying this test to a applied to any rare disease patients where transcriptome data from RNA-sequenc- cohort of muscle dystrophy and myopathy RNA-sequencing and genetic data exists. ing, they can now identify genes where patients, the researchers demonstrated the --New York Genome Center

12 systemsbiology.columbia.edu Pew-Stewart Scholar Dr. Xuebing Wu Molly Przeworski, PhD, Elected to the Focuses on Therapeutic Targets in National Academy Breast Cancer of Sciences proteins, but its molecules are like a string of sticky beads that can fold into complex shapes and block protein pro- duction. A group of molecular helpers called helicases can unwind those struc- tures and thus control gene expression. “Intriguingly, many helicases have shown abnormal activities in breast can- cer and other cancers but at this moment we don’t yet know what these helicase do to other genes,” says Dr. Wu. “We are developing new technologies that will tell us the shape of all mRNAs in the cell, and help us understand how they change in breast cancer and how they Xuebing Wu, PhD, was selected a respond to various treatment. We hope Molly Przeworski, PhD, specializes in Pew-Stewart scholar that our study will tell us the inner work- population genetics research ings of breast cancer and help guide us uebing Wu, PhD, has been selected in designing new, improved therapeutic olly Przeworski, PhD, professor of Xas a Pew-Stewart Scholar for his in- targets in breast cancer.” Mbiological sciences and of systems novative approaches to cancer research. At the center of Dr. Wu’s interests is biology, has been elected to the prestigious The Pew Charitable Trusts and the understanding the fundamental princi- National Academy of Sciences (NAS). An- Alexander and Margaret Stewart Trust ples of gene regulation in human cells nounced on April 27, Dr. Przeworski joins named five early-career researchers to through integrative genomics approach- two fellow Columbia University Irving its prestigious Pew-Stewart Scholars es. His previous work has uncovered Medical Center faculty members named Program for cancer research. This tal- important roles of RNA sequence and to the 2020 class, recognized for their dis- ented class of scholars will receive four tinguished and continuing achievements in structure signals in controlling the ex- years of funding to advance ground- original research. pression and evolution of the mamma- breaking research into the development, Dr. Przeworski’s work aims to under- lian genome. Dr. Wu and collaborators diagnosis, and treatment of the disease. stand how natural selection has shaped have been increasingly turning their at- Dr. Wu is an assistant professor of patterns of genetic variation and to iden- medicine and of systems biology and tention to genomic technologies such as tify the causes and consequences of varia- a member of the Herbert Irving Com- the revolutionary CRISPR/Cas system tion in recombination and mutation rates in prehensive Cancer Center at Columbia and a high throughput analysis technolo- humans and other organisms. Earlier this University Irving Medical Center. His gy called massively parallel reporter as- year, she was also elected to the American research seeks to bridge the discovery says (MPRA), as well as novel computa- Academy of Arts & Sciences, which rec- of basic mechanisms of gene regulation tional tools and deep learning models to ognizes and celebrates excellence of sci- with the development of novel thera- study gene regulation at a global scale. entists, artists, scholars, and leaders in the peutics for human diseases, focusing on The Pew Charitable Trust announced public, non-profit, and private sectors. cancer and cardiometabolic diseases. a total of 22 early-career researchers for A member of Columbia’s Program for As a Pew-Stewart scholar, Dr. Wu will its scholars program in the biomedical Mathematical Genomics, Dr. Przeworski is investigate the dysregulation of messen- sciences. At Columbia, Dr. Wu joins the recipient of the Distinguished Colum- ger RNA structure in the development of fellow faculty members, Dr. Samuel bia Faculty Award, the Howard Hughes breast cancer. Sternberg (biochemistry and molecular Medical Institute Early Career Scientist One of the least understood ways of biophysics) and Dr. Miguel Villavicen- award, the Rosalind Franklin Young In- controlling genes is by changing the cio Camarillo (neuroscience) as a new vestigator award, the Friedrich Wilhelm Bessel Research award, and an Alfred P. shape of the messenger RNA (mRNA), Pew scholar. an intermediate carrier of the genetic Sloan fellowship. information stored in genes. Messenger —Reprinted with permission The NAS has elected 120 members and RNA serves as the template for making by HICCC News 26 international members to its new class.

13 COLUMBIA UNIVERSITY DEPARTMENT OF SYSTEMS BIOLOGY Around the Department, 2019-2020 Grants, Awards, and More

Cory Abate-Shen, PhD, received a the sum of responses to the individual Sagi Shapira, PhD, and Nicholas Ta- Life Science Accelerator pilot grant for drugs. Motivated by this observation, they tonetti, PhD, received a COVID-19 pi- “Development of ATAD2 Inhibitors as a designed an algorithm able to predict syn- lot grant from Columbia’s Herbert Irving Novel Treatment for Metastatic Prostate ergistic drug combinations based on the Comprehensive Cancer Center for “Iden- Cancer.” gene expression of monotherapies. Re- tification of Adverse SARS-CoV-2 Infec- sults of this study were published in the tion Outcome Determinants.” Harmen Bussemaker, PhD, received journal eLife. The paper also presents a a Columbia Life Science Accelerator conceptual framework for the molecular Peter Sims, PhD, received a pilot grant award for “Data-Driven Design of Bio- underpinnings of the drug synergy. from the Herbert Irving Comprehensive logics for the Next Generation of Drug Cancer Center and Columbia Engineering Discovery.” Elise Flynn, PhD student in the Lappa- for collaborative cancer biology-engineer- lainen lab, received an F31 fellowship, and , Dr, and ing research. Andrea Califano Andrew MD/PhD student Molly Martorella, MD, the John Harris Associ- Lassman, an F30 fellowship, both from the National PhD, received a grant ate Professor of Neurology at Columbia Dennis Vitkup, Human Genome Research Institute. from the National Institutes of Health/ University Irving Medical Center, received National Institute of Mental Health for an award from the William Rhodes and , PhD, was awarded a Vage- Tal Korem “Discovery and Analysis of Brain Circuits Louise Tilzer-Rhodes Center for Glio- los Precision Medicine Pilot Grant for and Cell Types Affected in Autism and blastoma at NewYork-Presbyterian Hos- “Mechanistic Investigation of the Vaginal pital for “Precision Biology for Newly Di- Microbiome in Different Manifestations of Schizophrenia.” He also received a grant agnosed Glioblastoma—A Translational Spontaneous Preterm Birth.” from the National Institute of General Pilot Clinical Trial.” Medicine for “Systems Biology of Protein Tuuli Lappalainen, PhD, and Har- and Phenotypic Evolution.” Andrea Califano, Dr, and Peter men Bussemaker, PhD, were award- Sims, PhD, along with Hanina Hib- ed an R01 from the National Institute of Harris Wang, PhD, received a shoosh, MD, professor of pathology and Mental Health for “Integrative Analysis of Hirschl Trust Research Scientist Award cell biology; Kevin Kalinsky, MD (for- Genetic Variation and Transcription Fac- from the Irma T. Hirschl Trust for merly at CUIMC); and Gordana Vun- tor Networks to Elucidate Mechanisms of “Next-Generation Gut Biome Modula- jak-Novakovic, PhD, University Pro- Mental Health Disorders.” tors of Host Behavior and Cognition,” fessor at Columbia, received a grant from as well as a National Science Founda- the National Cancer Institute for develop- Dr. Lappalainen has joined the Ed- tion grant for “The Rules of Microbiota ment of a “cancer patient on a chip” for itorial Board of Cell, and the scientific Colonization of the Mammalian Gut” invasive human breast cancer. advisory boards of the Jackson Labo- and for the project “Towards Life with ratory and the Wellcome Trust Centre a Reduced Protein Alphabet.” He also In a study reported in Nature Scientif- for Human Genetics, Oxford, UK. She received a Columbia Life Science Accel- ic Reports, Andrea Califano, Dr; also served on the external panel for the erator Pilot Grant for “A Multimodal Brent Stockwell, PhD, Columbia’s quinquennial review of the Human Ge- Oral Non-Viral CRISPR-Cas Medical Departments of Biological Sciences and netics and Cellular Genetics programs at Countermeasure to Enhance Ionizing of Chemistry; and coauthors at Colum- the Wellcome Sanger Institute, and she Radiation Resilience and Survival.” bia and Harvard Medical School screened co-led the final phase of analysis of the neuroblastoma (NBL) tumor subtypes for GTEx Consortium, with multiple papers , PhD, received a Nation- selectively lethal compounds, to identify Xuebing Wu published in Science and other journals in al Institute of Health Director’s New metabolic dependencies that underpin September 2020. each subtype, in particular, the mesen- Innovator Award (DP2) for his project “Genome-Wide Studies of the Noncod- chymal NBL subtype. These biosynthetic Michael Murphy, a postdoc in the pathways, which are essential to cell vi- Xuebing Wu lab, received a postdoc- ing Functions and Mechanisms of Human ability, represent vulnerabilities that they toral fellowship from the American Heart mRNAs”; he was also named a Highly Cit- hope to exploit therapeutically. Association. ed Researcher in 2019 by Web of Science.

Scientists in the laboratories of Andrea Raul Rabadan, PhD, received Nation- Chaolin Zhang, PhD, received a Vage- Califano, Dr, and IBM’s Gustavo al Cancer Institute grants for “Dissecting los Precision Medicine Pilot Grant for Stolovitzky, PhD, demonstrated that the Glia Immune Microenvironment Using “Unbiased Screen of Proximal and Distal the transcriptomic response of cells to Random Matrix Theory” and for “Periph- Splicing Regulatory Elements Towards a combination of two drugs is more than eral T-Cell Lymphomas.” Drug Discovery.”

14 systemsbiology.columbia.edu

IN THE MEDIA PHD GRADUATES Single Cell Analysis Core since 2017. Dr. An article in Science, “Computer Algo- Congratulations to our recent grads! Sims’s primary focus is the development of single-cell approaches to systems biol- rithms Find Tumors’ Molecular Weak Tom Blazejewski (Wang lab) ogy. Researchers in his lab develop new Spots,” discusses the work of Andrea Margot Brandt (Lappalainen lab) Califano, Dr, and his research group on Jimin Park (Wang lab) tools for single-cell and cell type-specific the identification of master regulators, Ravi Sheth (Wang lab) analysis, focusing mainly on transcription- i.e., genes that orchestrate regulatory al and translational regulation. They use programs involved in cancer pathology. cutting-edge microscopy, next-generation A Nature Outlook article on genetically NEWLY TENURED FACULTY IN sequencing, and microfabrication to enable targeted cancer therapy, “Beyond the SYSTEMS BIOLOGY unbiased, genome-wide measurements of Genome,” also discusses Dr. Califano’s Congratulations to Drs. Lappalainen, Sims, biological samples. They apply these tools research on master regulators, as well as and Wang, of the Department of Systems on algorithms to suggest treatments. Biology, who have been awarded tenure broadly to problems in cancer biology, im- and promoted to associate professor. munology, and neuroscience.

COVID-19 ACTIVITIES (Related: Tuuli Lappalainen, Systems Biology Faculty Address the PhD, joined Columbia Global Pandemic, Page 3) University Irving Med- ical Center in 2014. At the beginning of the COVID-19 pan- She holds a joint ap- demic, Andrea Califano, Dr, along pointment in the De- with Stephen Goff, PhD, Depart- partment of Systems ments of Microbiology and Immunology Biology and the New and of Biochemistry and Molecular Bio- York Genome Center. physics; Eric Greene, PhD, Department Her research links computational and pop- of Biochemistry and Molecular Biophys- ulation genomics to experimental molecu- ics; and Andrew Marks, MD, Depart- lar biology, with a focus on characterizing Harris Wang, PhD, joined Columbia ments of Physiology and Cellular Bio- functional genetic variation in human pop- University Irving Medical Center in 2013. physics and of Molecular Physiology (in ulations and its contribution to traits and He has a joint appointment in the Depart- Medicine), organized a series of weekly diseases. The overall goal of her research ment of Systems Biology and the Depart- virtual symposia on the virus for re- program is to uncover general rules of the ment of Pathology and Cell Biology. His searchers and clinicians. The symposia, genomic sources of human variation and to which started in April, covered a broad push discoveries and methods from her re- research primarily focuses on applying range of scientific, clinical, economic, search projects toward clinical applications. systems and synthetic biology approaches and social aspects of the pandemic, and Dr. Lappalainen has made important con- to understand the organizing principles attracted hundreds of attendees. tributions to several international research that govern the structure and function of consortia in human genomics, including microbial communities, with a focus on Wellington Cardoso, MD, PhD, di- co-leading the final phase of the Geno- the mammalian gut microbiome. His lab- rector of the Columbia Center for Human type-Tissue Expression (GTEx) project. oratory pioneers new experimental and Development, and Andrea Califano, Dr, are conducting a study to identify and computational approaches, combined with Peter Sims, PhD, pharmacologically target key regulators joined Columbia Uni- in vitro cultures, mice models, and clinical of the epithelial response to COVID-19 versity Irving Medical specimens, to make entirely new types of infection in the respiratory tract, aiming Center in 2012. He has microbiome measurements and functional to reduce viral load and transmission. a joint appointment perturbations to study and engineer gut The research is supported by supplemen- in the Department of microbiota. His work employs a variety tal funding to Dr. Cardoso’s Outstanding Systems Biology and of high-throughput techniques including Investigator Award (R35 grant) from the the Department of CRISPR-Cas gene editing, de novo DNA National Institutes of Health, for “Mech- Biochemistry and Mo- anisms Controlling Expansion and Lineage lecular Biophysics. He has served as Direc- synthesis, and next-generation DNA se- Specification of Airway Progenitors in De- tor of Systems Biology Graduate Studies quencing towards unlocking the therapeu- velopment and Disease.” since 2016 and Director of the Columbia tic potential of the microbiome.

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Columbia University Department of Systems Biology Front cover: Irving Cancer Research Center Illustration of the novel SARS-CoV-2 (Credit: Nicoletta Barolini) 1130 St. Nicholas Avenue New York, NY 10032 Back cover: Image artistically depicts the complexity of gut microbiota. A recent study by the Vitkup lab revealed fundamental macroecological laws that To learn more about our research and programs, could help researchers better understand the gut microbiota dynamics visit systemsbiology.columbia.edu. and its role in human health and disease. (Credit: Irina Titkova)

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