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HARVARD UNIVERSITY
CHEMICAL BIOLOGY PHD PROGRAM
2016-2017 Student Handbook
Program Contacts Name Position Phone Email Dan Kahne Program Co-Director 496-0208 [email protected] Suzanne Walker
Program Co-Director 432-5488 [email protected]
Jason Millberg Program Coordinator 432-7935 [email protected] Program Advising Incoming students will meet with the program directors who will help plan the student’s initial program of graduate study. Program directors will meet with the first year students individually at the beginning of each semester. Laboratory Rotations Students in the Chemical Biology Program are expected to take 2-4 laboratory rotations before selecting a Dissertation Advisor. The program does not set time limits on rotations, but most rotations are expected to be 6-12 weeks long. Students should inform the program coordinator when they begin and complete their rotations. Rotations allow students to explore different research areas, identify potential collaborators, and experience the environment in different research groups. The purpose of the rotation is to facilitate the choice of the dissertation laboratory, not to accomplish a research project. The following faculty profiles represent Harvard faculty who have expressed an interest in having Chemical Biology Program Students in their labs. Students may rotate in the labs of faculty outside of our program but must submit a paragraph to (describing why they think this lab is a good fit for them to pursue Chemical Biology research) in addition to speaking with the co-directors if they decide to join an outside lab. First year students will be asked to present their lab rotations to one another at CB300, sharing the techniques they have learned, the data they have acquired and the scope of the project. First year students must choose their dissertation laboratory no later than June 30th.
Course Requirements
Students are required to take CB300: Introduction to Chemical Biology Research, CHEM171: Biological Synthesis, MedSci300: Conduct of Science, CB2200: Introduction to Chemical Biology, BCMP236: Modern Drug Discovery: From Principles to Patients, and three additional courses chosen in consultation with their program advisors. A current list of courses students commonly take is provided to students at the beginning of each semester.
Registration Students can register for courses online at www.my.harvard.edu. Once students complete online registration they are ready to begin using the online course shopping tool. Students will enter their course selection electronically. In order for students to be considered a full time student, they must sign up for 4 half courses each semester.
• Students who are not taking 4 “real” courses and have not joined a lab should sign up for the rotation course, CB399, catalog # 1888, the appropriate number of times.
• Students who have permanently joined a lab should use CB350, catalog # 9668, (under their PI’s name) the appropriate number of times.
Course Catalog http://my.harvard.edu Students can visit the FAS Registrar’s Office website to access an online version of the Courses of Instruction Book.
Quarter Courses https://nanosandquarters.hms.harvard.edu/ A quarter course is a half semester course that focuses on a specific topic, usually in the area of expertise of the faculty. The class meets for one 2-hour session per week. Meeting times are usually arranged at the initial session for convenience of faculty and students.
Nanocourses https://nanosandquarters.hms.harvard.edu/ Nanocourses are short graduate-level courses consisting of two class meetings which cover a specific subject in depth. Six nanocourses are equivalent to one half course. Students register for credit on their study cards in the semester that they plan to complete their sixth nanocourse, or when they plan to complete a combination of 3 nanocourses and one quarter course.
All YEAR
Chemical Biology 300hf. Introduction to Chemical Biology Research (REQUIRED) Suzanne Walker Half course (throughout the year). Wednesdays 4:30-5:30 alternating between the Cambridge (Naito, Room 205) and Longwood (Warren Alpert, Room 436) Campuses. Lectures introduce the research areas of current program faculty in chemical biology. *Note: Students will be emailed the finalized schedule prior to the official start of classes. A reminder will be sent out at the beginning of each week with location and Faculty presenter information. FALL Chemistry 171. Biological Synthesis Emily Patricia Balskus Half course (fall term). Tu., Th., 1–2:30. This course will examine synthesis from a biological perspective, focusing on how organisms construct and manipulate metabolites, as well as how biological catalysts and systems can be used for small molecule
production. Topics to be covered include mechanistic enzymology, biosynthetic pathways and logic, biocatalysis, protein engineering, and synthetic biology. J TERM Chemical Biology 2200. Introduction to Chemical Biology (Boot Camp: REQUIRED) Stephen Haggarty (Medical School) and Ralph Mazitschek (Medical School) Half course (spring term). M.- F., 9am–5pm (two weeks in January 1/9/17-1/20/17 ). This course will provide a survey of major topics, technologies, and themes in Chemical Biology, with hands-on exposure to a variety of experimental approaches, followed by an introduction to proposal writing. Note: Intended for first-year graduate students in the Chemical Biology program; permission of the instructor required for all others. This course will include an introduction to the use of MATLAB for model-building. SPRING BCMP 236. Modern Drug discovery: from principles to patients Nathanael Gray (Medical School), Tim Mitchison and members of the Department Half course (spring term). Tu., Th., 3:30-5. This course will familiarize students with central concepts in drug action and therapeutics at the level of molecules, cells, tissues and patients. These concepts and methods are central to modern drug development and regulatory evaluation. In the 1st half of the course we will cover drug-target interactions, Pharmacokinetics and Pharmacodynamics at a quantitative level, the clinical trials process, biomarkers and new frontiers in Therapeutic development. The 2nd half will focus on modern approaches to therapeutic discovery and development, both small molecules and protein based. Examples are drawn from numerous unmet medical needs including cancer, HIV, neurodegenerative and infectious diseases. The course will include computational exercises and a MATLAB workshop.
FALL (G2 year) Medical Sciences 300qc. Conduct of Science Raju Kucherlapati (Medical School) 4324 Quarter course (fall term). Hours to be arranged . Note: Restricted to GSAS graduate students on the Longwood campus. Fellowships The Chemical Biology Program requires all first year students who are eligible to apply for fellowships. To prepare students, one CB300 class will be devoted to a fellowship workshop. By October 15 of the first year, each student must submit their fellowship plans to the program coordinator. Teaching Students are required to complete one semester of teaching that is at minimum 0.25 FTE, preferably by the end of their second year. It is recommended that they do not teach and have their PQE during the same term. Students should inform the program coordinator office as they make plans to fulfill their teaching requirement.
When students are fulfilling the teaching requirement (aka the first semester of teaching that they perform), their stipend will be reduced by half of the TF salary. Stipends funded by agencies outside of Harvard (NSF, NDSEG, HERTZ, etc) will not be reduced. NSF fellowship winners should consult NSF regarding reaching restrictions. Once they have completed their teaching requirement for the program they will receive the full TF salary for any additional courses that they choose to teach. TF positions are arranged by each individual department so there are no universal deadlines or contacts. It is usually best to contact the faculty member or preceptor of the course that you are interested in teaching. Preliminary Qualifying Exam Guidelines (PQE)
The aim of the PQE is to assess the student's ability to review research in a particular field, to identify a problem or formulate a central hypothesis that is significant for the field, to design line(s) of experimentation to address the problem or test the hypothesis, and to describe how s/he will interpret the data that would result from the proposed experiment. The topic for the proposal may be related to a student’s dissertation research or the topic may be completely independent. Students may take the exam in the fall term or in the spring term (by April 15th) of their second year. It is advised that the student completes the teaching requirement in the semester without the PQE. A PQE Committee must be composed of three faculty members. Each student will be assigned a Chemical Biology Executive Committee Member to chair the PQE committee. The student will provide a one page outline of a possible topic to the chair as well as propose two additional faculty members to sit on the PQE committee. Once the chair of the committee has met with the student and approved the topic and other faculty members, the student should contact the Chemical Biology Coordinator to assist in scheduling the exam. It is anticipated that there will be discussions between the student and the Dissertation Advisor on the thesis topic but the PI should not be involved in the writing of the proposal or preparing for the oral exam. The student must not solicit direct input on the written proposal from any faculty member. All of the writing must be the student's own original work. Students are encouraged to actively seek advice and feedback from students and post-docs on all aspects including formulation and writing of the proposal as well as preparation for the oral exam. A one page specific aims write-up should be submitted to the committee three weeks prior to the exam date. The goal is to allow the students to receive feedback on how broad/narrow, etc their topic is. This is especially useful to those who will be writing a Proposal on their anticipated thesis research. The final written proposal should be submitted to the student’s Committee and the Chemical Biology Coordinator at least one week prior to the oral defense. The Advisor should not be included in that submission. The overall length not including figures and references should not normally exceed ten pages.
The format for the proposal is as follows:
• Background and Significance • Specific Aims • Preliminary Results • Future Plans
The student should be prepared to present a short (20 min) presentation of the proposal. Either during or following the presentation, faculty members will ask questions regarding the proposed research. The questions may also probe the student’s general knowledge beyond the specifics on the proposal. The oral exam is expected to last no longer than 1 hour and 15 minutes. The Dissertation Advisor will not be present during the exam but will give a private oral or written introduction about the student prior to the start of the exam. Following the exam, the Dissertation Advisor will be invited to speak briefly with the committee without the student being present. The committee, student and Dissertation Advisor will then discuss their evaluation. The evaluation will take into consideration both the written and the oral parts of the exam. The faculty will consider whether or not the student successfully justified the proposed research, the significance of the research, the degree of independent thinking that went into the proposal, the clarity of the writing, and the student’s breadth of knowledge relevant to the proposed research. The three possible outcomes of the exam are:
• The student will pass the exam. A pass means there are no significant weaknesses in proposal, oral exam, or general knowledge.
• Conditional Pass. This means any serious shortcomings, rewrites, lack of background knowledge. The student will be asked to rewrite or represent their proposal. There will be a deadline and set of instructions given to student at end of exam. At the re-examination the student can either pass and begin their proposed research, or fail and be asked to leave the program.
• Fail, in which case the student will be excused from the program. The chair of the exam committee is responsible for submitting a written report of the recommendations made by the PQE committee to the Chemical Biology Program Office. Dissertation Advisor and the Dissertation Advisory Committee Policy
Choosing a Dissertation Advisor When the Dissertation Advisor has been selected (usually by the end of year 1), students should email the program coordinator to formally declare their lab choice. Dissertation Advisory Committee (DAC)
After passing the PQE, a DAC of at least three members (in addition to the Dissertation Advisor) must be appointed by the end of August of the student’s third year and a meeting scheduled by the end of November. Students should meet with their advisor to select the committee; subject to program approval, any three faculty members may be on the committee. Once students have decided on their
committee they should email their selections to the Chemical Biology Coordinator for program approval. The Committee should meet with the student at least once a year through G5 and every six months thereafter, until Ph.D. dissertation writing is underway. The Chair of the DAC is responsible for the preparation of the DAC Report, which should be signed by all committee members at the conclusion of each meeting, and submitted to the Chemical Biology Coordinator. If these requirements have not been met, the student may not be allowed to register for the semester or their stipend could be withheld. Role of the DAC The role of the DAC is to assist the student in defining the dissertation project, review scientific progress, offer critical evaluation, suggesting extension or modification of objectives, arbitrate differences of opinion between the student and the advisor if they arise, and decide when the work accomplished constitutes a dissertation. Our hope is that the committee will help students in the early stages to get their research off to a good start, and that they will be a resource for students at any point during their graduate career. Procedures for Setting up DAC meetings Students should contact the Chemical Biology Coordinator, who will assist them in scheduling all meetings and who should receive a copy of all information that is given by the student to his or her DAC committee prior to the meeting. Dissertation Proposal and DAC Report Policy Students are to submit a brief summary of progress (five or fewer pages not including images and references) to their Dissertation Advisory Committee and Chemical Biology Coordinator at least one week before the meeting and be prepared to give a twenty minute presentation. The student is also responsible for bringing a copy of the DAC report to each meeting. This report is to be filled out by the Chair of the committee and returned to the Chemical Biology Coordinator immediately following the completion of the meeting. The chair of the committee is also responsible for designating time during the meeting for both the student and advisor to address to the committee separately. The chair should try to illicit information regarding how both the advisor and student assess work in the lab is going and if there are any issues or conflict. The format for the written report is as follows:
• Background and Significance • Specific Aims • Preliminary Results • Future Plans
Dissertation Preparation and Defense The Dissertation Advisory Committee, in consultation with the Dissertation Advisor, determines when it is time for a student to stop laboratory work and begin to write a dissertation. Once a student has been given permission to write a dissertation, the Chemical Biology Coordinator should be contacted to schedule an appointment to discuss requirements, dates, etc.
A pamphlet entitled “Form of the Doctoral Dissertation” describing the requirements of the University in writing the dissertation, is available at http://www.gsas.harvard.edu/current_students/form_of_the_phd_dissertation.php. Dissertation Examination Committee GSAS states that the Dissertation Examination Committee must be comprised of three faculty members. Two of the faculty must be FAS faculty or be a member of the program faculty. The third member can be from outside of Harvard. They strongly recommend that the chair of the committee be a FAS faculty member. The Chairperson of the DAC should preferably chair the examination, but students may invite another DAC member to do so. The role of the chairperson is to (a) be impartial, (b) arbitrate problems, and (c) administer the exam. The student and the Dissertation Advisor shall submit, in rank order, a list of potential examiners to a Co-Director, with whom, in consultation, a final list is generated. After the Co-Director approves the list of examiners, the student shall then set up the exam by contacting the examiners, giving them details as to date, time, etc. *Note: Please see the Chemical Biology PhD Program Dissertation Defense Policy for more information.
Events and Seminars
Data Talks – Student Talks Third year students will present their data in an informal setting to fellow students and faculty in the program. It is expected that all students will attend these monthly talks as they will serve as an invaluable part of their education and a wonderful opportunity to develop a dialogue to discuss the big questions of Chemical Biology. Retreat All current Chemical Biology students and faculty are invited to attend the Chemical Biology Program Retreat. The purpose of the retreat is to bring the entire community together to learn about research progress in Chemical Biology. Fifth year students will present their dissertation research to date orally and second, third and fourth year students will present through a poster. The schedule for the all day event will include faculty talks, a poster session, a guest speaker, and lunch.
CCB Seminars
The department of Chemistry and Chemical Biology offers a number of seminar series that feature a wide range of topics from organic and inorganic to human disease, etc. Many of the series feature
speakers that represent both CCB and CBP faculty as well as those from outside Harvard and MIT. To view the listing and who to contact to be added to the mailing lists please visit the CCB website and click on the “Courses and Seminars” tab (http://www.chem.harvard.edu/courses/seminars.php).
Other Seminar Series
Many of the individual departments throughout the Cambridge and Longwood Campuses offer seminar series that may interest students of the Chemical Biology Program. We encourage all of our students to explore the variety of seminar options and attend whenever feasible. CBP students should contact program or Department Coordinators to be added to seminar mailing lists that interest them.
Brigham and Womens HospitalNeurosurgery, BLI, room 137221 Longwood AveBoston MA 02115
NathalieAssociate Professor of Radiology
The research aims to develop and implement biochemical classifications to enable surgeons and oncologists to tailor treatment fromthe time of surgery, and allow personalized cancer care using molecular imaging with mass spectrometry. Molecular classification ofbrain tumors should allow to rapidly identify and grade tumors, and to predict a tumor’s behavior and its response to treatment.Together with the National Center for Image-Guided Therapy, Dr Agar’s group is developing a direct in vivo mass spectrometryanalysis of surgical tissue to assist in the evaluation of tumor margins during surgery. This state-of-the-art application relies on theintegration of a surgical probe with ambient ionization mass spectrometry and neuronavigation. The laboratory and its keycollaborators are devoted to combine approaches and expertise to expedite the development of diagnostic means to further personalizecancer care from surgery to the selection of adjuvant chemotherapy.
Email:
5-10
617-525-7374
Tel:
http://agarlab.bwh.harvard.edu/Agar_Lab/Home.html
Agar
Lab Size:
Publications:
Mallinckrodt 303N12 Oxford St.Cambridge, MA 02138
EmilyAssociate Professor of Chemistry and Chemical Biology
The focus of our research is the discovery of new enzymatic and non-enzymatic chemistry in living systems. We are particularlyinspired by the breadth of reactions used by microorganisms in both primary and secondary metabolism. Microbes are Nature’ssynthetic chemists, continually evolving elegant chemical solutions for problems inherent to their growth and survival in diverseenvironments. Understanding microbial chemistry is important; in addition to playing significant roles in the ecology of producingorganisms, small molecules made and manipulated by bacteria and fungi have medicinal and industrial applications. The emergingfield of synthetic biology has also fueled interest in engineering microbial metabolism to produce small molecules of natural and non-natural origins; such efforts will greatly benefit from the ability to introduce new chemistry, both enzymatic and non-enzymatic, intodesigned pathways.One area of interest is the discovery of new biosynthetic pathways and enzymes using a genome mining approach heavily influencedby our deep understanding of chemical reactivity. We are targeting pathways from both primary and secondary microbial metabolism.Within secondary metabolism, we focus on uncovering biosynthetic pathways for natural products of unusual molecular architectureand characterizing metabolic pathways from the gut microbiota that may influence various aspects of human health.We are also investigating whether it is possible to chemically modify small molecules in the presence of microorganisms usingmethods and design principles from synthetic chemistry. Our long-term goals in this area are to unite the fields of synthetic andbiological chemistry by developing biocompatible chemistry: non-enzymatic reactions that can alter the structures of cellularmetabolites. Ultimately, we will apply our methods to address problems in the areas of synthetic biology and medicine.
Email:
10 - 15
617-496-9921
Tel:
http://scholar.harvard.edu/balskus/
Balskus
Lab Size:
Haiser, Henry J.; Gootenberg, David B.; Chatman, Kelly; Sirasani, Gopal; Balskus, Emily P.; Turnbaugh, Peter J. “Predicting andManipulating Cardiac Drug Inactivation by the Human Gut Microbe Eggerthella lenta” Science 2013, 341, 295–298.
Nakamura, Hitomi; Balskus, Emily P. “Using Chemical Knowledge to Uncover New Biological Function: Discovery of theCylindrocyclophane Biosynthetic Pathway” Synlett,2013, 24, 1464–1470.
Brotherton, Carolyn A.; Balskus, Emily P. “A Prodrug Mechanism is Involved in Colibactin Biosynthesis and Cytotoxicity” Journalof the American Chemical Society, 2013, 135, 3359–3362.
Craciun, Smaranda; Balskus, Emily P. “Microbial Conversion of Choline to Trimethylamine Requires a Glycyl Radical Enzyme”Proceedings of the National Academy of Sciences USA 2012, 109, 21307–21312.
Nakamura, Hitomi; Hamer, Hilary A.; Sirasani, Gopal; Balskus, Emily P. “Cylindrocyclophane Biosynthesis InvolvesFunctionalization of an Unactivated Carbon Center” Journal of the American Chemical Society 2012, 134, 18518–18521.
Publications:
Dana Farber Cancer InstituteSmith Building 1022B1 Jimmy Fund WayBoston, MA 02115
Stephen C.Professor of Biological Chemistry and Molecular Pharmacology
Dr. Stephen C. Blacklow’s laboratory is dedicated to research that seeks to answer important, fundamental questions about thestructure and function of cell surface receptor molecules at the biochemical level. Among the receptors he studies is the multi-domainprotein receptor for low-density lipoprotein—better known as bad cholesterol—and a family of proteins called Notch receptors thatcommunicate signals between neighboring cells. Mutations in these and other cell surface receptors can result in a wide variety ofdisorders, including heart disease and cancer. Understanding how these receptor molecules function in normal and abnormal states isfundamental to understanding the patho- genesis of these diseases, and thereby provides new opportunities for the development oftargeted therapies.
Email:
Between 10 and 15
617 525 4415
Tel:
http://pathology.bwh.harvard.edu/
Blacklow
Lab Size:
Tiyanont, K, Wales, TE, Aste-Amezaga, M, Aster, JC, Engen, JR, and Blacklow, SC. Evidence for Increased Exposure of the Notch1Metalloprotease Cleavage Site upon Conversion to an Activated Conformation. Structure 2011;19(4):546-54. PMCID: PMC3075624
Arnett, KA, Hass, M, McArthur, DG, Ilagan, MXG, Aster, JC, Kopan, R, and Blacklow SC. Structural and Mechanistic Insights intoCooperative Assembly of Dimeric Notch Transcription Complexes. Nature Structural and Molecular Biology 2010;17(11):1312-7(Cover article). PMCID: PMC3024583
Gordon, WR, Vardar-Ulu, D, Sanchez-Irizarry, C, Histen, G, Aster, JC, and Blacklow, SC. Structural Basis for Autoinhibition ofNotch. Nat Struct and Mol Biol 2007; 14(4):295-300.
Nam Y, Sliz P, Song L, Aster JC, Blacklow SC. Structural basis for cooperativity in recruitment of MAML co-activators to Notchtranscription complexes. Cell. 2006;124:973-983.
Fisher C, Beglova N, Blacklow SC. A general mode for recognition of ligands by lipoprotein receptors from the structure of anLDLR-RAP complex. Molecular Cell. 2006;22:277-283
Publications:
Dana-Farber Cancer Institute44 Binney Street, D510DBoston, MA 02115
JamesAssociate Professor of Medicine
The Bradner Laboratory studies gene regulatory pathways using the emerging discipline of chemical biology. We focus on cancer, ascancer is a dreadful disease which remains largely incurable. We choose to study cancer biology with chemistry, because if we aresuccessful in controlling cell identity in this manner, new types of chemical probes and therapeutics will emerge directly from theseefforts.
We consider cancer as a disease of cell state, caused by genetic alterations but influenced also by the cell type of origin and themanner in which the genome is packaged. The insight that no known set of genetic alterations are capable of causing cancer in all celltypes establishes the plausibility that reprogramming the cell's fundamental identity may subvert the aggressive behavior of cancer. Inaddition, recent research has observed high genetic complexity, heterogeneity, plasticity and redundancy of signaling networks incancer. These findings further establish the pressing need for molecules directed against the master regulatory proteins maintainingcancer cell identity.
We have initiated research aimed at three sets of targets:1. Transcription Factors2. Chromatin modifying enzymes3. Histone binding modules
We perform this research at the Dana-Farber Cancer Institute and the Harvard Medical School, in close collaborative proximity ofscientists, clinicians and patients.In the post-genomic era, the discovery of cancer genes has become relatively straightforward. Cancer biologists and geneticists nowrace, like modern cartographers, to assimilate this information as a unified geography of cell signaling pathways. For the cancerpatient, these advances allow a detailed, highly individualized understanding of cancer's hard-wiring. Unfortunately, the delay in thediscovery and delivery of targeted therapeutics remains a significant concern. We invoke a utilitarian model of drug discovery whichis not restricted by any individual chemistry or technology. We support a collaborative, creative approach to drug discovery focusedon the most pressing targets irrespective of perceived 'drugability' or profitability.
Email:
Between 5 and 10.
(617) 632-6629
Tel:
http://bradner.dfci.harvard.edu/
Bradner
Lab Size:
Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, MunroS, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thangue N, French CA, Wiest O,Kung AL, Knapp S and Bradner JE. Selective inhibition of BET bromodomains. Nature. 2010. 468:1067-73Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, Kung AL, Gilliland DG, Verdine GL and Bradner JE.Direct inhibition of the NOTCH transcription factor complex. Nature. 2009 Nov 12; 462: 182-188.Bowers A, Greshock TJ, West N, Estiu G, Schreiber SL, Wiest O, Williams RM and Bradner JE. Synthesis and Conformation-Activity Relationships of the Peptide Isosteres of FK228 and Largazole. Journal of the American Chemical Society. 2009 Mar 4;131(8):2900-5.
Publications:
Longwood Center, LC3311360 Longwood Ave.Boston, MA 02215
SaraAssistant Professor of BCMP
Proper regulation of protein homeostasis is required for nearly every aspect of cell life including DNA repair, cell cycle regulation,innate immunity and transcription. Dysregulation of proteostasis drives many types of cancer, infection and neurodegeneration. Theubiquitin system performs a central role in maintenance of proteostasis through reversible post-translational addition of (poly)ubiquitin to proteins, a mark that: 1) tags substrates for destruction by the proteasome or lysosome and 2) functions as a switch forgene expression through ubiquitylation of histone lysine sidechains. Ubiquitylation is coordinated by the action of ubiquitinactivating, conjugating, ligating (E1, E2, E3) and deubiquitylating enzymes (DUB). The mission of our group is to develop first-in-class inhibitors and prototype drugs for DUBs that can utilized to pharmacologically validate members of the gene family as newtargets for cancer treatment and other diseases.DUBs have garnered significant attention as potential therapeutic targets in the field of oncology due to their removal of degradativeubiquitin marks from cancer causing proteins. For example, the DUBs USP1, USP2, USP7, USP8 and USP12 have been shown torescue oncogenes ID1, cyclin D1, MDM2, EGFR and Androgen receptor, respectively, from degradation in multiple cancers usingprimarily genetic methods. It has been demonstrated for a limited number of DUBs that small molecule inhibition of DUB proteaseactivity can promote degradation of substrate oncoproteins. For example we developed a novel USP1 inhibitor and demonstrated incollaboration with Professor Alan D’Andrea that pharmacological inhibition of USP1 promotes degradation of the transcription factorID1 in acute myeloid leukemia. At present, there are approximately 95 recognized human DUB enzymes belonging to 5 distinctfamilies.Our approach to DUB inhibitor development and target validation is to: 1) Execute target, gene family and peptidomimeticapproaches to achieve new DUB inhibitors; 2) Screen DUB inhibitor libraries for anti-cancer activities; and 3) Pursue validation andmechanistic work for selected DUBs and compounds. We are also committed to developing technologies that accelerate ubiquitinsystem and especially DUB research. To accomplish these goals we work as a collaborative team of synthetic chemists, biochemists,cell biologists and structural biologists.
Email:
617-632-1963
Tel:
http://buhrlagelab.dana-farber.org/
Buhrlage
Lab Size:
Ritorto, M. S.; Ewan, R.; Perex-Oliva, A.; Knebel, A.; Buhrlage, S. J.; Wightman, M.; Kelly, S. M.; Wood, N. T.; Gray, N. S.;Morrice, N. A.; Alessi, D. R.; Trost, M. ‘Screening of DUB activity and specificity by MALDI-TOF mass spectrometry,’ Nat.Comm., 2014, 5, 4763.Mistry, H.; Hsieh, G.; Buhrlage, S. J.; Huang, M.; Park, E.; Cuny, G. D.; Galinsky, I.; Stone, R.; Gray, N.; D’Andrea, A. D.; Parmar,K. ‘Small molecule inhibitors of USP1 target ID1 degradation in leukemic cells,’ Mol. Can.Ther., 2013, 12, 2651-2662.Yang, G.; Zhou, Y.; Liu, X.; Xu, L.; Cao, Y.; Manning, R. J.; Patterson, C. J.; Buhrlage, S. J.; Gray, N.S.; Tai, Y.; Anderson, K. C.;Hunter, Z. R. Treon, S. P. ‘A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation ofBruton’s Tyrosine Kinase in Waldenstrom’s Macroglobulinemia,’ Blood, 2013, 122, 1222-1232.
Buhrlage, S. J.; Bates, C. A.; Rowe, S. P.; Minter, A. R.; Brennan, B. B.; Majmudar, C. Y.; Wemmer, D. E.; Al-Hashimi, H.; Mapp,A. K. ‘Amphipathic small molecules mimic the binding mode and function of endogenous transcription factors,’ NMR Investigationof Small Molecule Transcriptional Activator Interactions with Protein Targets,’ ACS Chem. Biol. 2009, 4, 335-344.Buhrlage, S. J.; Brennan, B. B.; Minter, A. R.; Mapp, A. K. ‘Stereochemical Promiscuity in Artificial Transcription Activators,’ J.Am. Chem. Soc. 2005, 12, 12456-12457.
Publications:
Harvard Institute of Medicine 570A4 Blackfan CircleBoston, MA 02115
AmitAssistant Professor of Medicine
Our goal is to identify molecules that regenerate beta-cell mass and prevent beta-cell dysfunction and death. We also develop broadly-applicable chemical technologies with the intent of applying these technologies to specific avenues in beta cell biology. Below is asampling of current research projects:1) Exceptional organisms: Nature has evolved organisms that survive conditions considered pathological to humans. We areunraveling the molecular mechanisms by which infrequent feeding reptiles avert metabolic disorders despite possessing lifestyles thatwill be pathological to humans.2) Chemical Technologies: Motivated by key challenges in diabetes research, we are developing the following tools/methods:a) Next-generation genome-engineering: CRISPR-based technologies hold immense promise for therapeutic genome editing and
transcriptional regulation in beta cells but suffer from several issues, including those about specificity and in vivo delivery. We areapplying chemistry-based approaches to solve these issues.b) Protein Stability in vivo: Protein misfolding and aggregation is the key driver of beta cell failure in type 2 diabetes. We aredeveloping a general, sensitive, and label-free method that will accurately and precisely report on the changes in protein’sconformational stability and microenvironment in cellulo and in vivo.c) Beta cell imaging and therapeutic delivery: We are developing methods for targeted delivery of therapeutic and imaging agents tothe beta cells in vivo.
Email:
5-10
617-714-7445
Tel:
scholar.harvard.edu/c_amit/home
Choudhary
Lab Size:
Chou, D H-C§, Vetere, A§, Choudhary, A§ et al "Kinase-independent small molecule inhibition of JAK-STAT signaling". J. Am.Chem. Soc. 2015, 137; 7929–7934.Choudhary, A. §; Hu He, K.§; Mertins, P. et al “Quantitative phosphoproteomics comparison of alpha and beta cells to uncover noveltargets for lineage reprogramming”. PLOS ONE. 2014, DOI: 10.1371/journal.pone.0095194Vetere, A.§; Choudhary, A.§; Burns, S. M.§; Wagner, B. K.* “Targeting pancreatic beta cell to treat diabetes”. Nature Rev. DrugDiscov. 13; 278-289.Bartlett, G. J.§; Choudhary, A.§ et al “n→π* Interaction in proteins”, Nat. Chem. Biol. 2010, 6, 615–620.
Choudhary, A.; Gandla, D. et al “Nature of amide carbonyl–carbonyl interactions in proteins”, J. Am. Chem. Soc. 2009, 131, 7244–7246.
Publications:
77 Avenue Louis PasteurNew Research Building, 356Boston, MA 02139617-520-4881
StirlingAssistant Professor of Genetics
Diverse control mechanisms converge to ensure that gene transcripts are expressed and processed accurately. Dissection of theseinteractions has proven challenging, because most experimental approaches record downstream products fed by multiple pathways –for example, mature mRNA as the combined product of transcription and splicing.
The Churchman lab enables direct mechanistic insights into fundamental biological processes by developing and applying quantitativeapproaches that create high-resolution views of genome function. Our group has developed methods for genome-scale, high-precisionmeasurement of Pol II transcription in yeast and mammalian cells (Churchman and Weissman, Nature 2011; Mayer et al., Cell 2015).These approaches have enabled fundamental insights into many aspects of eukaryotic transcriptional control, such as transcriptionalpausing, and they bridge the divide between the wealth of in vitro biophysical studies and in vivo genomics.
Aside from eukaryotic transcription regulation, we are interested in the mechanisms that couple gene expression processes, with twocurrent areas of focus: 1) the coupling of transcription elongation with co-transcriptional processes, particularly splicing; and 2) thecoordination of mitochondrial and nuclear gene expression in the assembly of oxidative phosphorylation complexes. By determiningthe molecular mechanisms that control transcription and couple gene expression processes, we aim to open new vistas on potentialtherapeutic strategies for correcting the defects in splicing dysfunction and energy production that are increasingly recognized asdrivers of disease states.
Email:
617-520-4881
Tel:
http://churchman.med.harvard.edu/
Churchman
Lab Size:
Mayer A., di Iulio, J., Maleri, S., Eser U., Vierstra, J., Reynolds, A., Sandstrom R., Stamatoyannopoulos J.A., Churchman, L.S.(2015). Native elongating transcript sequencing reveals human transcriptional activity at nucleotide resolution, Cell 161(3), 541-554.
Churchman, L.S., and Weissman, J.S. (2011). Nascent transcript sequencing visualizes transcription at nucleotide resolution. Nature469, 368–373.
Publications:
Room C-643240 Longwood Ave.Boston, MA 02115
JonHsien Wu and Daisy Yen Wu Professor of Biological Chemistry and MolecularPharmacology
The laboratory studies how naturally occurring small molecules, especially those from bacteria, control biological processes.Organizing themes include: 1) function-based discovery of microbially-produced small molecules and their roles in multilateralsymbioses, 2) function-based discovery of biologically active small molecules controlling eukaryotic development, 3) genome-baseddiscovery of bacterially-produced small molecules. The laboratory is also involved in infectious disease research especiallyalternative approaches to treating bacterial and fungal infections.
1. In the past few years, we have focused on multilateral symbioses involving bacteria, partly because they are widespread andinteresting and partly because they lead to the discovery of new useful molecules in the biological context in which they evolved.Current projects involve the bacterial symbionts of fungus-farming ants, bark beetles, termites, and most recently social amoebas.
2. We also continue to discover small molecules in a more medically relevant context: how bacterially produced small moleculesregulate eukaryotic evolution, development, and immune responses.
3. In the past few years, it has become quite clear that well studied bacteria – including the producers of drugs that are used on the tonscale – are genetically capable of producing many more potentially useful small molecules. The biosynthetic genes can be identifiedin sequenced genomes but the associated molecules have never been characterized. We are working on several approaches todiscovering these cryptic metabolites.
Email:
Lab Members: Between 10 and 12.
617-432-3801
Tel:
http://clardy.med.harvard.edu/
Clardy
Lab Size:
A bacterial symbiont is converted from an inedible producer of beneficial molecules into food by a single mutation in the gacA gene.Stallforth P, Brock DA, Cantley AM, Tian X, Queller DC, Strassman JE, Clardy J. Proc. Natl. Acad. Sci. USA 2013,Synthesis and activity of biomimetic biofilm disruptors. Böttcher T, Kolodkin-Gal, Kolter R, Losick R, Clardy J. J. Am. Chem. Soc.2013, 135;2927-2930.A bacterial sulfonolipid triggers multicellular development in the closest living relatives of animals. Alegado RA, Brown LW, Cao S,Dermenjian RK, Zuzow R, Fairclough SR, Clardy, J, King N. eLife 2012, 1:e00013.Mixing and matching siderophore clusters: structure and biosynthesis of serratiochelins from Serratia sp. V4. Seyedsayamdost MR,Cleto S, Carr G, Vlamakis H, Joao Veira M, Clardy J. J. Am. Chem. Soc. 2012, 134:13550-13553.Small molecule perimeter defense in entomopathogenic bacteria. Crawford JM, Portmann C, Zhang X, Roeffaers MB, Clardy J.Proc. Natl. Acad. Sci. USA 2013, 109:10821-10826.
Publications:
Department of Chemistry and Chemical BiologyMallinckrodt 11512 Oxford StreetCambridge, MA 02138
AdamProfessor of Chemistry and Chemical Biology and of Physics
My lab develops new physical tools to study molecules and cells, and we apply these tools to make new measurements. We combinenanofabrication, optics, microfluidics, electronics, and biochemistry to generate data; and we apply statistics and physical modeling tounderstand the data. Current projects include: development of nanofabricated devices for trapping and studying single biomolecules infree solution; development of fluorescent voltage-indicating proteins; studies on optical spectroscopy in highly contortedelectromagnetic fields; experiments on magnetically sensitive photochemical reactions; and studies of the mechanochemistry ofbiological hydrogels.
Email:
Between 10 and 15.
617-496-9466
Tel:
https://www2.lsdiv.harvard.edu/labs/cohen/
E Cohen
Lab Size:
J. Kralj*, A. D. Douglass*, D. R. Hochbaum*, D. Maclaurin, A. E. Cohen, “Optical recording of action potentials in mammalianneurons using a microbial rhodopsin,” Nature Methods, 9, 90-95 (2012)
J. Kralj, D. R. Hochbaum, A. D. Douglass, A. E. Cohen, “Electrical spiking in Escherichia coli probed with a fluorescent voltage-indicating protein,” Science, 333, 345-348 (2011)
A. P. Fields, A. E. Cohen, “Electrokinetic trapping at the one nanometer limit,” Proc. Natl. Acad. Sci. USA, 108, 8937-8942 (2011)
Y. Tang and A. E. Cohen, “Enhanced enantioselectivity in excitation of chiral molecules by superchiral light,” Science, 332, 333-336(2011)
H. Lee, N. Yang, A. E. Cohen, “Mapping nanomagnetic fields using a radical pair reaction,” Nano Letters, 11, 5367-5372 (2011)
Publications:
Northwest BuildingOffice Number: 445.352 Oxford St.Cambridge, MA 02138
VladimirAssistant Professor of Molecular and Cellular Biology
The Denic lab takes advantage of novel methodologies for studying large-scale genetic interactions in budding yeast as well as massspectrometry-based characterization of natively-isolated protein complexes in order to identify the essential components required forseveral membrane-associated cellular processes. We then carry out targeted and systematic biochemical reconstitution strategies usingthe identified components in order to go from parts lists to functional and mechanistic insights.
Email:
Fewer than 5.
Tel:
http://labs.mcb.harvard.edu/denic/
Denic
Lab Size:
Denic V., Weissman J. S. (2007). A Molecular Caliper Mechanism for Determining Very Long-ChainFatty Acid Length. Cell; 130, 663-67
Schuldiner M.,* Metz J., Schmid V., Denic V.* et al. (2008). The Get Complex Mediates Insertion ofTail-Anchored Proteins into the ER. Cell; 134, 634-45 (*co-first author)
Quan, E.M., Kamiya, Y., Kamiya, D., Denic, V., Weibezahn, J., Kato, K., Weissman, J.S. (2008). Defining the Glycan DestructionSignal for Endoplasmic Reticulum-Associated Degradation. Molecular Cell; 32, 870-877.
Jonikas, M. C., Collins, S. R., Denic, V., Oh, E., Quan, E. M., Schmid, V., Weibezahn, J., Schwappach, B., Walter, P., Weissman, J.S., Schuldiner, M. The Anatomy of a Cellular Folding Compartment. Science; in press. Science. 2009 Mar 27;323(5922):1693-7.PMID: 19325107
Publications:
SGM 617250 Longwood Ave.Boston, MA 02115
SloanAssistant Professor of BCMP
Our lab uses small molecules to study and manipulate human-associated bacteria in order to better understand how the microbiomeaffects human health and disease. The lab leverages expertise from different fields, including synthetic organic chemistry, molecularbiology, microbiology, analytical chemistry, and bioinformatics. Project areas in the lab include:
1) Uncovering how and why bacteria metabolize bile acids. Bacteria in the large intestine transform human-derived primary bile acidsinto secondary bile acids in near-quantitative fashion. Secondary bile acids exert wide-ranging biological effects, from acting ascausative agents in colon and liver cancer to binding nuclear receptors and initiating downstream metabolic cascades. Despite theirimportant role in human health, we know very little about which bacteria metabolize bile acids or which genes are responsible. Byuncovering how and why bacteria transform these compounds, we will pave the way for the rational alteration of the human gutmicrobiome to treat diseases such as inflammatory bowel disease and obesity.
2) Monitoring and altering bacterial metabolism in vivo. The composition and metabolic output of the gut bacterial communitychanges in response to diet, lifestyle, and other environmental factors. Our ability to understand these changes is limited because werely on excretions or post-mortem analyses to study bacterial populations and metabolic products. We are designing, synthesizing, andutilizing activity-based small molecule probes to selectively monitor and affect bacterial metabolism in vivo.
3) Developing novel synthetic methods to access antibiotic scaffolds. Researchers in the human microbiome field need better tools todifferentiate between and control the levels of pathogenic and commensal bacteria in vivo. In addition, there is a pressing medicalneed for new antibiotics targeting pathogenic bacteria. We are developing novel methods to rapidly access oxidized core structuresfound in selected classes of bioactive natural products with demonstrated antibiotic activity but for which no facile method ofsynthesis has yet been elucidated.
Email: [email protected]
Tel:
http://devlin.hms.harvard.edu/
Devlin
Lab Size:
Devlin, A.S. & Fischbach, M.A. “A biosynthetic pathway for a prominent class of microbiota-derived bile acids.” Nat. Chem. Bio.2015, 11, 685.David, L.A., Maurice, C.M., Carmody, R.N., Gootenberg, D.B., Button, J.E., Wolfe, B.E., Ling, A.V., Devlin, A.S., Varma, Y.,Fischbach, M.A., Biddinger, S.B., Dutton, R.J. & Turnbaugh, P.J. “Diet rapidly and reproducibly alters the human gut microbiome.”Nature, 2014, 505, 559.Devlin, A.S. & Du Bois, J. “Modular Synthesis of the Pentacyclic Core of Batrachotoxin and Select Batrachotoxin AnalogueDesigns.” Chem. Sci., 2013, 4, 1053.Wolckenhauer, S.A., Devlin, A.S. & Du Bois, J. “δ-Sultone Formation Through Rh-Catalyzed C–H Insertion.” Org. Lett. 2007, 9,4363.
Publications:
360 Longwood AveLC-4312Boston, MA 02215
EricAssistant Professor of BCMP
The Ubiquitin Proteasome System (UPS) is involved in virtually any cellular process and frequently implicated in human pathologies.Ubiquitin, through the action of a three-enzyme cascade (E1, E2 and E3), becomes attached to substrate proteins. Theposttranslational modification with ubiquitin can serve a multitude of functions depending on the type and length of the ubiquitinchain attached to the substrate, including the control of protein abundance via proteasomal degradation. The human genome encodesfor more than 600 E3 ligases, which confer specificity in the ubiquitin signaling cascade. While the process of ubiquitin transfer iswell understood, the biological function and molecular mechanisms of the majority of ubiquitin ligases remain obscure.We combine structural biology, cell biology and biochemical reconstitutions to address the molecular workings of these multi-component ubiquitin ligases. In particular, we are interested in protein complexes and pathways that contribute to the control of geneexpression and are frequently associated with human disease and cancer. Intimate understanding of the structure allows us to dissectthe complex mechanisms that underlie function and regulation of such molecules and to probe their biology in a cellular context. Weseek to leverage our molecular understanding to propose and test new avenues of therapeutic intervention.Work on the efficacy target of the widely used anti-cancer drugs thalidomide, lenalidomide, pomalidomide, the CRL4CRBN ubiquitinligase, illustrates the general approach. We successfully determined the structure of the DDB1-CRBN complex bound to thalidomide,lenalidomide and pomalidomide. The structure established CRBN as the CRL4CRBN substrate receptor, which enantioselectivelybinds thalidomide and its analogues, lenalidomide and pomalidomide. Utilizing mass spectrometry and protein microarrays, weperformed unbiased proteome-wide screens to identify CRL4CRBN ligase substrates. Using biochemistry, chemical biology and cellbiology methods, we confirmed that thalidomide prevents MEIS2 binding to CRBN thus inhibiting MEIS2 ubiquitination andturnover. At the same time, we could provide a structural rationale for the action of thalidomide analogues in promoting CRL4CRBNmediated degradation of Ikaros/Aiolos transcription factors as well as Ck1. Our findings thus, provide a molecular mechanism forthalidomide action that involves inhibition of CRL4CRBN-mediated ubiquitination of endogenous substrates, while simultaneouslyacting as agonist on neo-substrates such as Ikaros transcription factors.
Email:
617-582-9281
Tel:
Fischer
Lab Size:
1. Fischer, E.S., Böhm, K., Lydeard, J.R., Yang, H., Stadler, M.B., Cavadini, S., Nagel, J., Acker, V., Tichkule, R., Forrester,W.C., Schirle, M., Hassiepen, U., Ottl, J., Hild, M., Beckwidth, R.E.J., Harper, J.W., Jenkins, J.L., Thomä, N.H. Structure of theDDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 2014; 512(7512): 49-53. PMCID: PMC4423819.2. Lingaraju, G.M.*, Bunker, R.D.*, Cavadini, S., Hess, D., Hassiepen, U., Renatus, M., Fischer, E.S., Thomä, N.H. Crystalstructure of the human COP9 Signalosome. Nature 2014; 512(7513): 161-165.3. Fischer, E.S., Scrima, A.*, Boehm, K., Matsumoto, S., Lingaraju, G.M., Faty, M., Yasuda, T., Cavadini, S., Wakasugi, M.,Hanaoka, F., Iwai, S., Gut, H., Sugasawa, K., Thomä, N.H. The molecular basis of CRL4DDB2/CSA Ubiquitin Ligase Architecture,Targeting and Activation. Cell 2011; 147(5): 1024-1039.
Publications:
Gaudet LabNorthwest Building, Room 311.1352 Oxford StCambridge, MA 02138
RachelleProfessor of Molecular and Cellular Biology
We use a combination of x-ray crystallography, biophysical and biochemical techniques, and functional assays to study thestereochemistry of signaling and transport through biological membranes. We have a particular interest in multidomain proteins andhow the individual structure and properties of each domain is integrated to shape the function of the whole protein.
Structural studies of TRP channelsThe goal is to elucidate the gating mechanism of TRP ion channels involved in temperature sensing and understand modulatoryinteractions of proteins and small molecules with TRP channels. We are particularly interested in determining the molecularmechanism of temperature sensing. We therefore focus on the temperature-sensing TRP channels such as TRPV1, and TRPM8.Several temperature-sensing TRP channels are expressed in nociceptor neurons, and therefore responsible for pain sensations inresponse to noxious stimuli. The biophysical and biochemical mechanisms of pain and heat sensing are therefore not only of academicinterest, but also of medical and pharmacological interest. We have determined the structures of several TRPV channel cytosolicdomains. We are also using patch-clamp electrophysiology and other functional assays to understand the role of ligand interactionswith the cytosolic domains in TRP channel function.
Structural studies of TAP, the transporter associated with antigen processingThe goal is to elucidate how TAP, a heterodimer of two membrane-spanning proteins, TAP1 and TAP2, transports peptides generatedby the proteasome in the cytosol into the endoplasmic reticulum for loading onto MHC class I molecules. Loaded class I moleculesthen travel to the cell surface and present the peptides to T cells, an immune system mechanism to recognize and eliminatederegulated or tumorigenic cells, virally-infected cells and foreign cells (e.g. graft rejection). Through structural and biochemicalstudies of the cytosolic nucleotide-binding domains of TAP1 and TAP2, we have gained a better understanding of how ATP bindingand hydrolysis fuels peptide transport. More recently, we are turning our attention to questions regarding substrate selectivity and thecoupling between ATP hydrolysis, peptide binding and transport.
Structural studies of Nramp proteinsMetals like iron and manganese are essential to physiological processes such as oxygen transport and energy metabolism. Nramps(natural resistance-associated macrophage proteins) are transporters that allow the proton-driven import of divalent metals into cells.Humans have two Nramp homologs. Nramp1 transports metals across the phagolysosomal membrane of macrophages and isimportant for the antimicrobial function of these cells. DMT1 (divalent metal transporter 1 or Nramp2) is responsible for absorption ofdietary iron and manganese in the proximal duodenum and assimilation of iron by the red blood cell precursors. The goal of this
Email:
Between 5 and 10
617-495-5616
Tel:
http://labs.mcb.harvard.edu/gaudet/
Gaudet
Lab Size:
M. Sotomayor, W. A. Weihofen, R. Gaudet and D. P. Corey (2012) Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction. Nature 492, 128-132. PMCID: PMC3518760
S.Y. Lau, E. Procko, and R. Gaudet (2012) Distinct properties of Ca2+-calmodulin binding to N- and C-terminal regulatory regionsof the TRPV1 channel. Journal of General Physiology 140, 541-555. PMCID: PMC3483115
M. Sotomayor, W. A. Weihofen, R. Gaudet and D. P. Corey (2010) Structural determinants of cadherin-23 function in hearing anddeafness. Neuron 66, 85-100. PMCID: PMC2948466
E. Procko, M. L. O'Mara, W. F. D. Bennett, D. P. Tieleman, and R. Gaudet (2009) The mechanism of ABC transporters: generallessons from structural and functional studies of an antigenic peptide transporter. FASEB Journal 23, 1287-302.
P. V. Lishko, E. Procko, X. Jin, C. B. Phelps and R. Gaudet (2007) The Ankyrin Repeats of TRPV1 Bind Multiple Ligands andModulate Channel Sensitivity. Neuron 54, 905-918.
Publications:
Seeley G. Mudd Building - Rm 321250 Longwood AveHarvard Medical SchoolBoston, MA 02115
DavidProfessor of Biological Chemistry and Molecular PharmacologyDean for Graduate Education, HMS
Our goals are to understand the molecular interactions controlling protein and lipid mobility and distribution in cell membranes, theroles these mechanisms play in interactions between cells, and the relationships between derangements in these mechanisms and thepathophysiology of disease. We have designed and constructed several time-resolved scanning laser microscopes for interactivemonitoring, tracking, and manipulating of biological samples at the single-cell and single-molecule levels on the µs-ms time scale andnm distance scale. Using these instruments, we are investigating: 1) Molecular interactions in erythroid cell membranes. We aim todefine the modes of motion and strengths of interactions involving individual molecules in the mature red cell membrane, and toinvestigate the development of a functional membrane skeleton during erythroid cell differentiation. 2) Single molecule analysis ofsickle erythrocyte adhesion. We aim to define the molecular mechanisms mediating adhesion of sickle red cells to activated Tlymphocytes, monocytes, neutrophils and endothelial cells, and to investigate correlations between the level of adhesion and thepathophysiology of painful crisis episodes in patients with sickle cell disease. 3) Molecular interactions in immune synapse formation.We aim to define the modes of motion, cell surface distribution, and two-dimensional binding interactions of T-cell adhesionmolecules in natural and artificial membrane systems. 4) Quantitative analysis of the interaction between lipopolysaccharide (LPS)from Pseudomonas aeruginosa and the cystic fibrosis transmembrane conductance regulator (CFTR) protein. We aim to quantify thephysical properties of LPS and CFTR at sites of contact between P. aeruginosa and pulmonary epithelial cells, and to characterize themolecular mechanisms mediating uptake of LPS by such cells. 5) Cellular imaging of protein-protein interactions: visualizing thedynamic regulation of eNOS and caveolin in calcium-dependent signal transduction. We aim to visualize the dynamic regulation ofendothelial nitric oxide synthase, caveolin, and related signaling molecules in vascular cells in culture and in the intact vasculature.Graduate student rotation projects are available in each of these areas
Email:
Between 5 and 10
617-432-2257
Tel:
https://golan.med.harvard.edu/
Golan
Lab Size:
Yin, J.; Straight, P.D.; McLoughlin, S.M.; Zhou, Z.; Lin, A.J.; Golan, D.E.; Kelleher, N.L.; Kolter, R.; Walsh, C.T.. Geneticallyencoded short peptide tag for versatile protein labeling by Sfp phosphopantetheinyl transferase. Proceedings of the NationalAcademies of Sciences of the United States of America, 102, 15815-15820, (2005).
Yin, J; Lin, AJ; Buckett, PD; Wessling-Resnick, M; Golan, DE; Walsh, CT. Single-Cell FRET Imagind of Transferrin ReceptorTrafficing Dynamics by Sfp-Catalyzed, Site-Specific Protein Labeling. Chemistry & Biology, 12 (9): 999-1006, (2005).
Kedersha, N; Stoecklin, G; Ayodele, M; Yacono, P; Lykke-Andersen, J; Fitzler, MJ; Scheuner, D; Kaufman, RJ; Golan, DE;Anderson, P. Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. Journal of Cell Biology, 169(6): 871-884, (2005).
Erwin, PA; Lin, AJ; Golan, DE; Michel, T. Receptor-regulated dynamic S-nitrosylation of endothelial nitric-oxide synthase invascular endothelial cells. Journal of Biological Chemistry, 280 (20): 19888-19894, (2005).
Publications:
Dana Farber Cancer InstituteLongwood Center 2209450 Brookline AveBoston, MA 02115
NathanaelProfessor of Biological Chemistry and Molecular Pharmacology
Our lab is interested in the following general questions: 1. How can small molecule inhibitors with selectivity towards a desired wild-type or drug-resistant kinase be efficiently developed? 2. How can we use kinase inhibitors to dissect the molecular wiring ofsignaling pathways? 3. What are the most efficient ways to develop small molecule modulators for protein targets for which no ligandis currently known? 4. How do you develop a small molecule modulator for biological pathways for which very little is known? 5.What are new methods for identifying the biological targets for small molecules of unknown mechanism?
Synthetic Chemistry: Our lab uses synthetic organic chemistry to make combinatorial gene-family targeted libraries. We typicallybase the libraries on close variants of scaffolds that have been previously shown to have interesting biological activity (so called'privileged scaffolds'). We use solution and solid-phase chemistry and employ 'directed-sorting' technology to enable efficient libraryproduction. We also perform medicinal chemistry to improve the potency, cellular activity, specificity, stability and pharmacologicalproperties of our initial 'lead' compounds.
Functional Small Molecule Discovery: Following synthesis of new compounds, we use three distinct but complementary approachesto discover and optimize their biological function: (1) target-based biochemical screening (2) functional target-based cellular assaysand (3) cellular or organismal 'phenotypic' screening. Target-based screening supported by cellular assays that precisely monitor theactivity of interest and that can guide chemical optimization is the most direct means to obtain functional inhibitors. The target-basedcellular screens present a significant advantage over biochemical assays because the kinases are expressed in an appropriate cellularcontext allowing compounds to be identified that may possess a number of distinct mechanisms including: direct inhibition of theactive kinase, binding to the inactive form of the kinase, inhibiting activating phosphorylations, or interacting with negativeregulators. We are in the process of creating a battery of such cellular assays that will allow us to more fully annotate the kinaseselectivity of a given compound which can then be used as a chemical probe in various biological systems. In contrast, phenotypicscreening provides a means to interrogate a pathway in an unbiased fashion with small molecules. Provided that the molecular target(s) of the compound can be identified (usually by affinity chromatography, genetic complementation, or expression profiling),phenotypic screening can deliver new biological insight in addition to yielding useful small molecules.
Email:
Between 5 and 10
617-582-8590
Tel:
http://graylab.dfci.harvard.edu/
Gray
Lab Size:
Galkin AV, Melnick JS, Kim S, Hood TL, Li N, Li L, Xia G, Steensma R, Chopiuk G, Jiang J, Wan Y, Ding P, Liu Y, Sun F, SchultzPG, Gray NS, Warmuth M. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc NatlAcad Sci U S A 2007;104:270-5.
Pan S, Mi Y, Pally C, Beerli C, Chen A, Guerini D, Hinterding K, Nuesslein-Hildesheim B, Tuntland T, Lefebvre S, Liu Y, Gao W,Chu A, Brinkmann V, Bruns C, Streiff M, Cannet C, Cooke N, Gray N. A monoselective sphingosine-1-phosphate receptor-1 agonistprevents allograft rejection in a stringent rat heart transplantation model. Chem Biol 2006;13:1227-34.
Okram B, Nagle A, Adrian FJ, Lee C, Ren P, Wang X, Sim T, Xie Y, Wang X, Xia G, Spraggon G, Warmuth M, Liu Y, Gray NS. Ageneral strategy for creating 'inactive-conformation' abl inhibitors. Chem Biol 2006;13:779-86.
Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2006;2:358-64.
Publications:
Center for Human Genetic ResearchSimches Research Center, CPZN-5242185 Cambridge StreetBoston, MA 02114
StephenAssociate Professor of Neurology
The focus of the Haggarty Laboratory is on the use of chemical biological approaches to define and dissect the role of neuroplasticityin health and disease. Our long-term goal is to translate this knowledge into the discovery of novel, disease mechanism-based,targeted therapeutics for the treatment of psychiatric and neurodegenerative disorders.
Members of the lab have developed powerful, in vitro experimental systems in which populations of defined neuronal subtypesbelonging to specific neurotransmitter classes and regional identities with the ability to form synapses and electrically active, neuralnetworks, can be directly identified, manipulated pharmacologically and genetically, and characterized using functional genomics,proteomics, and high-throughput screening modalities. This has lead to the discovery, characterization, and optimization of novelchemical probes of critical neuroplasticity mechanisms—the regulation of neurotrophic factor signaling, the epigenetic regulation ofneuronal gene expression through histone deacetylases (HDACs) and histone demethylases (HDMs), and the regulation of Wnt/GSK3signaling. To address the challenge of target identification, we have also integrated the use of systematic RNAi-mediated genesilencing and quantitative mass spectrometry strategies. In order to explore new directions for human disease modeling, we have mostrecently implemented reprogramming methods for creating induced pluripotent stem cells (iPSCs) and induced neurons (iNs) frompatient-derived somatic cells. These iPSCs can be differentiated in vitro into functional neurons with the capacity to form synapsesand regulate genes in an activity-dependent manner opening new avenues for chemical genomic studies of neuroplasticity and forunderstanding human disease biology. Current projects include the development, characterization and screening of human iPSCmodels of neuropsychiatric (bipolar disorder, schizophrenia, Pitt-Hopkins Syndrome, Rett Syndrome, Fragile X Syndrome) andneurodegenerative disorders (Alzheimer’s Disease and Frontotemporal Dementia), all of which aim to establish novel paradigms fortarget identification and discovery of small-molecule probes. Finally, we are investigating the in vivo effects of a number of our novelsmall-molecule probes using animal behavioral models relevant to cognitive and mood disorders, as well as with positron emissiontomography to image targets and neural activity in the context of intact neurocircuits.
We conduct our research program in close collaboration with other members of the Harvard and MIT research community, includingthe MGH Molecular Neurogenetics Unit, MGH Psychiatric & Neurodevelopmental Genetics Unit, MGH Center for ExperimentalDrugs & Diagnostics, Lurie Center for Autism, Stanley Center for Psychiatric Research at the Broad Institute, and the Harvard StemCell Institute.
Email:
Between 10 and 12
(617) 643-3201
Tel:
http://haggartylab.org
Haggarty
Lab Size:
Haggarty, S.J. & Tsai, L.H. (2011). Probing the role of HDACs and mechanisms of chromatin-mediated neuroplasticity.Neurobiology of Learning & Memory, 96: 41-52.
Fass, D.M., Shah, R., Ghosh, B., Hennig, K., Norton, S., Zhao, W.N., Reis, S., Klein, P., Mazitschek, R., Maglathlin, R., Lewis, T. &Haggarty, S.J. (2011). Effect of inhibiting histone deacetylase with short-chain carboxylic acids and their hydroxamic acid analogs onvertebrate development and neuronal chromatin. ACS Medicinal Chemistry Letters, 2:39-44.
Pan, J.Q., Lewis, M.C., Ketterman, J.K., Clore, E.L., Riley, M., Richards, K.R., Berry-Scott, E., Liu, X., Wagner, F.F., Holson, E.B.,Neve, R.L., Biechele, T.L., Moon, R.T., Scolnick, E.M., Petryshen, T.L. & Haggarty, S.J. (2011). AKT kinase activity is required forlithium to modulate mood-related behaviors in mice. Neuropsychopharmacology, 36:1397-1411.
Kuai, L, Ong, S.E., Madison, J.M., Wang, X, Duvall, J.R., Lewis, T.A., Luce, C.J., Conner, S.D., Pearlman, D.A., Wood, J.L.,Schreiber, S.L., Carr, S.A., Scolnick, E.M. & Haggarty, S.J. (2011). Identification of AAK1 as an inhibitor of neuregulin-1/ErbB4-dependent neurotrophic factor signaling using integrative chemical genomics and proteomics. Chemistry & Biology, 18:891-906.
Covington, H.E., Maze, I.S., LaPlant, Q.C., Vialou, V.F., Yoshinori, O.N., Berton, O., Fass, D.M., Renthal, W., Rush, A.J., Wu, E.T.,
Publications:
Ghose, S., Krishnan, V., Russo, S.J., Tamminga, C., Haggarty, S.J. & Nestler. E.J. (2009). Antidepressant actions of HDACinhibitors. Journal Neuroscience, 29:11451-11460.
The Haigis LabHarvard Medical SchoolSGM 329C240 Longwood Ave.
MarciaAssociate Professor of Pathology
Our laboratory focuses on understanding the role that mitochondria play in mammalian aging and disease. Mitochondria are dynamicorganelles that provide cells with energy even during dramatic changes in diet, stress and development. Mitochondria are also a majorsite for reactive oxygen species production, ion homeostasis, and apoptosis. Not surprisingly, mitochondrial dysfunction has beenimplicated in aging, neurodegeneration and metabolic diseases, such as diabetes.
The regulation of aging is highly conserved. For example, an extra copy of SIR2 (silent information regulator; sirtuins) significantlyincreases the lifespan of yeast, worms and flies. Mammals have seven homologs of SIR2, three of which are found in mitochondria.Recent studies have shown that sirtuins affect mitochondrial biogenesis and energy production. Our lab is interested in understandinghow sirtuins mediate the interplay between mitochondrial activity and aging.
The main goals of our research are: 1) to identify signals generated by mitochondria that contribute to aging and to identify thoseregulated by mammalian sirtuins, 2) to determine molecular mechanisms for these signals, and 3) to understand how these pathwaysregulate biological functions that decline during normal aging. To accomplish these goals, our research integrates biochemistry,proteomics, cell biology and mouse genetics. These studies have the potential to lead to novel therapies that could treat a spectrum ofhuman diseases.
Email:
Greater than 10
617-432-6865
Tel:
https://haigis.hms.harvard.edu/
Haigis
Lab Size:
Laurent G., German NJ, Saha AK, de Boer VCJ, Davies M, Koves TR, Dephoure N, Fischer F, Boanca G, Vaitheesvaran B, LovitchSB, Sharpe AH, Kurland IJ, Steegborn C, Gygi SP, Muoio DM, Ruderman NB, Haigis MC. SIRT4 coordinates the balance betweenlipid synthesis and catabolism by repressing malonyl-CoA decarboxylase. Molecular Cell. 2013; 50:686-698. PMID: 23746352
Jeong SM, Xiao C, Finley LW, Lahusen T, Souza AL, Pierce K, Li YH, Wang X, Laurent G, German NJ, Xu X, Li C, Wang RH, LeeJ, Csibi A, Cerione R, Blenis J, Clish CB, Kimmelman A, Deng CX, Haigis MC. SIRT4 Has Tumor-Suppressive Activity andRegulates the Cellular Metabolic Response to DNA Damage by Inhibiting Mitochondrial Glutamine Metabolism. Cancer Cell. 2013;23:450-463. PMID: 23562301
Finley LW, Lee J, Souza A, Desquiret-Dumas V, Bullock K, Rowe GC, Procaccio V, Clish CB, Arany Z, Haigis MC. Skeletalmuscle PGC-1alpha mediates mitochondrial, but not metabolic, adaptation to calorie restriction. Proc Natl Acad Sci U S A. 2012;109:2931-2936. PMID: 22308395
Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, Teruya-Feldstein J, Moreira PI, Cardosa SM, Clish CB, Pandolfi PP,Haigis MC. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell. 2011; 19:416-428. PMID: 21397863.
Haigis MC, Yankner BA. The aging stress response. Mol. Cell. 2010; 40:333-344. PMID: 20965426.
Publications:
Harvard Medical School240 Longwood Ave, C2-427Boston MA 02115
WadeBert and Natalie Vallee Professor of Molecular Pathology
Ubiquitin and ubiquitin-like (UBL) protein conjugation systems control a vast array of cellular processes, and impact virtually everybiological system. In this process, UBLs are activated through an ATP-driven activation and conjugation cascade before attachment totarget proteins. Conjugation of ubiquitin itself is best known for its role in protein turnover via the proteasome, but ubiquitinconjugation can also provide regulatory functions in solid-state signaling networks.
Our work seeks to employ systematic genetic and proteomic approaches to elucidate the mechanisms and biology of ubiquitin andUBL protein conjugation systems, including the autophagy system. Much of our efforts have been devoted to elucidating thecomponents and targets of a superfamily of E3 ubiquitin ligases referred to as cullin-RING ubiquitin ligases. We have explored theroles of these E3s in cell cycle and DNA damage checkpoint control and are currently employing systematic proteomic approaches toidentify substrates and biological processes of many poorly understood ubiquitination pathways. We have recently elucidated thenetwork organization of human deubiquitinating enzymes, the human autophagy system, the ERAD system, the ubiquitin modifiedproteome, and the mechanism of activation and action of the PARKIN ubiquitin ligase, a protein that is mutated in familial forms ofParkinson’s Disease. An additional area of interest concerns the use of proteomic methods to dissect protein networks involved inassembly and regulation of mitochondria in mammalian cells.
A major emphasis is placed on the development of proteomic tools, methods, and software for quantitative analysis of signalingpathways and ubiquitination. This includes the use of AQUA proteomics, Parallel Reaction Monitoring (PRM) and Tandem MassTagging (TMT) based methods. We are using these approaches to examine the dynamics of multiple signaling pathways.
Email:
617-432-6590
Tel:
https://harper.hms.harvard.edu/
Harper
Lab Size:
Publications:
Builing 149, Room 230113th StreetCharlestown, MA 02129
JacobAssociate Professor of Radiology
Research in the Hooker Lab is diverse ranging from palladium to the pallidum. In short, we develop and use chemical biology toolsto understand physiology in vivo. Our biggest focus area is in neurochemistry and we often use positron emission tomography (PET)and magnetic resonance imaging (MRI) as tools for measure neurochemical dynamics in the human brain. Of course studies of thehuman brain of this type require a translational program that encompasses chemistry (e.g. synthesis methodology), biology (e.g.recombinant proteins, cell culture models, ex vivo tissue analysis), animal models (e.g. rodent and non-human primates) and expertisein other disciplines (e.g. neuroscience and medical physics). The Hooker Lab is unique in both its make-up and capabilities.
Active projects in the Hooker lab develop tools for and/or study the chemical and molecular basis for autism, mental illness, andchronic pain. A major focus area is the characterizing normal brain neurochemical function and epigenetic changes that can occurover one's life.
Email:
617-726-6596
Tel:
http://hookerlab.martinos.org
Hooker
Lab Size:
Wey HY, Wang C, Schroeder FA, Logan J, Price J, Hooker JM. Kinetic Analysis and Quantification of [11C]Martinostat for in vivoHDAC Imaging of the Brain. ACS Chemical Neuroscience. 2015.Loggia ML, Chonde DB, Akeju O, Arabaz G, Catana C, Edwards RR, Hill E, Hsu S, Izquierdo-Garcia D, Ji R, Riley M, Wasan AD,Zurcher NR, Albrecht DS, Vangel MG, Rosen BR, Napadow V, Hooker JM. Evidence of brain glial activation in chronic painpatients. Brain. 2015Villien M, Wey HY, Mandeville JB, Catana C, Polimeni JR, Sander CY, Zürcher NR, Chonde DB, Fowler JS, Rosen BR, HookerJM. Dynamic Functional Imaging of Brain Glucose Utilization using fPET-FDG. NeuroImage. 2014.Diyabalanage HVK, Van de Bittner GC, Ricq EL, Hooker JM. A chemical strategy for the cell-based detection of HDAC activity.ACS Chemical Biology. 2014
Publications:
Simches Research CenterCPZN 7208185 Cambridge StreetBoston, MA 02114
DebAssociate Professor of Microbiology and Molecular Genetics
The goal of research in the Hung Lab is to understand in vivo mechanisms of bacterial pathogenesis by studying pathogen-hostinteractions. By merging the fields of chemical genetics and bacterial genetics/genomics, we hope to provide insight into possible newparadigms for addressing infectious diseases.Despite recent, largely genetic, technical advances in the field of in vivo pathogen-host interactions, many important questions relatedto the mechanisms of bacterial pathogenesis remain unanswered, in part because of the inability of in vitro conditions to accuratelymimic in vivo ones. The newly developing field of chemical genetics offers a novel and promising approach to studying thesemechanisms, thus complementing traditional genetic studies. Chemical genetics uses small, organic molecules as specific tools toconditionally induce a phenotype by activating or inhibiting specific protein targets, thus allowing the manipulation of relevantpathways in vitro and in vivo, on very short time scales.
In concert with taking a chemical biological approach to pathogenesis, our lab is interested in developing powerful genomicapproaches to systematically and comprehensively identify all bacterial genes required for infection and to facilitate rapididentification of small molecule targeted pathways and interactions. Using small molecules that we identify and develop from high-throughput, forward phenotypic screens and arrayed, knockout libraries of different pathogens, including Vibrio cholerae,Pseudomonas aeruginosa and Mycobacterium tuberculosis, we hope to identify new approaches to disease intervention.
Email:
Between 10 and 15
617-643-3117
Tel:
http://chemicalbiology.mgh.harvard.edu/labs-hung.htm
Hung
Lab Size:
Clatworthy AE, Pierson E, Hung DT. Targeting virulence: a new paradigm for antibiotic therapy, Nature Chemical Biology, 2007: 3,541-548.
Hung, D.T.; Rubin, E.J. 2006 Chemical biology and bacteria: not simply a matter of life or death. Current Opi. Chem. Bio., 10:321-326.
Clatworthy AE, Lee JS, Leibman M, Kostun Z, Davidson AJ, Hung DT. Pseudomonas aeruginosa infection of zebrafish involvesboth host and pathogen determinants, Infection and Immunity, April 2009, 77(4): 1293-303.
Hung, D.T.; Shakhnovich, E.A.; Pierson, E.; Mekalanos, J.J. 2005 Small molecule inhibitor of Vibrio cholerae virulence andintestinal colonization. Science, 310;670-674.
Publications:
EricSheldon Emery Professor of ChemistryChair, Department of Chemistry and Chemical Biology
Catalysts not only accelerate chemical reactions, but can also exert remarkable kinetic control over product distribution. My researchgroup is interested in all aspects of selective catalysis, and especially in the design, discovery, and study of systems that mediatefundamentally interesting and useful organic reactions. The search for practical and widely applicable catalysts for organic synthesisprovides a strong driving force for our research. In addition, we apply the tools of physical-organic chemistry to gain insight into thetransition structure geometries and molecular recognition events that control selectivity.
The following topics in selective catalysis are currently under investigation in our laboratories:• Asymmetric Catalysis• Selective C- C Bond Formation and Cleavage• Natural-Product and Diversity-Oriented Synthesis• Mimics of Physiologically Important Enzymes• New Approaches to Catalyst DesignThe control of absolute and relative stereochemistry is an underlying goal in much of this work because of the crucial role played bythe three-dimensional structure of molecules in their biological function. The development of enantioselective oxidation catalysts hasbeen of particular interest to us, and we have succeeded in devising highly enantioselective small-molecule catalysts in whichselectivity is predicated solely through non-bonded interactions. The utility of these catalysts has been illustrated in our group throughtheir application to the synthesis of various classes of important biologically active compounds.
Email:
Greater than 10
617-496-3688
Tel:
http://www.chem.harvard.edu/groups/Jacobsen/
Jacobsen
Lab Size:
Zuend, S. J.; Coughlin, M. P.; Lalonde, M. P.; Jacobsen, E. N. “Scaleable catalytic asymmetric Strecker syntheses of unnatural -amino acids,” Nature 2009, 461, 968–970.
Zuend, S. J., Jacobsen, E. N. “Mechanism of Amido-Thiourea Catalyzed Enantioselective Imine Hydrocyanation: Transition StateStabilization via Multiple Non-Covalent Interactions,” J. Am. Chem. Soc. 2009, 131, 15358–15374.
Xu, H.; Zuend, S. J.; Woll, M. P.; Tao, Y.; Jacobsen, E. N. “Asymmetric Cooperative Catalysis of Strong Brønsted Acid-PromotedReactions Using Chiral Ureas,” Science 2010, 327, 986–990.
Knowles, R. R.; Lin, S.: Jacobsen, E. N. “Enantioselective Thiourea-Catalyzed Cationic Polycyclizations,” J. Am. Chem. Soc. 2010,132, 5030–5032.
Publications:
Harvard University12 Oxford StreetCambridge, MA 02138
DanielProfessor of Chemistry and Chemical Biology and of Biological Chemistry andMolecular PharmacologyC Di t Ch i l Bi l PhD P
For many years our research group has been interested in the mechanisms of various antibiotics that kill Gram-negative bacteria andthe fundamental cellular processes they inhibit. We have primarily focused on drugs that target bacterial cell wall biosynthesis,including the beta-lactams, vancomycin, and moenomycin. We use these molecules to study the protein machines that synthesize anddegrade the bacterial cell wall. Because we are interested in antibiotics that kill Gram-negative organisms by targeting their cellenvelope, we are also interested in how the structure of the outer membrane is established and maintained. This is a stereochemicalproblem since biological membranes are asymmetric and require proper spatial organization of their constituent lipids and proteins inorder to function correctly. The assembly of this organellar membrane must be accomplished outside the cell in the absence of anobvious energy source. Our research focuses on two multi-protein complexes that are involved in assembling membrane proteins andlipopolysaccharide. We want to understand how the different components of these machines function in the proper assembly of thismembrane barrier as well as the mechanisms that lead to defects.
Email:
Greater than 10
617-496-0208
Tel:
http://www.chem.harvard.edu/groups/kahne/
Kahne
Lab Size:
S. Okuda, E. Freinkman, D. Kahne. Cytoplasmic ATP hydrolysis powers transport of lipopolysaccharide across the periplasm in E.coli. Science 2012; 338:1214-7.
S.S. Chng, M. Xue, R.A. Garner, H. Kadokura, D. Boyd, J. Beckwith, D. Kahne. Disulfide rearrangement triggered by transloconassembly controls lipopolysaccharide export. Science 2012; 337:1665-8.
C.L. Hagan, S. Kim, D. Kahne. Reconstitution of outer membrane protein assembly from purified components. Science 2010;328:890-2.
S. Kim, J.C. Malinverni, P. Sliz, T.J. Silhavy, S.C. Harrison, D. Kahne. Structure and function of an essential component of the outermembrane protein assembly machine. Science 2007; 317:961-964.
T. Wu, J. Malinverni, N. Ruiz, S. Kim, T.J. Silhavy, D. Kahne. Identification of a multi-component complex required for outermembrane biogenesis in Escerichia coli. Cell 2005; 121:235-246.
Publications:
Dana Farber Cancer InstituteLC-3214450 Brookline AveBoston, MA 02215
JustinAssistant Professor of BCMP
Research in our lab takes a bottom-up approach to tackling molecular challenges in cancer biology. Basic chemical research –development of new reactions, exploration of novel synthetic strategies, discovery of new molecular reactivity, and synthesis ofcomplex molecular architectures – fuels our drive to access useful compounds for the study and manipulation of biological systems.Our biological interests lie in the areas of tumor hypoxia, gram-negative pathogens, and protein-protein interactions.
Exploiting functional specificity: Drug discovery efforts predominantly target human pathologies by exploiting the structuralcomplementarity between small molecules and the binding pockets of dysregulated proteins. We envision the design of newtherapeutic and imaging agents that are responsive to the unique chemical microenvironments of diseased cells and pathogens. Such astrategy, enabled by fundamental chemical developments and access to new compositions of matter, will facilitate both the discoveryof new pharmaceutical agents and the repurposing of old drugs for new diseases.
Probing macromolecular interactions: Our lab will take a chemical approach to targeting macromolecular interactions. While much oflife’s processes are governed by protein-protein and protein-nucleic acid interactions, only a small fraction of these can bemanipulated using small molecules. The identification of small organic molecules capable of binding flat interfacial surfaces isincredibly difficult, but we envision that the development of a high throughput discovery platform employing a set of privilegedmolecular scaffolds will enable us to target some of these traditionally undruggable targets.
Natural product synthesis: Designing potent bioactive small molecules with drug-like properties de novo is undoubtedly challenging.Natural products have long been a source of inspiration for the development of new therapeutic agents. A majority of pharmaceuticalagents that have gained clinical approval over the past several decades derive from naturally occurring metabolites. We aim tosynthesize potent bioactive natural products as the first step in elucidating their biology, creating structural derivatives, anddeveloping new tool compounds and therapeutic agents.
Email:
5-10
617-632-6488
Tel:
www.kimlab.dana-farber.org
Kim
Lab Size:
Kim, J.; Bertozzi, C. R. Angew. Chem. Int. Ed. 2015, 54, 15777–15781. “Bioorthogonal Reaction of N-oxide and Boron Reagents.”
Coste, A.; Kim, J.; Adams, T. C.; Movassaghi, M. Chem. Sci. 2013, 4, 3191–3197. “Concise Total Synthesis of (+)-Bionectins A andC.”
Kim, J.; Movassaghi, M. J. Am. Chem. Soc. 2011, 133, 14940–14943. “Concise Total Synthesis and Stereochemical Revision of (+)-Naseseazines A and B: Regioselective Arylative Dimerization of Diketopiperazine Alkaloids.”
Kim, J.; Movassaghi, M. J. Am. Chem. Soc. 2010, 132, 14376–14378. “General Approach to Epipolythiodiketopiperazine Alkaloids:Total Synthesis of (+)-Chaetocins A and C and (+)-12,12'-Dideoxychetracin A.”
Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Science 2009, 324, 238–241. “Total Synthesis of (+)-11,11'-Dideoxyverticillin A.”
Publications:
Building C-2 666A240 Longwood AvenueBoston, Massachusetts 02115
RandyProfessor of Cell Biology
Our laboratory studies how ubiquitin‐dependent protein degradation controls cell cycle progression in normal and cancer cells. We
integrate biochemical, cell biological, and chemical approaches to study the ubiquitin-proteasome pathway. We are interested in theregulation of the Anaphase‐Promoting Complex (APC), a large multisubunit ubiquitin ligase that targets important mitotic
regulators for destruction by the ubiquitin pathway. We are especially interested in the development of new small molecule inhibitorsthat block APC-dependent degradation, which may be useful for treatment of cancer. Recently, we have also identified smallmolecules that accelerate proteasomal degradation, which may be useful for treatment of neurodegerative disease. We are alsointerested in the development of new technologies including novel screening methods and imaging approaches, including long-termtime lapse imaging.
Email:
Between 5 and 10
617-432-4964
Tel:
http://king.med.harvard.edu/
King
Lab Size:
F.D. Sigoillot, R.W. King."Vigilance and validation: Keys to succes in RNAi screening".ACS Chemical Biology 2011, 6:47-60.
X. Zeng, F. Sigoillot, S. Gaur, S. Choi, K.L. Pfaff, D.C. Oh, N. Hathaway, N. Dimova, G.D. Cuny, R.W. King. "Pharmacologicinhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindledamage".Cancer Cell 2010, 18: 382-95.
B.H. Lee, M.J. Lee, S. Park, D.C. Oh, S. Elsasser, P.C. Chen, C. Gartner, N. Dimova, J. Hanna, S.P. Gygi, S.M. Wilson, R.W. King,D. Finley. "Enhancement of proteasome activity by a small-molecule inhibitor of USP14".Nature 2010, 467:179-84.
X. Zeng, R.W. King. "An APC/C inhibitor stabilizes cyclin B1 by prematurely terminating ubiquitination." Nature Chem Biol 2012,8:383-92.
N.V. Dimova, N.A. Hathaway, B.H. Lee, D.S. Kirkpatrick, M.L. Berkowitz, S.P. Gygi, D. Finley, R.W. King. "APC/C-mediatedmultiple monoubiquitylation provides an alternative degradation signal for cyclin B1." Nature Cell Biol. 2012, 8:383-92.
Publications:
SGM Room 232A250 Longwood AveBoston, MA 02115
AndrewAssistant Professor of BCMP
G protein-coupled receptors (GPCRs) are cell-surface receptors that regulate neurotransmission, cardiovascular function, metabolichomeostasis, and many other physiological processes. Due to their central role in human physiology, these receptors are among themost important targets of therapeutic drugs, and are they among the most extensively studied proteins. To better understand GPCRsignal transduction at a molecular level, we are using structural biology and biophysical methods to study model GPCRs such asmuscarinic acetylcholine receptors. In addition, we are using new approaches in combinatorial biology to facilitate structural studiesand to create protein ligands of GPCRs.
We are also interested in signal transduction pathways that remain less extensively studied than GPCRs, particularly receptorsinvolved in the regulation of human metabolic homeostasis. In the long term, we hope to leverage our understanding of molecularsignal transduction to guide the development of new and better therapeutics that modulate these pathways.
Email:
617-432-3252
Tel:
http://kruse.hms.harvard.edu/
Kruse
Lab Size:
1. Schmidt HR, Zheng S, Gurpinar E, Koehl A, Manglik A, Kruse AC. Crystal structure of the human sigma-1 receptor (2016)Nature 532 , 527-530.
2. Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hübner H, Pardon E, Valant C, Sexton PM, Christopoulos A, FelderCC, Gmeiner P, Steyaert J, Weis WI, Garcia KC, Wess J, Kobilka BK. Activation and allosteric modulation of a muscarinicacetylcholine receptor. (2013) Nature 504, 101-106.
3. Kruse AC, Weiss DR, Rossi M, Hu J, Hu K, Eitel K, Gmeiner P, Wess J, Kobilka BK, Shoichet BK. Muscarinic receptors asmodel targets and antitargets for structure-based ligand discovery. (2013) Mol. Pharm. 84, 528-540.
4. Kruse AC, Hu J, Pan AC, Arlow DH, Rosenbaum DM, Rosemond E, Green HF, Liu T, Chae PS, Dror RO, Shaw DE, WeisWI, Wess J, Kobilka BK. Structure and dynamics of the M3 muscarinic acetylcholine receptor. (2012) Nature 482, 552-556.
Publications:
Department of Chemistry and Chemical Biology12 Oxford StreetCambridge, MA 02138
BrianAssistant Professor of Chemistry and Chemical Biology
The Liau lab is building a multidisciplinary research program at the interface of chemistry, gene regulation, and epigenetics research.Layered atop the genetic code, ‘epigenetic’ chromatin modifications have been implicated in regulating cell state and are oftenderegulated in human disease, suggesting that intervention in these pathways may hold great promise for potential therapeuticapplications. However, the underlying molecular mechanisms that govern these epigenetic processes and gene regulation remainunclear. To address this, we are developing novel chemical biology and functional genomic approaches to illuminate such molecularmechanisms, while exploring the promise of chromatin regulators as therapeutic targets for cancer. Technology development willblend chemistry with molecular and cell biology, and downstream applications and studies will integrate functional genomics andcancer biology.
Email:
617-496-6501
Tel:
www.liaulab.org
Liau
Lab Size:
Flavahan, W. A.*, Drier, Y.*, Liau, B. B., Gillespie, S. M., Venteicher, A. S., Stemmer-Rachamimov, A. O., Suvà, M. L. &Bernstein, B. E. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114 (2016).
Pelish, H. E.*, Liau, B. B.*, Nitulescu, I. I., Tangpeerachaikul, A., Poss, Z. C., Da Silva, D. H., Caruso, B. T., Arefolov, A., Fadeyi,O., Christie, A. L., Du, K., Banka, D., Schneider, E. V., Jestel, A., Zou, G., Si, C., Ebmeier, C. C., Bronson, R. T., Krivtsov, A. V.,Myers, A. G., Kohl, N. E., Kung, A. L., Armstrong, S. A., Lemieux, M. E., Taatjes, D. J. & Shair, M. D. Mediator kinase inhibitionfurther activates super-enhancer-associated genes in AML. Nature 526, 273–276 (2015).
Lee, A. S., Liau, B. B. & Shair, M. D. A unified strategy for the synthesis of 7-membered-ring-containing Lycopodium alkaloids. J.Am. Chem. Soc. 136, 13442–13452 (2014).
Liau, B. B., Milgram, B. C. & Shair, M. D. Total syntheses of HMP-Y1, hibarimicinone, and HMP-P1. J. Am. Chem. Soc. 134,16765–16772 (2012).
Liau, B. B. & Shair, M. D. Total synthesis of (+)-fastigiatine. J. Am. Chem. Soc. 132, 9594–9595 (2010).
Publications:
Harvard Medical School240 Longwood AvenueSeeley Mudd Building, Room 529Boston, Massachussetts 02115
StephenAssistant Professor of Cell Biology
MOLECULAR BASIS OF INSTINCTIVE ANIMAL BEHAVIORNeural circuits that generate perception and control behavior are poorly understood at a molecular level. We are interested inunderstanding how the brain processes external sensory and internal homeostatic signals to initiate behavioral responses. First, westudy olfactory cues, such as pheromones, food odors, and predator odors that elicit innate mating, foraging, and avoidance responsesin mice. Second, we are identifying hypothalamic genes that control feeding behavior and other instinctive drives.
1. OLFACTION AND PHEROMONE SIGNALING IN MAMMALSMany social behaviors of the mouse, such as mating, fighting, and nurturing of young, involve the transmission and detection ofpheromones. Sensory neurons in the mouse nose detect odors and pheromones using ~1,600 different G Protein-Coupled Receptors(GPCRs). We recently identified two novel families of mammalian olfactory receptors, termed trace amine-associated receptors(TAARs) and formyl peptide receptors (FPRs), some of which are prime candidates to detect semiochemicals such as pheromones andpredator odors.
Trace amine-associated receptorsTAARs are olfactory receptors in diverse vertebrates- there are 15 in mice, 6 in human, and 113 in zebrafish. These receptors likelyevolved from receptors for aminergic neurotransmitters and hormones that control behavior and emotion. Several TAAR ligands aremetabolites that occur naturally in urine, a rich source of social odors for many mammals. Furthermore, the biosynthesis of someTAAR ligands is highly dynamic, varying with age, gender, or behavioral state. One TAAR ligand is a reported pheromone, raisingthe possibility that some TAARs are pheromone receptors that stimulate innate behaviors and physiological responses. We arestudying all aspects of TAAR-mediated signaling, from the identity of natural product ligands to the characterization of neuralpathways that influence behavior.
Formyl peptide receptorsFPRs are key mediators of the innate immune response to invasive bacteria. The Fpr gene family underwent sudden and recentexpansion in rodents but not other placental mammals, creating novel rodent Fpr genes of unknown function. We recently found thatfive mouse FPRs acquired a distinct physiological role, as chemosensory receptors in the vomeronasal organ (VNO). Like other VNOreceptors, these FPRs are selectively expressed in dispersed subsets of VNO sensory neurons. Immune system FPRs recognizeformylated peptides, which are synthesized by bacteria, mitochondria, and chloroplasts, and would represent a novel VNO ligandclass, distinct from other VNO-activating peptides, such as MHC peptides and various urine- and gland-derived peptides. We are
Email:
Between 5 and 10.
617-432-7283
Tel:
https://liberles.med.harvard.edu/
Liberles
Lab Size:
Ferrero, D.M., et al, “Detection and avoidance of a carnivore odor by prey,” (2011), PNAS
Liberles, S.D., et al, “Formyl peptide receptors are candidate chemosensory receptors in the vomeronasal organ”, (2009), PNAS, 106(24): 9842-9847
Liberles, S.D. and Buck, L.B., “A second class of chemosensory receptors in the olfactory epithelium”, (2006) Nature, 442 (7103),645-650
Publications:
12 Oxford StreetDepartment of Chemistry and Chemical BiologyConant Labs 224Harvard University
DavidProfessor of Chemistry and Chemical Biology
Programming Human Biology to Illuminate and Treat Disease
The past century of life sciences research has resulted in an emerging understanding of the ways in which DNA, RNA, proteins, andsmall molecules regulate information flow in living systems. This understanding has made increasingly realistic the possibility of notjust reading but precisely manipulating biological information in humans by altering the structure of our genomes, altering geneexpression patterns, engineering new conditions under which genes are expressed, or creating new circuits that interface exogenoussynthetic molecules with gene expression programs. The purposeful manipulation of information flow in human cells and patients hasthe potential both to reveal and validate causal relationships between genes, gene products, and human disease, and to generatebreakthrough small-molecule or macromolecular therapeutics that address disease at the most fundamental level of our software, thehuman genome.
While the vision of manipulating gene sequences and gene regulation with molecular precision in mammalian cells and, eventually,in humans is a compelling one with enormous potential to benefit society, a number of daunting challenges must be overcome beforethis vision can be fully realized. Perhaps the most significant of these challenges is how to create with a practical efficiency andsuccess rate the many protein or nucleic acid machines that are needed to alter genomes, transcriptomes, or proteomes with asufficiently high degree of selectivity and potency. To realize a vision in which arbitrary genes, transcripts, or proteins can bemanipulated at will in mammalian cells, fundamentally new approaches to generating macromolecules and small molecules withtailor-made properties and at an unprecedented scale must be implemented.
Towards this vision, our laboratory develops and applies new approaches to chemical and biological discovery that are driven by theprinciples underlying biological evolution. Our research program focuses on three major problems:
1) We aim to precisely manipulate information flow in mammalian cells through the development and application of syntheticregulatory elements (SREs), proteins and nucleic acids that modify genes and gene products with tailor-made specificities. Achievingthis ambitious goal requires addressing two longstanding challenges in the molecular life sciences: (i) the development of a system forthe continuous directed evolution of proteins and nucleic acids, and (ii) the development of a general platform for the delivery ofmacromolecules into mammalian cells in vitro and in vivo. Our research efforts over the past five years resulted in new solutions toboth challenges.
Email:
Greater than 20
617-496-1067
Tel:
http://evolve.harvard.edu/
R Liu
Lab Size:
“A System for the Continuous Directed Evolution of Biomolecules” Esvelt, K. M.; Carlson, J. C.; Liu, D. R. Nature 472, 499–503(2011).
“Highly Specific, Bisubstrate-Competitive Src Inhibitors From DNA-Templated Macrocycles” Georghiou, G.; Kleiner, R. E.;Pulkoski-Gross, M.; Liu, D. R.; Seeliger, M. A. Nature Chemical Biology 8, 366-374 (2012).
“Comprehensive Off-Target DNA Cleavage Profiling Reveals RNA-Programmed Cas9 Nuclease Specificity” Pattanayak, V.; Lin, S.;Guilinger, J.P.; Ma, E.; Doudna, J. A.; Liu, D. R. Nature Biotechnology in press (2013).
“Enzyme-Free Translation of DNA into Sequence-Defined Synthetic Polymers Structurally Unrelated to Nucleic Acids” Niu, J.; Hili,R.; Liu, D. R. Nature Chemistry 5, 282-292 (2013).
“Engineering, Identifying, and Applying Supercharged Proteins for Macromolecule Delivery into Mammalian Cells” Thompson, D.B.; Cronican, J. J.; Liu, D. R. Methods in Enzymology 503, 293-319 (2012).
Publications:
Harvard Medical SchoolSGM 204A250 Longwood Ave.Boston, MA 02115
JosephAssociate Professor BCMP
The laboratory is primarily focused on developing and applying single-molecule methods to better understand the molecular dynamicsof the multi-protein complexes that are involved in genome maintenance. Areas of current interest include:
Regulation of translesion synthesisDNA damage acts as a potent block to the replication machinery. Error-prone translesion synthesis (TLS) is one pathway utilized toovercome this challenge. In TLS, translesion polymerases are recruited to sites of DNA damage to carry out strand extension overDNA lesions enabling resumption of DNA replication. Using the bacterial replisome as a model, we are studying how TLSpolymerases are recruited to the replisome, how protein-protein interactions control their access to DNA and how other factorsexpressed during the SOS damage response might further regulate their activity.
Repair of double-strand DNA breaks by non-homologous end joiningDNA double strand breaks (DSBs) are extremely toxic lesions that can arise spontaneously or be induced by agents such as ionizingradiation or endonucleases involved in programmed genome rearrangements. For the majority of the cell cycle DSBs are repaired byNHEJ, a process that robustly ligates even damaged or incompatible DNA ends, albeit in a way that often generates insertion ordeletion mutations. We are using single-molecule FRET approaches to directly visualize the repair of DSBs in reconstituted systemsand in vertebrate cell free extracts. We aim to understand how the assembly of the NHEJ machinery is controlled, how DNA ends areheld together by this machinery, and how mutations are minimized during repair.
The role of nucleoid associated proteins in bacterial chromosome organizationBacteria typically store their genetic information in a single circular chromosome that is several million DNA bases long. In order tomaintain and duplicate this chromosome, called the nucleoid, bacteria must accomplish two major feats of structural engineering:First, a giant 1.5 millimeter-long DNA molecule must be packaged into a bacterial cell that is over a thousand times shorter. Second,newly replicated sister chromosomes must be disentangled and separated without the advantage of the sophisticated mitotic machinerythat is present in eukaryotic cells. We are developing single-molecule approaches to directly probe how nucleoid associated proteinscondense DNA.
Email:
617-432-5586
Tel:
https://loparo.hms.harvard.edu/
Loparo
Lab Size:
Multistep assembly of DNA condensation clusters by SMC. Kim, H.; Loparo, J.J.Nat Commun (Accepted 2015)
Mechanical allostery: Evidence for a force requirement in the proteolytic activation of Notch. Gordon, W.R.; Zimmerman, B.; He, L.;Miles, L.J.; Huang, J.; Tiyanont, K.; McArthur, D.G.; Aster, J.C.; Perrimon, N.; Loparo, J.J.*, Blacklow, S.C.* Dev. Cell 33 (2015)729-736.
ParB spreading requires DNA bridging. Graham, T.G.W.; Wang, X.; Song, D.; Etson, C.M.; van Oijen, A.M.; Rudner, D.Z.; Loparo,J.J. Genes Dev 28 (2014) 1228-38.
Polymerase exchange on single DNA molecules reveals processivity clamp control of translesion synthesis. Kath, J.E,; Jergic, S.;Heltzel, J.M.H.; Jacob, D.T.; Dixon, N.E.; Sutton, M.D.; Walker, G.C.; Loparo, J.J. Proc. Natl. Acad. Sci. USA 111 (2014) 7647-52.
Publications:
Massachusetts General HospitalSimches Research Bldg. 5.212185 Cambridge Street, Boston MA 02114
RalphAssistant Professor of Radiology
Exploring and understanding biological systems at the molecular level with a tool set offered by modern chemistry is the commonmotif of my research interests. As a Chemical Biologist I find it intriguing to use small organic compounds, either derived from natureor by rational design, to study complex biological processes with a resolution that is neither offered by genetic nor biochemicalapproaches. Consequently the research in my lab is centered on the interface of biology and organic synthetic chemistry, in particularthe synthesis of diversity-oriented-synthesis (DOS) derived libraries for biochemical and in vitro screening, as well as thedevelopment of small molecule tool compounds and novel biochemical assay systems for high-throughput screening. One major focusin my group is in the development of subtype specific histone deacetylase (HDAC) inhibitors. HDACs have originally beendiscovered as chromatin modifying enzymes, however, recent research suggests that regulation of non-histone proteins by acetylationis more abundant than originally anticipated and comparable to other posttranslational modifications. The development of HDACinhibitors (as tool compounds or as drug) has paid little attention to subtype specificity, which is limiting the applicability of thesecompounds. Our goal is it to understand the features that convey selectivity and to develop tools to selectively study the function ofHDACs isoforms (in particular class II enzymes) in cellular systems.
Email:
Fewer than 5
617-643-6286
Tel:
https://csb.mgh.harvard.edu/mazitschek
Mazitschek
Lab Size:
Bradner JE, West N, Grachan ML, Greenberg EF, Haggarty SJ, Warnow T, Mazitschek R. Chemical phylogenetics of histonedeacetylases. Nat Chem Biol. 2010;6(3):238-243 - PMID: 20139990 - PMCID: PMC2822059 - Cover
Devaraj NK, Hilderbrand S, Upadhyay R, Mazitschek R, Weissleder R. Bioorthogonal Turn-On Probes for Imaging Small Moleculesinside Living Cells. Angew Chem Int Edit. 2010;19 (49):2869-2872 - PMID: 20306505
Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE,DePinho RA, Jaenisch R, Tsai LH. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature. 2009; 459(7243):55-60 - PMID: 19424149
Sundrud MS, Koralov SB, Feuerer M, Calado DP, Kozhaya AE, Rhule-Smith A, Lefebvre RE, Unutmaz D, Mazitschek R, WaldnerH, Whitman M, Keller T, Rao A. Halofuginone Inhibits TH17 Cell Differentiation by Activating the Amino Acid StarvationResponse. Science. 2009;324(5932):1334-1338 - PMID: 19498172 - PMCID: PMC2803727
Publications:
Harvard Medical School536 Warren Alpert Building200 Longwood AvenueBoston, MA 02115
TimothyHasib Sabbagh Professor of Systems BiologyDeputy Chair, Systems Biology PhD Program co-Director
My lab is interested in the structure, dynamics, and function of the cytoskeleton. We use imaging-based assays in living cells and invitro extracts, in conjunction with molecular biology and biochemical fractionation approaches, as well as theory and modeling. Mostof of the lab works on cell division in some way. One major focus is on the mechanism of mitotic spindle assembly in Xenopus eggextracts. We use a variety of imaging methods, including single molecule imaging, to probe protein localization and dynamics,biochemistry and pharmacology to perturb assembly, and theory/modeling to rationalize the results. We are increasing interested in anapplied problem, cancer chemotherapy directed at the mitotic spindle. We are performing imaging and biochemistry experiments indifferent cancer cell lines to understand how current chemotherapy works, and how we might improve it. A key question is tounderstand differences between cell types in drug response. Part of the lab works on how the actin cytoskeleton is organized, duringcytokinesis and also in the comet tails of Listeria, a pathogenic bacterium. Current foci include understanding monopolar cytokinesis,and the mechanism by which actin filaments turn over rapidly in the cytoplasm.
Email:
Between 10 and 15
617-432-3805
Tel:
http://mitchison.hms.harvard.edu/
Mitchison
Lab Size:
Kueh, H.Y., Brieher, W.M., & Mitchison, T.J. (2010). Quantitative analysis of actin turnover in Listeria comet tails: evidence forcatastrophic filament turnover. Biophysical Journal, 99(7), 2153-2162. PMID: 20923649. PMCID: PMC3042591.
Yang, R., Niepel, M., Mitchison, T.K., & Sorger, P.K. (2010). Dissecting Variability in Responses to Cancer Chemotherapy ThroughSystems Pharmacology. Clinical Pharmacology and Therapeutics, 88(1), 34-8. PMID: 20520606. PMCID: 2941986. pdf.
Mitchison, T.J. (2010). Cell biology: How cilia beat. Nature , 463(7279), 308-309. PMID: 20090745.
Needleman, D.J., Groen. A., Ohi, R., Maresca, T., Mirny, L., & Mitchison, T. (2010). Fast microtubule dynamics in meiotic spindlesmeasured by single molecule imaging: evidence that the spindle environment does not stabilize microtubules. Molecular Biology ofthe Cell, 21(2), 323-333. PMID: 19940016. PMCID: PMC2808228.
Huang, H.C., Shi, J., Orth, J.D., & Mitchison, T.J. (2009). Evidence that mitotic exit is a better cancer therapeutic target than spindleassembly. Cancer Cell, 16(4), 347-358. PMID: 19800579. PMCID: PMC2758291. pdf.
Dumont, S. & Mitchison, T.J. (2009). Compression regulates mitotic spindle length by a mechanochemical switch at the poles.Current Biology, 19(13), 1086-1095. PMID: 19540117. PMCID: PMC2722833. pdf.
Publications:
Massachusetts General HospitalDepartment of Molecular Biology185 Cambridge Street, CPZN 7250Boston, MA 02114
VamsiProfessor of Medicine and of Systems Biology
Our laboratory focuses on mitochondria. These tiny organelles found in virtually all human cells, serving as the center stage forenergy metabolism, ion homeostasis, and apoptosis. Their composition, copy number, and efficiency are dynamic properties, varyingacross cell types and remodeling during growth and differentiation. Mitochondrial dysfunction underlies rare, inborn errors ofmetabolism, as well as some of the most common human diseases, such as diabetes, cancer, and neurodegeneration. Given theirimportance in basic biology and clinical medicine, mitochondria represent an excellent "model" for basic and clinical systems biology.
Our group is broadly interested in characterizing the structure and dynamic properties of mitochondria, understanding how geneticvariation influence mitochondrial physiology, and exploiting the network properties of the organelle to design therapies for humandisease. To achieve these goals, we combine classic biochemistry and physiology with the new tools of genomics, proteomics, andchemical biology. In recent years, we have used mass spectrometry, microscopy, and computation to define the mitochondrialproteome (an inventory we call MitoCarta). We have subsequently coupled MitoCarta with human genetics to discover over onedozen Mendelian disease genes. We have used computational and comparative genomics in combination with RNAi screens topredict and validate the function of proteins comprising the mitochondrial calcium uniporter.
Current areas of focus include: (1) nuclear:mitochondrial cross-talk in the control of mitochondrial biogenesis, (2) membranebiochemistry and biophysics of ion and metabolite transport, (3) next-gen sequencing and functional studies of human mitochondrialdisease, (4) metabolomics approaches to mitochondrial function, and (5) chemical biology approaches to modulating mitochondrialcopy number and function.
Email:
Between 10 and 15
617-643-3059
Tel:
http://mootha.med.harvard.edu/
Mootha
Lab Size:
Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, Walford GA, Sugiana C, Boneh A, Chen WK, Hill DE, Vidal M,Evans JG, Thorburn DR, Carr SA, Mootha VK. A mitochondrial protein compendium elucidates complex I disease biology. Cell2008; 134(1):112-23.
Perocchi F, Gohil VM, Girgis H, Bao R, McCombs J, Palmer A, Mootha VK. MICU1 encodes a mitochondrial EF hand proteinrequired for Ca2+ uptake. Nature 2010; 467(7313):291-6.
Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, BogoradRL, Koteliansky V, Mootha VK. Integrative genomics identifies MCU as an essential component of the mitochondrial calciumuniporter, Nature 2011: 476(7360):341-5.
Bick AG, Calvo SE, Mootha VK. Evolutionary diversity of the mitochondrial calcium uniporter, Science 2012: 336(6083):86.
Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza A, Kafri R, Kirschner MW, Clish CB, Mootha VK. Metaboliteprofiling reveals a key role for glycine in rapid cancer cell proliferation, Science 2012: 336(6084): 1040-44.
Publications:
12 Oxford St.Cambridge, MA02138
MyersAmory Houghton Professor of Chemistry and Chemical Biology
Professor Myers' research program involves the synthesis and study of complex molecules of importance in biology and humanmedicine. His group has developed laboratory synthetic routes to a broad array of complex natural products, including the ene-diyneantibiotics neocarzinostatin chromophore, dynemicin A, N1999A2, and kedarcidin chromophore, undertakings greatly complicated bythe chemical instability of all members of the class. His laboratory developed the first practical synthetic route to the tetracyclineantibiotics, allowing for the synthesis of more than three thousand fully synthetic analogs (compounds inaccessible by semi-synthesis:chemical modification of natural products) by a scalable process. A portfolio of clinical candidates for the treatment of infectiousdiseases, all fully synthetic tetracycline analogs, are currently in development at Tetraphase Pharmaceuticals, a company founded byMyers. In addition, the Myers' laboratory has developed short, practical and scalable synthetic routes to the saframycin, cytochalasin,stephacidin B-avrainvillamide, and trioxacarin classes of natural antiproliferative agents, in each case by the modular assembly ofsimple components of similar synthetic complexity.
Myers and his students have also developed numerous reagents and procedures of general utility in the construction of complexmolecules. These include the development of methodology for the preparation of highly enantiomerically enriched ketones,aldehydes, alcohols, carboxylic acids, organofluorine compounds, α-amino acids, and molecules containing quaternary carbon centersusing pseudoephenamine and pseudoephedrine as chiral auxiliaries, a method for the reductive deoxygenation of alcohols that doesnot involve metal hydride reagents, methods for the stereoselective synthesis of alkenes from sulfonyl hydrazones, a stereospecificsynthesis of allenes from propargylic alcohols, a 1,3-reductive transposition of allylic alcohols, a silicon-directed aldol additionreaction, a method for the reductive coupling of aldehydes and allylic alcohols, the discovery of the powerful reductant lithiumamidotrihydroborate, the use α-amino aldehydes in synthesis, methods for the synthesis and transformation of diazo compounds, ahighly diversifiable method for the synthesis of isoquinolines, as well as others.
Email:
Greater than 15
617-495-5679
Tel:
http://www.chem.harvard.edu/groups/myers/index.html
Andrew
Lab Size:
Synthesis of Cortistatins A, K, J, and L. Alec Flyer, Chong Si, and Andrew G. Myers. Nature Chemistry. 2010, 2, 886.
A Multiply Convergent Platform for the Synthesis of Trioxacarcins. Jakub Svenda, Nick Hill, and Andrew G. Myers. PNAS. 2011,17, 6709.
A Practical, Convergent Route to the Key Precursor to the Tetracycline Antibiotics. David Kummer, Derun Li, Amelie Dion,and Andrew G. Myers. Chemical Science. 2011, 2 (9), 1710 – 1718.
Pseudoephenamine: A Practical Chiral Auxiliary for Asymmetric Synthesis. Marvin R. Morales, Kevin T. Mellem, and Andrew G.Myers. Angewandte Chemie, International Edition. 2012, 51 (19), 4568.
Component-Based Syntheses of Trioxacarcin A, DC-45-A1, and Structural Analogs. Daniel J. Smaltz, Jakub Švenda, and Andrew G.Myers. Nature Chemistry, 2013, In Press.
Publications:
Dana-Farber Cancer InstituteSmith Building, Room 97044 Binney StreetBoston, MA 02115
TomProfessor of Biological Chemistry and Molecular Pharmacology
Signaling Mechanisms and Cancer
Through the process of signal transduction, cells communicate what is happening on their surfaces to the regulatory machinery inside.This process is facilitated by a class of enzymes called kinases, which help activate specific genes in the long strands of DNA in acell's nucleus. An overactive kinase can lead to an overactive gene and, ultimately, to cancer. Our laboratory is researching the role ofthese catalysts of cell growth and division and has discovered how several work. Our discoveries have become the basis of new drugsthat target the actions of specific kinases. This class of drugs, called kinase inhibitors, offers extraordinary hope for the future ofcancer care.
Research in the laboratory currently focuses on three areas. One is how particular kinases are involved in cancer. For instance, thekinase termed PI3K blocks the orderly process of cell death, called apoptosis. Thus, inhibiting PI3K should lead to tumor cell death.We are also exploring new ways to measure kinase activity in tumors. Every tumor is unique, with its own pattern of activatedkinases. Because there are more than 600 different kinases in a given tumor, it is important to find which ones are activated so that weknow which ones to inhibit. Finally, our laboratory is developing murine model systems to study kinases in tumors.
Once kinases have been pinpointed, our laboratory develops the techniques and technology that allow pharmaceutical companies tomake new drugs that target them. We supply the company with the reagents necessary to test the effect of drugs on the action oftyrosine kinases. In addition, DFCI scientists have developed the means to make kinases for testing. This collaboration has led to thecreation of several new drugs. In particular, the drug Gleevec has been approved by the FDA against chronic myeloid leukemia(CML). More recently we have been working with Novartis on PI3k inhibitors. PI3K inhbitors from Novartis and other companiesare now entering Phase 2 trials
Email:
Greater than 10.
617-632-3049
Tel:
http://www.hms.harvard.edu/dms/BBS/fac/robertst.php
Roberts
Lab Size:
Jia S, Gao X, Lee SH, Maira SM, Wu X, Stack EC, Signoretti S, Loda M, Zhao JJ, Roberts TM (2013).Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention Cancer Discov. 2013 3(1):44-51.PMCID: PMC3546223Jia S*, Liu Z*, Zhang S*, Liu P, Lee S, Zhang J, Lee S, Zhang J, Signoretti S, Loda M, and Roberts TM, and Zhao JJ (2008).Essential roles of PI(3)K-p110b in cell growth, metabolism and tumorigenesis Nature 454:776-9. PMCID: PMC2750091.
Qi HH*, Sarkissian M*, Bhattacharjee A, Gordon B, Lan F, Huarte M, Yaghi NK, Lim H, Brizuela L, Roberts TM# and Shi Y#(2010). The mental retardation gene PHF8 mediates histone H3K9/H4K20 demethylation and regulates zebrafish craniofacialdevelopment. Nature 466:503-7. PMCID: PMC3072215.
Ilic N, Utermark T, Widlund HR, Roberts TM. (2011) PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis. Proc Natl Acad Sci U S A. Aug 29. Epub ahead of print
Tamara Utermark*, Trisha Rao*, Hailing Cheng, Qi Wang, Sang Hyun Lee, Charles Zhigang Wang, J. Dirk Iglehart, Thomas M.Roberts1, William J. Muller* and Jean J. Zhao* (2012) The p110 and p110 isoforms of PI3K play divergent roles in mammary
gland development and tumorigenesis Genes & Development 26(14):1573-86
Publications:
Seeley G Mudd 520250 Longwood AvenueBoston, MA 02115
AdrianAssociate Professor of Cell Biology
Our lab has two main interests: 1) Understanding the mechanisms involved in cell-cell signaling through the vertebrate Hedgehogpathway; and 2) Synthesizing and validating new chemical probes for microscopic imaging and functional assays of variousbiological molecules (nucleic acids, proteins, lipids), in cells and in animals.
1) Mechanisms of Hedgehog signalingThe Hedgehog pathway plays a critical role in developing embryos as well as in the maintenance of adult stem cells. UnregulatedHedgehog signaling is implicated in a large number of human cancers. We are using biochemistry, cell and chemical biology toelucidate how vertebrate cells send and respond to Hedgehog signals. The key questions of Hedgehog signaling that we areinvestigating are:
A) How is the secreted Hedgehog protein activated?Hedgehog becomes active through a unique posttranslational process involving the attachment of both cholesterol and palmitate. Weare using biochemistry to reconstitute these complex reactions and dissect their mechanism. We also use live cell imaging toinvestigate the subcellular dynamics of Hedgehog activation. Finally, we are using chemical biology approaches to identify othercholesterol-modified proteins and study them functionally in cells.
B) How does Hedgehog signaling control the Gli transcription factors?In vertebrates, Hedgehog signaling initiated in primary cilia activates the membrane protein Smoothened and leads to activation of Gliproteins, the transcriptional effectors of the pathway. In the absence of signaling, Gli proteins are inhibited by the cytoplasmic proteinSuFu. We found that Hedgehog stimulation quickly recruits endogenous SuFu-Gli complexes to cilia and causes rapid dissociation ofthe SuFu-Gli complex, thus allowing Gli to enter the nucleus and activate transcription. We are using biochemical reconstitution andcell biology to dissect this simple mechanism of vertebrate Hedgehog signaling. We plan to use live cell imaging to understand thespatial and temporal aspects of SuFu-Gli regulation by Hedgehog signaling at the primary cilium.
C) What is the role of sterols in Hedgehog signal transduction?Sterols are required for normal Hedgehog signaling and Hedgehog signaling is defective human diseases of cholesterol metabolism.Furthermore, oxysterols are potent activators of the Hedgehog pathway, suggesting a role for endogenous sterols in Hedgehogsignaling. We are using chemical biology, biochemistry and cellular approaches to understand how sterols regulate the membraneprotein Smoothened, which is critical for transducing Hedgehog signals.
Email:
Greater than 5
617-432-6341
Tel:
https://salic.med.harvard.edu/
Salic
Lab Size:
1) Nedelcu D, Liu J, Xu Y, Jao C and Salic A – 2013 Oxysterol binding to the extracellular domain of Smoothened is required forvertebrate Hedgehog signaling, Nat Chem Biol, advance online publication.
2) Tukachinsky H, Kuzmickas RP, Jao CY, Liu J and Salic A – 2012 Dispatched and Scube mediate the efficient secretion of thecholesterol-modified Hedgehog ligand, Cell Rep, 2(2), 308-20.
3) Liu J, Xu Y, Stoleru D, and Salic A – 2012 Imaging protein synthesis in cells and tissues with an alkyne analog of puromycin,PNAS, 109(2), 413-8.
4) Chen X, Tukachinsky H, Huang CH, Jao C, Chu YR, Tang HY, Mueller B, Schulman S, Rapoport TA and Salic A – 2011Processing and turnover of the Hedgehog protein in the endoplasmic reticulum, J Cell Biol, 192(5), 825-38.
5) Tukachinsky H, Lopez L and Salic A – 2010 A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociationof SuFu-Gli protein complexes, J Cell Biol, 191(2), 415-28.
Publications:
7 Cambridge CenterCambridge, MA 02142
StuartMorris Loeb Professor of Chemistry and Chemical Biology
The Schreiber laboratory is focused on the science of small-molecule drug discovery. The lab discovers small-molecule probes oftargets and processes revealed by human genetics to be essential for disease, especially human cancers, diabetes and Crohn’s disease.It is also determining the genetic features of human cancers that correlate with small-molecule drug efficacy so that medicines can beidentified that target the vulnerabilities revealed by the genetics of a patient’s tumor.To facilitate the discovery of small-molecule probes and drugs, the Schreiber lab develops and applies next-generation organicsynthesis, cell-based methods of small-molecule screening, and unbiased methods for understanding mechanism-of-action. The lab’sbasic research tests emerging concepts in human disease with small-molecule probes or drugs in physi¬ologically relevant conditions.
Email:
Between 15 and 20
617-714-7080
Tel:
http://www.broadinstitute.org/chembio/lab_schreiber/home.php
Schreiber
Lab Size:
Schreiber, Stuart L. “Organic synthesis towards small-molecule probes and drugs”, Proc. Natl. Acad. Sci., U.S.A., 2011, 108, 6699-6702.
Schreiber, Stuart L., et al. “Towards patient-based cancer therapeutics”, Nature Biotech., 2010, 28, 904-906.
Schreiber, Stuart L. ʺMolecular diversity by designʺ. Nature, 2009, 457, 153‐154.
Schreiber, Stuart L. ʺThe gap between scientistsʹ aspiration and societyʹs expectationsʺ. ChemBioChem,200, 10, 26‐29.
Publications:
Department of Chemistry & Chemical BiologyMallinckrodt 31512 Oxford StCambridge, MA 02138
MatthewProfessor of Chemistry and Chemical Biology
The Shair research group is working in two main areas: organic synthesis and chemical biology. Most projects involve syntheses ofnaturally occurring complex molecules that challenge the state-of-the-art of organic synthesis. We have chosen target molecules thatare structurally unique and that have interesting, unstudied biological properties. We choose molecules that are different from othercomplex molecules that have been synthesized since this enables us to explore new areas of organic chemistry, especially with respectto reactivity and selectivity. We are particularly interested in developing cascade reactions for each of our synthesis targets, in order toachieve the most efficient and rapid syntheses possible.
We are also attracted to molecules that have unique biological properties. Our syntheses, in many cases, are the only means ofaccessing additional material and designed analogs to uncover the molecule’s cellular target(s) and mechanism(s). We also have acollaboration with Professor Tom Kirchhausen’s lab in the Cell Biology Department at Harvard Medical School on the discovery anduse of small molecules to probe vesicular traffic and Golgi organization in cells.
Email:
Between 10 and 15
617-495-5008
Tel:
http://www.chem.harvard.edu/research/faculty/matthew_shair/
Shair
Lab Size:
Fortner, D. C.; Kato, D.; Tanaka, Y.; Shair, M. D. Enantioselective Synthesis of (+)-Cephalostatin 1. J. Am. Chem. Soc. 2009, ASAP.
Morris, W. J.; Shair, M. D. Org. Stereoselective Synthesis of 2-Deoxy-ß-glycosides Using Anomeric O-Alkylation/Arylation. Lett.2008, 11, 9–12.
Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. Enantioselective Synthesis of (+)-Cortistatin A, a Potent and Selective Inhibitor ofEndothelial Cell Proliferation. J. Am. Chem. Soc. 2008, 130, 16864–16866.
Krygowski, E. S.; Murphy-Benenato, K.; Shair, M. D. Angew. Enantioselective Synthesis of the Central Ring System of LomaiviticinA in the Form of an Unusually Stable Cyclic Hydrate. Chem. Int. Ed. Engl. 2008, 47, 1680-1684.
Publications:
Department of Systems BiologyHarvard Medical School200 Longwood Ave. WAB 536Boston, MA 02115
PamelaProfessor of Systems Biology
We seek to both enhance our understanding of natural biological design, and to develop tools and concepts for designing cells, tissuesand organisms. In the long term, we hope to develop principles for building novel cells that act as sensors, memory devices, bio-computers, producers of high value commodities and energy from the sun, and to build novel subsystems such as proteins withdesigned properties for therapeutic use. Current projects use mammalian cells, simple eukaryotes and prokaryotes. Understandinghow to program cells in a rational way will have value, for example, in stem cell design, drug therapy and the environment. Theseexperiments use a combination of theoretical and experimental approaches that are well suited to students with a background inbiology, engineering, or any allied field.
We also take advantage of the spatial organization of cells to further understand key disease pathways. For example, the movement ofkey proteins in and out of the nucleus is often one of the downstream steps in signal response. We have taken advantage of this spatialorganization to screen for small molecules and genes that affect signaling pathways and therapeutic targets. We employ acombination of high-resolution microscopy, modeling and cell-based screens. We also study the dynamics of post-transcriptionalregulation in response to drugs and diseases. Results from these experiments provide a basis for some of the synthetic biologicaldesigns.
Email:
Over 20
617-432-6401
Tel:
http://silver.med.harvard.edu/
Silver
Lab Size:
Burrill DR, Inniss MC, Boyle PM, Silver PA. (2012) Synthetic memory circuits for tracking cell fate. Genes & Dev. 26(13):1486-97.PMCID: PMC3403016.
Burrill DR, Boyle PM, Silver P. (2011) A new approach to an old problem: Synthetic biology tools for human disease & metabolism.Cold Spring Harbor 76th Symposium on Quantitative Biology. Dec 14 76:145-54.
Delebecque CJ, Lindner AB, Silver PA, Aldaye FA. (2011) Organization of Intracellular Reactions with Rationally Designed RNAAssemblies. Science. 333(6041):470-4. PMID: 21700839.
Smolke, C.D., and Silver, P.A. (2011). Informing biological design by integration of systems and synthetic biology. Cell. 255(6). 855-9. PMID: 21414477.
Savage DF, Afonso B, Chen AH, Silver PA. (2010). Spatially ordered dynamics of the bacterial carbon fixation machinery. Science.327(5970):1258-61. PMID: 20203050.
Publications:
250 Longwood Ave.Rm SGM-130,Boston, MA 02115
PiotrAssociate Professor of Pediatrics and of Biological Chemistry and MolecularPharmacology
To fully elucidate reaction mechanisms, develop effective functional probes, or rationalize searches for small molecule inhibitors, oneusually needs to determine the precise position of atoms in active sites of macromolecules. In our laboratory we determine highresolution atomic structures of proteins and RNAs using X-ray crystallography. We are positioned on the interface of structuralbiology and computations, allowing us to deploy a variety of modern tools to study macromolecules.
Our three key areas of interest include:
• Mechanistic studies of Lin28: a microRNA biogenesis regulator, a reprogramming factor, and an oncofetal protein. We haverecently determined high resolution crystal structures of Lin28 in complexes with various microRNAs. The Lin28/microRNAcomplex is an intriguing system that our laboratory now uses to explore general principles of protein:RNA interactions and developsmall molecule probes.• Mechanistic studies of proteins from the microRNA biogenesis pathway. Let7 microRNA precursors are processed intomature microRNAs by Dicer and DGCR8/Drosha, and this activity can be inhibited by interaction of let7s with Lin28. Lin28 can alsoinduce degradation of let7 though the uridylase/exonuclease pathway (TUT4/Dis3l2). We are interested in the mechanism of thisdegradation and are pursuing structural and functional studies of macromolecular complexes involved in this pathway. This work issupplemented by computational simulations.• Deployment of research computing “cloud” resources to accelerate structure determination. Our group has developed aglobal computing infrastructure that supports structure determination efforts in hundreds of structural biology laboratories (www.sbgrid.org). Some of the most computationally demanding workflows rely upon the vast resources of the Open Science Grid andaccess to this infrastructure contributes to our structure determination projects.
Email:
Greater than 5
617-432-5608
Tel:
http://hkl.hms.harvard.edu/
Sliz
Lab Size:
Yunsun Nam, Casandra Chen, Richard I Gregory, James Chou and Piotr Sliz. Molecular Basis for Interaction of let-7 MicroRNAswith Lin28. Cell 5: 1080-91 (2011).Michael Lazarus, Yunsun Nam, Jiaoyang Jiang, Piotr Sliz and Suzanne Walker. Structure of human O-GlcNAc transferase and itscomplex with a peptide substrate. Nature 469: 564-569 (2011).Ian Stokes-Rees and Piotr Sliz. Protein Structure Determination by exhaustive search of Protein Data Bank derived databases. PNAS(2010).Andrew Morin, Jennifer Urban, Paul D Adams, Ian Foster, Andrej Sali, David Baker and Piotr Sliz. Shining Light into Black Boxes.Science 6078: 159-160 (2012).
Publications:
Harvard Medical School, Department of Systems BiologyAlpert Building, Room 438200 Longwood AveBoston, MA 02115
PeterProfessor of Systems Biology
The Sorger Laboratory studies mammalian cancer biology with a focus on cell signaling networks involved in disease and thetherapeutic drugs that target them. We combine cell biological, biochemical and mathematical approaches with the overall aim ofderiving novel mechanistic and systems-wide insight into cellular physiology and human disease. Modeling methods range frompurely statistical and correlative to physicochemical and mechanistic but in all cases we rigorously link models to experimental dataon protein states, signaling biochemistry, and cellular phenotypes.
Our laboratory is particularly interested in death and survival signaling in response to death ligands such as TRAIL and TNF andgrowth factors such as EGF, IGF and HGF. We study how these ligands affect normal cells and how the signals they provoke aremisregulated in cancer. A significant fraction of the lab’s effort is devoted to developing and applying new mathematical methods formodel assembly, calibration and validation (including logic-based modeling, rules-based physicochemical modeling, Bayesiancalibration and optimal experimental design). We also develop and exploit mouse “models” of cancer that recapitulate key features ofhuman disease (particularly breast cancer and hepatocellular carcinoma). Finally, we develop and apply a wide variety of live-cellmicroscopy methods as well as multiplex approaches to biochemical measurement. Individual lab members are encouraged toundertake projects that combine computation and experimentation.
Email:
Over 20
617-432-6901
Tel:
http://sorger.med.harvard.edu/
Sorger
Lab Size:
Chen WW, Niepel M, and Sorger PK (2010). Classic and Contemporary Approaches to Modeling Biochemical Reactions. Genes Dev24, 1861-1875. PMC2932968.
Alexopoulos LG, Saez-Rodriguez J, Cosgrove BD, Lauffenburger DA, and Sorger PK (2010). Networks Inferred from BiochemicalData Reveal Profound Differences in Toll-Like Receptor and Inflammatory Signaling between Normal and TransformedHepatocytes. Mol Cell Proteomics 9, 1849-1865. PMC2938121.
Lazzara MJ, Lane K, Chan R, Jasper PJ, Yaffe MB, Sorger PK, Jacks T, Neel BG, and Lauffenburger DA (2010). Impaired Shp2-Mediated Extracellular Signal-Regulated Kinase Activation Contributes to Gefitinib Sensitivity of Lung Cancer Cells with EpidermalGrowth Factor Receptor-Activating Mutations. Cancer Res 70, 3843-3850. PMC2862125.
Cosgrove BD, Alexopoulos LG, Hang TC, Hendriks BS, Sorger PK, Griffith LG, and Lauffenburger DA (2010). Cytokine-Associated Drug Toxicity in Human Hepatocytes Is Associated with Signaling Network Dysregulation. Mol Biosyst 6, 1195-1206.PMC2943488.
Espelin CW, Goldsipe A, Sorger PK, Lauffenburger DA, de Graaf D, and Hendriks BS (2010). Elevated Gm-Csf and Il-1beta LevelsCompromise the Ability of P38 Mapk Inhibitors to Modulate Tnfalpha Levels in the Human Monocytic/Macrophage U937 Cell Line.Mol Biosyst.
Publications:
Massachusetts General HospitalRichard B. Simches Research Center185 Cambridge StBoston MA 02114
RadhikaAssistant Professor of Genetics
For a living cell to function properly, its cellular processes must be strictly controlled not only in time but also in space. We areinterested in how intracellular spatial organization on the micron-length scale is achieved by the collective activity of nanometer-sizedproteins. We investigate this problem in the context of the microtubule cytoskeleton.
In eukaryotes, a wide range of cellular processes such as cell division, cell migration, axonal growth and assembly of flagella and ciliarely on the dynamic and precise organization of microtubules into specialized architectures. Increasingly sophisticated genomic andproteomic analyses have now provided us with a near-complete ‘parts-list’ of the proteins involved in assembling these microtubule-based structures. However, the molecular mechanisms underlying the proper formation and activity of even the minimal functionalunits of these structures still remain poorly understood. We aim to bridge this knowledge gap by ‘building’ or reconstitutingmicrotubule-based architectures from the individual components.
We use a diverse set of experimental tools in our endeavor: integrating angstrom and nanometer-length scale information from X-raycrystallography and single-molecule visualization techniques with micron-length scale analysis of microtubule architectures usingmulti-color TIRF microscopy-based in vitro assays and cellular analyses of the cytoskeletal structures.
Email:
617-724-4062
Tel:
https://molbio.mgh.harvard.edu/laboratories/subramanian
Subramanian
Lab Size:
He M, Subramanian R, Bangs F, Omelchenko T, Liem KF, Kapoor TM, Anderson KV. The kinesin-4 protein Kif7 regulatesmammalian Hedgehog signalling by organizing the cilium tip compartment. Nat. Cell Biol. 2014 Jul; 16(7):663-72.
Subramanian R, Kapoor TM. Slipping past the spindle assembly checkpoint. Nat. Cell Biol. 2013 Nov; 15(11):1261-3.
Subramanian R, Ti SC, Tan L, Darst SA, Kapoor TM. Marking and measuring single microtubules by PRC1 and kinesin-4. Cell 2013Jul 18; 154(2):377-90.
Subramanian R, Kapoor TM. Building complexity: insights into self-organized assembly of microtubule-based architectures. Dev.Cell 2012 Nov 13; 23(5):874-85.
Subramanian R, Wilson-Kubalek EM, Arthur CP, Bick MJ, Campbell EA, Darst SA, Milligan RA, Kapoor TM. Insights intoantiparallel microtubule crosslinking by PRC1, a conserved nonmotor microtubule binding protein. Cell 2010 Aug 6; 142(3):433-43.
Publications:
Mayer Building, Room 664450 Brookline AvenueBoston, MA 02115
LorenAssociate Professor of Pediatrics
The Walensky laboratory focuses on the chemical biology of deregulated apoptotic and transcriptional pathways in cancer. Our goal isto develop an arsenal of new compounds-a “chemical toolbox”-to investigate and block protein interactions that cause cancer andother diseases. To achieve these objectives, we take a multidisciplinary approach that employs synthetic chemistry, structural biology,and biochemistry, cell biology, and mouse modeling to systematically dissect the pathologic signaling pathways of interest. We haveapplied a chemical strategy, termed hydrocarbon stapling, to generate highly specific and stable peptidic compounds that preserve thestructure of bioactive peptides, maximizing their potential as therapeutic reagents and as novel tools to elucidate biological pathwaysin normal and diseased tissues. For example, we have synthesized and deployed “stapled” peptides to structurally define the elusiveactivation sites and trigger mechanisms of essential executioner proteins of the apoptotic pathway, reactivate the p53 tumor suppressorpathway in chemoresistant solid tumors, overcome the apoptotic blockades of chemoresistant hematologic cancer cells, and advance anovel proteomic technology to capture alpha-helical targets and define their interaction sites. We believe that the development ofstapled peptides will extend the potential for discovery of novel and unforeseen protein interactions and how they impact health anddisease. Indeed, the constructs used to dissect disease pathways can be applied to interrogate them in a cellular context and providethe templates for next generation therapeutics.
Our studies emphasize the chemical, structural, and cellular biology of BCL-2 family proteins. These proteins are master regulatorsof programmed cell death and, when deregulated, can contribute to a host of human diseases characterized by pathologic cell survivalor premature cell death. We believe that by dissecting the protein interactions of this pathway and probing the functionalconsequences of chemical modulation of the signaling network, new therapeutic strategies will emerge for enhancing or subvertingcell survival for therapeutic benefit.
My laboratory is comprised of a diverse group of predoctoral and postdoctoral talent, whose expertise includes chemistry, structuralbiology, biochemistry, cell biology, immunology, hematopathology, pharmacology, mouse modeling, preclinical testing, and clinicaloncology. By attacking clinically-relevant research challenges using a cache of techniques drawn from diverse basic disciplines, wehope to break new ground in our understanding of the protein interactions that govern the critical balance between cellular life anddeath.
Email:
Lab Members: Greater than 12
617-632-6307
Tel:
http://www.hms.harvard.edu/dms/bbs/fac/walensky.php
Walensky
Lab Size:
Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, Tu HC, Kim H, Cheng EH, Tjandra N, Walensky LD. BAXactivation is initiated at a novel interaction site. Nature. 2008 Oct 23; 455(7216):1076-81.Stewart ML, Fire E, Keating AE, Walensky LD. The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. NatChem Biol. 2010 Aug; 6(8):595-601.Bernal F, Wade M, Godes M, Davis TN, Kung AL, Wahl GM, Walensky LD. A stapled p53 Helix overcomes HDMX-mediatedsuppression of p53. Cancer Cell, 2010, Nov 16; 18: 411-22.Labelle JL, Katz SG, Bird GH, Gavathiotis E, Stewart ML, Lawrence C, Fisher JK, Godes M, Pitter K, Kung AL, Walensky LD. Astapled BIM peptide overcomes apoptotic resistance in hematologic cancers. J Clin Invest. 2012 Jun 1; 122(6):2018-31.Gavathiotis E, Reyna DE, Bellairs JA, Leshchiner ES, Walensky LD. Direct and selective small-molecule activation of proapoptoticBAX. Nat Chem Biol. 2012 Jul;8(7):639-45.
Publications:
Department of Microbiology & ImmunologyHIM, Room 10134 Blackfan CircleBoston, MA 02115
SuzanneProfessor of Microbiology and Molecular GeneticsCo-Director, Chemical Biology PhD Program
The Walker Group has expertise in studying bacterial cell wall biosynthesis and its inhibition. We have developed chemicalapproaches to study the membrane-linked steps of peptidoglycan and teichoic acid biosynthesis, and have made fundamentalcontributions to understanding the enzymes involved in these processes and the mechanisms of action of antibiotics that inhibit them.We work on Gram positive organisms, including the pathogens Staphylococcus aureus and Enterococcus faecalis, and a majorresearch focus includes exploring novel strategies to overcome antibiotic resistant microorganisms. My research program combinesorganic chemistry, enzymology, high throughput screening, biophysics, and bacterial genetics to address problems of interest.
Email:
Lab Members: Greater than 10
617-432-5488
Tel:
http://www.chem.harvard.edu/groups/walker/index.html
Walker
Lab Size:
Lazarus MB, Jiang J, Gloster TM, Zandberg WF, Whitworth GE, Vocadlo DJ, Walker S. Structural snapshots of the reactioncoordinate for O-GlcNAc transferase. Nat Chem Biol 2012; 8:966-8.
Brown S, Xia G, Luhachack LG, Campbell J, Meredith TC, Chen C, Winstel V, Gekeler C, Irazoqui JE, Peschel A, Walker S.Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids. Proc Natl Acad Sci USA 2012; 109:18909-14.
Jiang J, Lazarus M, Pasquina L, Sliz P, Walker S. A neutral diphosphate mimic that crosslinks the active site of human O-GlcNActransferase. Nat Chem Biol 2012; 8:72-7.
Lazarus MB, Nam Y, Jiang J, Sliz P, Walker S. Structure of human O-GlcNAc transferase and its complex with a peptide substrate.Nature 2011; 469: 564-7.
Brown S, Meredith T, Swoboda J, Walker S. Staphylococcus aureus and Bacillus subtilis W23 make polyribitol wall teichoic acidsusing different enzymatic pathways. Chem Biol 2010; 17:1101-10.
Publications:
Department of Chemistry and Chemical Biology12 Oxford StreetCambridge, MA 02138
ChristinaAssistant Professor of Chemistry and Chemical Biology
Biological insight to the mechanisms underlying small molecule action in the proteome will require new chemical approaches toaccess bioactive molecules andprecisely evaluate their proteomic activity. The Woo group draws from the fields of chemical biology, organic synthesis, and massspectrometry to address such areas.Specifically, we develop chemical biology probes to delineate the precise endpoints and functions of a small molecule in theproteome. We concurrently use the powerof organic synthesis to access unusual natural product scaffolds and study their biological activity. We then harness the power ofliquid chromatography-massspectrometry (LCMS) to pursue chemical proteomics methods for surveying proteomic interactions of small molecules, naturalproducts, and metabolites likeglycans or lipids. In particular, the use of isotope recoding and computational algorithms to detect and identify molecular interactionsin the proteome accelerates our mass spectrometry studies. Finally, a bioinformatics and molecular biology approach is taken to revealthe functional relationship between observed molecularinteractions and biological phenotype. Studies from the Woo laboratory will have implications in protein targets (and off-targets) fordrug discovery, develop syntheticaccess to novel probes and small molecules, and reveal new mechanisms by which small molecules influence biological systems.
Email:
5-10
617-495-3858
Tel:
woolab.org
Woo
Lab Size:
Woo, C. M.; Bertozzi, C. R. “Isotope targeted glycoproteomics (IsoTaG) to characterize intact, metabolically labeled glycopeptidesfrom complex proteomes.” Curr. Protoc. Chem. Bio. 2016, 8, 59.
Woo, C. M.; Li, Z.; Paulson, E.; Herzon, S. B. “Structural basis for DNA cleavage by the potent antiproliferative agent (–)-lomaiviticin A.” Proc. Natl. Acad. Sci. 2016, 11, 2851.
Woo, C. M.; Iavarone, A. T.; Spiciarich, D. R.; Palaniappan, K. K.; Bertozzi, C. R. “Isotope Targeted Glycoproteomics (IsoTaG): Amass independent platform for intact N- and O-glycopeptide discovery.” Nat. Meth., 2015, 12, 561.
Woo, C. M.; Gholap, S. L.; Lu, L.; Kaneko, M.; Li, Z.; Ravikumar, P. C.; Herzon, S. B. “Development of enantioselective syntheticroutes to (-)-kinamycin F and (-)-lomaiviticin aglycon.” J. Am. Chem. Soc. 2012, 134, 17262.
Woo, C. M.; Beizer, N. E.; Janso, J. E.; Herzon, S. B. “Isolation of lomaiviticins C-E. Transformation of lomaiviticin C tolomaiviticin A, complete structure elucidation of lomaiviticin A, and structure-activity analyses.” J. Am. Chem. Soc. 2012, 134,15285.
Publications:
Boston Children's HospitalCLSB-30993 Blackfan CircleBoston MA 02115
HaoProfessor of Biological Chemistry and Molecular Pharmacology; Professor ofPediatrics
The Wu laboratory of structural immunology focuses on elucidating the molecular mechanism of signal transduction by immunereceptors, especially innate immune receptors. The lab began its studies on the signaling of a classical cytokine produced by theinnate immune system, tumor necrosis factor (TNF), which induces diverse cellular responses such as NF-κB activation and celldeath. Receptors for TNF belong to the large TNF receptor (TNFR) superfamily. The second pursuit of the lab has been the Toll-likereceptor (TLR)/interleukin-1 receptor (IL-1R) superfamily, which induces signaling pathways overlapping with those of the TNFRsuperfamily. TLRs are transmembrane receptors that sense a discrete collection of molecules of microbial origin in the extracellularspace and endosomes and members of IL-1R family are receptors for cytokines IL-1 and IL-18. TLRs and IL-1Rs share similarcytoplasmic domains. The lab recently expanded its research to a number of cytosolic pattern recognition receptors that provideintracellular surveillance of infections. Some of these intracellular sensors can induce pathways overlapping with those of TLRs suchas activation of NF-κB and interferon regulatory factors. Others mediate the formation of inflammasomes that control activation ofcaspase-1, which in turn regulates maturation of the proinflammatory cytokines IL-1 and IL-18 and induces pyroptosis, a rapidinflammatory form of cell death.
The overall objective of the Wu lab has been to determine how macromolecular interactions mediate the transmission of signals fromreceptors to effectors to direct innate immune responses using the core approaches of structural biology. These structural studieschallenge the traditional view of signal transduction as a string of recruitment and allosteric events. As a recurrent theme, the lab’sresearch revealed that upon ligand stimulation, many innate immune receptors assemble large oligomeric intracellular signalingcomplexes, or “signalosomes,” to induce the activation of caspases, kinases and ubiquitin ligases, leading to cell death, cytokinematuration or expression of gene products for immune and inflammatory responses. The different scaffolds identified by thesestructural studies provide a molecular foundation for understanding the formation of microscopically visible signaling clusters in cells.
Email:
20
617.713.8160
Tel:
http://labs.idi.harvard.edu/wu/
Wu
Lab Size:
Qian Yin, David P. Sester, Yuan Tian, Yu-Shan Hsiao, Alvin Lu, Jasmyn A. Cridlan, Vitaliya Sagulenko, Sara J. Thygesen, DivakerChoubey, Veit Hornung, Thomas Walz, Katryn J. Stacey, and Hao Wu. Molecular Mechanism for p202-mediated Specific Inhibitionof AIM2 Inflammasome Activation. Cell Reports. 2013 Jul 9.
Wu H. Higher Order Assemblies in a New Paradigm of Signal Transduction. Cell. 2013 April 11. 153(2):287-292.
Yin Q, Tian Y, Kabaleeswaran V, Jiang X, Tu D, Eck MJ, Chen ZJ, Wu H. Cyclic di-GMP sensing via the innate immune signalingprotein STING. Mol Cell. 2012 Jun 29;46(6):735-45.
Fontan L, Yang C, Kabaleeswaran V, Volpon L, Osborne MJ, Beltran E, Garcia M, Cerchietti L, Shaknovich R, Yang SN, Fang F,Gascoyne RD, Martinez-Climent JA, Glickman JF, Borden K, Wu H, Melnick A MALT1 Small Molecule Inhibitors SpecificallySuppress ABC-DLBCL In Vitro and In Vivo Cancer Cell. 2012 Dec 11;22(6):812-24.
Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A, Chan FK, Wu H.The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell. 2012 Jul 20;150(2):339-50
Publications:
Cutaneous Biology Research CenterMassachusetts General HospitalHarvard Medical SchoolBuilding 149, 13th Street
XuAssociate Professor, Dermatology
The Wu laboratory is interested in using chemical biology and functional genomics approaches to study lipid biology, developmentalsignaling networks and cellular processes in normal physiology and diseases.
We focus on studying developmental signaling pathways, such as Wnt, Hedgehog, Hippo and JAK-STAT signaling, and aim todiscover novel chemical modulators of stem cell fate and cancers. In addition, we develop and utilize chemical probes to study proteinfatty acylation (myristoylation, palmitoylation, stearoylation etc.), and to identify novel enzymes or enzyme-like activities involved indynamic regulation of protein lipidations (fatty acyltransferases and deacylases). We aim to reveal the functions of protein lipidation,and to understand how deregulation of lipid metabolism leads to diseases.
The specific research projects in our lab include:1. Chemical approaches to study posttranslational protein lipidation and lipid metabolism in cellular processes2. Chemical approaches to dissect signal cross-talking and “rewiring” in degenerative diseases and cancers3. Chemical and functional genomic approaches to explore cellular senescence and terminal differentiation
Email:
Lab Members: Between 5 and 10
617-726-4438
Tel:
http://www.xwulab.org
Wu
Lab Size:
Baoen Chen, Baohui Zheng, Micael DeRan, Gopala K. Jarugumilli, Jianjun Fu, Yang S. Brooks and Xu Wu* “ZDHHC7-Mediated S-Palmitoylation of Scribble Regulates Cell Polarity” Nature Chemical Biology, 2016, DOI:10.1038/nchembio.2119.
PuiYee Chan, Xiao Han, Baohui Zheng, Michael DeRan, Jianzhong Yu, Gopala K. Jarugumilli, Hua Deng, Duojia Pan, Xuelian Luo* and Xu Wu* “Autopalmitoylation of TEAD Proteins Regulates Transcriptional Output of the Hippo Pathway” Nature ChemicalBiology, 2016, 12(4):282-9.
Michael DeRan, Jiayi Yang, Che-Hung Shen, Eric C. Peters, Julien Fitamant, Puiyee Chan, Mindy Hsieh, Shunying Zhu, John M.Asara, Bin Zheng, Nabeel Bardeesy, Jun Liu, Xu Wu* “Energy Stress Regulates Hippo-YAP Signaling Involving AMPK-MediatedRegulation of Angiomotin-like 1 Protein” Cell Reports 2014, 9(2), 495-503.
Baohui Zheng, Michael DeRan, Xinyan Li, Xuebin Liao, Masaki Fukata, and Xu Wu* “2-Bromopalmitate Analogues as Activity-Based Probes To Explore Palmitoyl Acyltransferases” J. Am. Chem. Soc., 2013, 135(19), 7082-5.
Publications:
Harvard University12 Oxford StreetDepartment of Chemistry and Chemical BiologyCambridge, MA 02138
SunneyMallinckrodt Professor of Chemistry and Chemical Biology
Recently we have taken the single-molecule experiment to live cells and have begun real-time imaging of gene expression, both at thetranscriptional and translational level. To accomplish this, we have developed several strategies to achieve single-molecule sensitivitywith high specificity, millisecond time resolution, and nanometer precision in a living cell. We have observed protein being generatedone molecule at a time in E. coli cells, and studied how a transcription factor binds to DNA and regulates gene expression. We foundthat a single-molecule event can be solely responsible for the life changing decision of a cell.Finally, we continue to push for state-of-the-art techniques for imaging intracellular dynamics. Our group has led in the rapiddevelopment of coherent anti-Stokes Raman scattering (CARS) microscopy, which allows imaging of live cells and organisms basedon vibrational spectroscopy. This allows noninvasive imaging of small molecules, such as metabolites and drugs, without theintroduction of natural or artificial fluorophores. Meanwhile, CARS is becoming a powerful imaging method for biomedicine. Forexample, it enables imaging of skin at the video rate, mapping the distribution of lipids, water and drug molecules, as well as braintissue with the ability to identify brain tumors.We are in a new era, when biology is becoming a data-rich and quantitative science with a wealth of physical and chemical tools. Ourgroup is thrilled to be able to make both scientific and technological contributions to the biomedical field at this exciting time.
Email:
Lab Members: Greater than 20
617-496-9925
Tel:
http://bernstein.harvard.edu/
Xie
Lab Size:
Blainey, Paul C.; Luo, Guobin; Kou, S.C.; Mangel, Walter F.; Verdine, Gregory L.; Bagchi, Biman; Xie, X. Sunney "Nonspecificallybound proteins spin while diffusing along DNA" Nature Structural & Molecular Biology, 16, 1224-1229 (2009).
Lu, Ju; Min, Wei; Conchello, Jose-Angel; Xie, X. Sunney; Lichtman, Jeff W. "Super-Resolution Laser Scanning Microscopy throughSpatiotemporal Modulation" Nano Letters, 9, 3883-3889 (2009).
Min, Wei; Lu, Sijia; Holtom, Gary R.; Xie, X. Sunney "Triple-Resonance Coherent Anti-Stokes Raman ScatteringMicrospectroscopy" ChemPhysChem, 10, 344-347 (2009).
Murugkar, S.; Evans, C.L.; Xie, X.S.; Anis, H. "Chemically specific imaging of cryptosporidium oocysts using coherent anti-StokesRaman scattering (CARS) microscopy" Journal of Microscopy, 233, 244-250 (2009).
Publications:
Yang LabDepartment of Microbiology and ImmunobiologyHarvard Medical School200 Longwood Ave
PriscillaAssociate Professor of Microbiology and Molecular Genetics.
My group’s focus has been on the study of mammalian viruses that are significant causes of morbidity and mortality in humans, inparticular hepatitis B virus (HBV), hepatitis C virus (HCV), and dengue virus. We have been especially interested in using chemicaltools to elucidate molecular mechanisms underlying the replication of viral pathogens to pioneer and validate new antiviral targets andstrategies. Current themes in my laboratory include the use of small molecules and RNAi as complementary tools to interrogate therole of specific host factors in viral replication; the use of mass spectrometry-based methods to investigate the structure and functionof specific lipids in viral replication; the use of activity-based chemoproteomic profiling to characterize virus-induced changes in thehost NTPome; exploitation of the host reactive “cysteineome” to develop irreversible, host-targeted antiviral compounds; and theinvestigation of polypharmacology as a strategy to develop more effective antivirals with higher barriers to resistance.
Email:
Lab Members: Between 5 and 10.
617-432-5416
Tel:
http://yanglab.med.harvard.edu/
Yang
Lab Size:
de Wispelaere, M., LaCroix, A., and Yang, P.L. (2013) The Small Molecules AZD0530 and Dasatinib Inhibit Dengue Virus RNAReplication via Fyn kinase. Journal of Virology, published ahead of print 24 April 2013, doi: 10.1128/JVI.00632-13. PMCID:PMC3700292.Vetter, M.L., Rodgers, M.A., Patricelli, M.P., and Yang, P.L. (2012) Chemoproteomic Profiling Identifies Changes in DNA-PK asMarkers of Early Dengue Virus Infection. ACS Chemical Biology, 7(12):2019-2026. NIHMSID # 410237, PMCID: PMC3528803.Chosen for the cover and author highlightZhang, Z., Kwiatkowski, N., Zeng, H., Lim, S.M., Gray, N.S., Zhang, W., and Yang, P.L. (2012) Leveraging kinase inhibitors todevelop small molecule tools for imaging kinases by fluorescence microscopy. Mol. BioSyst., 8(10):2523-2526. PMCID:PMC3616611. Highlighted by the journal as a HOT Articlede Wispelaere, M. and Yang, P.L. (2012) Mutagenesis of the domain I - domain III linker in the Dengue Virus envelope proteinimpairs viral particle assembly. Journal of Virology, 86(13):7072-7083. PMCID: PMC3416339.Rodgers, M.A., Villareal, V.A., Schaefer, E.A., Peng, L.F., Corey, K.E., Chung, R.T., and Yang, P.L. (2012) Lipid metaboliteprofiling identifies desmosterol metabolism as a new antiviral target for hepatitis C virus. Journal of the American Chemical Society,134(16):6896-6899. PMCID: PMC3375380.
Publications:
Harvard Medical SchoolWarren Alpert 149G200 Longwood AveBoston, MA 02115
YiProfessor of Genetics
The genomes of eukaryotic cells are organized by chromatin. Chromatin is subject to a variety of covalent modifications in bothhistones and DNA. These covalent modifications play essential roles in regulate chromatin structures and consequently impactchromatin functions, include transcription, development, cell fate reprogramming and differentiation. Deregulation of chromatinmodifications contribute to the development of various diseases including neurological diseases and cancers. Our long-term goal is toapply what we have learned in basic research to the study of human diseases.
Over the past decade, the Zhang lab has identified and characterized several classes of chromatin modifying enzymes that include (1)the ATP-dependent nucleosome-remodeling and histone deacetylase complex NuRD; (2) histone methyltransferases (eg. EZH2 andhDOT1L); (3) the JmjC-family histone demethylases; (4) histone H2A ubiquitin E3 ligase PRC1; and (5) the Ten ElevenTranslocation (Tet) family of 5-methylcytosine dioxygenases. Build upon the success of biochemical approaches, the lab has alsodeveloped the capabilities of mouse genetics, high-throughput genomics and epigenomics, single-cell transcriptomics, DNAmethylome, CRISPR-based screen and imaging, etc. The lab is currently focused on understanding the mechanism of preimplantationdevelopment, somatic cell nuclear transfer reprogramming, reward-related learning and memory, and cancer development, with aparticular emphasis on the role of dynamic chromatin modifications in the above processes.
Email:
617-713-8666
Tel:
http://zhanglab.tch.harvard.edu/lab.htm
Zhang
Lab Size:
Lu, F., Liu, Y., Inoue, A., Suzuki, T., Zhao, K., and Zhang, Y. (2016). Establishing chromatin regulatory landscape during mousepreimplantation development. Cell 165, 1375-1388.Chung, Y.G., Matoba, S., Liu, Y., Eum, J.H., Lu, F., Jiang, W., Lee, J.E., Sepilian, V., Cha, K.Y., Lee, D.R., and Zhang, Y. (2015).Histone demethylase expression enhances human somatic cell nuclear transfer efficiency and promotes derivation of pluripotent stemcells. Cell Stem Cell 17, 758-766.Wu, H., Wu, X., Shen, L., and Zhang, Y. (2014). Single-base resolution analysis of active DNA demethylation using methylase-assisted bisulfite sequencing. Nature Biotech. 32, 1231-40.Matoba, S., Liu, Y., Lu, F., Iwabuchi, K.A., Shen, L., Inoue, A., and Zhang, Y. (2014). Embryonic development following somaticcell nuclear transfer impeded by persisting histone methylation. Cell 159, 884-895.Inoue, A., and Zhang, Y. (2014). Nucleosome assembly is required for nuclear pore complex assembly in mouse zygotes. NatureSMB 21, 609-16.
Publications:
Harvard University12 Oxford StreetCambridge, MA, 02138
XiaoweiProfessor of Chemistry and Chemical Biology and of Physics
The Zhuang research lab develops and applies advanced optical imaging techniques to study the behavior of individual biologicalmolecules and complexes in vitro and in live cells.Our current research is focused on three major directions: (1) Developing super-resolution optical microscopy that allows cell andtissue imaging with molecular-scale resolution and applying this technology to cell biology and neurobiology, (2) Studying howbiomolecules function, especially how proteins and nucleic acids interact, using single-molecule imaging; (3) Developing live-cellimaging techniques and investigating virus-cell interactions using live-cell imaging.
Email:
Lab Members: Between 15 and 20
(617) 496-9558
Tel:
http://zhuang.harvard.edu/
Zhuang
Lab Size:
T. Blosser, J. Yang, M. Stone, G. Narlikar, X. Zhuang, Dynamics of nucleosome remodeling by individual ACF complexes. Nature462, 1022-1027 (2009)
E. Abbondanzieri, G. Bokinsky, J. W. Rausch, J. X. Zhang, S. F. J. Le Grice, X. Zhuang. Dynamic binding orientations direct activityof HIV reverse transcriptase. Nature 453, 184-189 (2008).
B. Huang, W. Wang, M. Bates, X. Zhuang. Three-dimensional super-resolution imaging by stochastic optical reconstructionmicroscopy. Science 319, 810-813 (2008).
M. Bates, B. Huang, G. Dempsey, X. Zhuang. Multicolor super-resolution imaging with photo-switchable fluorescent probes. Science317, 1749-1753 (2007).
M. Lakadamyali, M. J. Rust, X. Zhuang. Ligands for clathrin-mediated endocytosis are differentially sorted into distinct populationsof early endosomes. Cell 124, 997-1009 (2006).
Publications:
Children's HospitalKarp Laboratories, 7th Floor300 Longwood AvenueBoston, MA 02115
LenProfessor of Stem Cell and Regenerative BiologyGrousbeck Professor of Pediatrics
The laboratory focuses on the developmental biology of hematopoiesis and cancer. We have collected over 30 mutants affecting thehematopoietic system. Some of the mutants represent excellent animal models of human disease. We also have undertaken chemicalgenetic approach to blood development and have found that prostaglandins upregulates blood stem cells. This has led to a clinicaltrial to improve engraftment for patients receiving cord blood transplants. We recently developed suppressor screening genetics andfound that transcriptional elongation regulates blood cell fate.The laboratory has also developed zebrafish models of cancer. We have generated a melanoma model in the zebrafish system usingtransgenics. Transgenic fish get nevi, and in a combination with a p53 mutant fish develop melanomas. We recently found a histonemethyltransferase that can accelerate melanoma, and discovered a small molecule that blocks transcription elongation and suppressesmelanoma growth.
Email:
Lab Members: Greater than 20.
(617) 919-2069
Tel:
http://zon.tchlab.org/
Zon
Lab Size:
White RM, Cech J, Ratanasirintrawoot S, Lin CY, Rahls PB, Burke CJ, Langdon E, Tomlinson ML, Mosher J, Kaufman C, Chen F,Long HK, Kramer M, Datta S, Neuberg D, Granter S, Young RA, Morrison S, Wheeler GN, and Zon LI. DHODH modulatestranscriptional elongation in the neural crest and melanoma. Nature. 2011, Mar 24:471, 518-522.
Ceol CJ, Houvras Y, Jane-Valbuena J, Bilodeau S, Orlando DA, Battisti V, Fritsch L, Lin WM, Hollmann TJ, Ferre F, Bourque C,Burke C, Turner L, Uong A, Johnson LA, Beroukhim R, Mermel CH, Loda M, Slimane A-S-A, Garraway L, Young RA, and Zon LI.The histone methyltransferase SETDB1 is currently amplified in melanoma and accelerates its onset. Nature, 2011, Mar 24:471, 513-517.
Bai X, Kim J, Yang Z, Jurynec M, Lee J, LeBlanc J, Sessa A, Jiang H, Grunwald DJ, Lin S, Orkin SH, Zon LI. TIF1 controlserythroid cell fate by regulating transcriptional elongation. Cell, 2010 Jul 9;142(1):133-143. (PMC code pending)
North TE, Goessling W, Peeters M, Li P, Lord AM, Dzierzak E, and Zon LI. Hematopoietic stem cell development is dependent onblood flow and nitric oxide signaling. Cell, 2009, 137(4):736-748. PMC 2722870
Publications: