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Graduate Application Requirements
Application requirements.
Applications are managed by the Harvard Griffin GSAS Office of Admissions, and become available in September. Admission is for the fall term only. Please note all supporting materials and required components must be submitted electronically as part of the application. Harvard Griffin GSAS does not accept materials in any other way.
- Application
- Statement of Purpose
- Letters of Recommendation
- Transcripts
- Recommended Coursework
- English Proficiency
- Application Fee
1. APPLICATION
Applications are submitted through the Harvard Griffin GSAS Applicant Portal and will become available in September 2024. You can access the application by clicking the apply button on the apply page . Please note all supporting materials and required components must be submitted electronically as part of the application. No materials will be accepted in any other way. The application includes biographical and academic information, an abstract of all courses, and a statement of purpose. Although the abstract of courses may duplicate information available on your transcript(s), it is essential that the admissions committee receive this orderly summary of your courses.
2. STATEMENT OF PURPOSE
Describe your reasons and motivations for pursuing a graduate degree in your chosen degree program, noting the experiences that shaped your research ambitions, indicating briefly your career objectives and concisely stating your past work in your intended field of study and in related fields. Your statement should not exceed 1,000 words.
In addition to the above guidance, your statement of purpose should also address the following questions:
- The focus of this question should be a discovery in which you had substantial engagement and personal impact on the research. Do not reference a large group project simply because it was interesting.
- If you have not had significant research experience, please describe a scientific discovery that motivated you to pursue research.
- Using simple language, describe what you or others did, why, and what it means.
- Molecular Mechanism
- Cell and Developmental Biology
- Molecular Ecology and Evolution
- Choose two MCO faculty members that you are interested to work with and explain why using a specific example from their published work.
3. LETTERS OF RECOMMENDATION
Submit a minimum of three letters of recommendation from professors or others qualified to evaluate your potential for graduate study. At least one letter should be from a faculty member at the last school you attended as a full-time student unless you have been out of school for more than five years. Substitutions for faculty recommendations may include work associates or others who can comment on your academic potential for graduate work. Indicate on the recommendation form whether you are waiving your right to see the letter of recommendation.
Please note that your letters must be received by the application deadline in order for your application to be evaluated by the Admissions Committee. Please note that recommenders must submit their letters through the recommender portal: letters submitted any other way will not be accepted.
4. TRANSCRIPTS
Applicants are required to upload transcripts from each institution attended as part of their application. We do not accept mailed or email transcripts during the application submission and review process. Any transcripts sent in this manner will be discarded.
Official transcripts are only required from those who have been admitted and accepted the offer of admission. Instructions for submitting official transcripts will be provided in spring/summer prior to enrollment.
Transcripts from international institutions must be in English or be accompanied by a certified English translation. All translations must be literal and complete versions of the original records. International transcripts should include:
- Courses, seminars, and examinations taken
- Grades, scores, and grading scales
- Confirmation of degree conferral and date
Students who are unsure of the U.S. equivalency of their degree(s) should consult a reputable credential evaluation service.
The University reserves the right to request additional academic documents.
5. RECOMMENDED COURSEWORK
Entering students should have a record of introductory courses in chemistry, biology, physics, and mathematics. While the following courses should not be regarded as prerequisites for admission to graduate study, most admitted students have completed these courses as undergraduates:
- Biology (at least one general course in biology and two terms of biology at a more advanced level)
- Biochemistry
- Organic Chemistry
- Physical Chemistry
- Physics (a general course)
- Mathematics (a basic knowledge of differential and integral calculus). Competence in elementary programming is also desirable.
- Laboratory in Biology, Biochemistry, or Instrumental Analysis.
6. ENGLISH PROFICIENCY
Adequate command of spoken and written English is essential to success in graduate study at Harvard. Applicants who are non-native English speakers can demonstrate English proficiency in one of three ways:
- Receiving an undergraduate degree from an academic institution where English is the primary language of instruction.
- Earning a minimum score of 100 on the internet based test (iBT) of the Test of English as a Foreign Language (TOEFL)*
- Earning a minimum score of 7 on the International English Language Testing System (IELTS) Academic test.*
Please refer to all policies and instructions regarding English proficiency on the Griffin GSAS Admissions website .
7. APPLICATION FEE
The application fee is $105 payable by credit card. Harvard Griffin GSAS is committed to ensuring that our fee does not create a financial obstacle. Applicants can determine eligibility for a fee waiver by completing a series of questions in the Application Fee section of the application. Once these questions have been answered, the application system will provide an immediate response regarding fee waiver eligibility. The application fee is not refundable
Please note that GRE scores are no longer accepted.
Application Questions : [email protected]
Phone Hours: Monday and Wednesday through Friday, 9:00 a.m. — 12:00 p.m. Eastern Time Tuesday, 2:00 p.m. — 5:00 p.m. Eastern Time 617-496-6100
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Prospective Students
Ccb is committed to enrolling students from groups underrepresented in graduate study. for advice about applying, including how to prepare a competitive application, check out the diversity at gsas page. .
Harvard’s policy is to make decisions concerning applicants on the basis of what each individual can contribute to the University’s educational objectives and institutional needs. The University does not discriminate on the basis of race, color, sex, sexual orientation, religion, age, national origin, political beliefs, veteran status, or disability unrelated to job or course of study requirements. Immigration status does not factor into decisions about admissions and financial aid. For more information, see Undocumented at Harvard .
Our diversity webpage outlines the core values we rely on to guide our actions and create an inclusive departmental culture.
Our degree programs
We offer two distinct graduate degrees in Chemistry and Chemical Biology and Chemical Physics . Both programs take an average of 5 to 6 years to complete.
Course Requirements
Chemistry and Chemical Biology Ph.D. candidates must pass four advanced courses in chemistry and/or related fields (e.g. biochemistry, physics, etc.). Chemical Physics Ph.D. candidates must pass four advanced courses in chemistry and/or related fields (e.g. biochemistry, physics, etc.).
Check out our course requirements page to learn more about the specific requirements for each program and take a look at the graphic below for a general timeline of what you'll need to accomplish in which year of your Ph.D.
Tuition and Fees
The department covers the cost of tuition for all PhD students. Learn more on our graduate student financial support page. CCB provides a stipend of $49,000 (plus $1,000 to cover additional student expenses like enrolling in dental coverage) to all students in good standing.
Required Tests
Anyone who did not graduate from a 4 year undergraduate institution where English is the first language, must submit either the TOEFL or IELTS.
Submission of the general GRE test scores is required. The chemistry subject test is optional.
Application
The Graduate School of Arts and Sciences facilitates the application submission process for both the Chemistry and Chemical Physics PhD programs.
The application deadline is December 1st . The department announces admissions decisions in February and invites accepted students to an official visit during March. We typically host an admitted student visit in either late February or early March.
GSAS at a Glance
- Degree candidates: 4,814 (4,521 PhD candidates; 293 master’s candidates)
- Degree programs: 59
- 47 percent of GSAS students are women
- 34 percent of GSAS students are international
- 12 percent of GSAS students are underrepresented minorities
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Prospective students, current graduate students, ccb admissions contact.
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Fitness, Physics, and Fighting Pathogens
Vaibhav Mohanty, MD-PhD student
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Vaibhav Mohanty is an MD-PhD student in the Department of Chemistry and Chemical Biology who studies how theoretical physics and evolutionary biology can be combined to fight disease. Mohanty discusses his research, his academic pathway from Harvard to Oxford and back, and how he is making memories—and music—at Harvard Griffin GSAS.
Peaks and Plateaus
We usually think of evolution as a slow process that takes thousands of years, but in reality, all of us are affected by it daily. Viruses, bacteria, and even certain kinds of cancers rapidly accumulate mutations to try to escape our immune system. During the COVID-19 pandemic, for instance, the virus spread very quickly, mutating along the way and creating many different strains.
People also often associate evolution with “survival of the fittest.” If viruses were simply becoming fitter and fitter over time, then once a virus population reached “peak” fitness, it would stop evolving and the immune system would find a way to kill the viruses once and for all. But evolution isn’t just driven by survival of the fittest. What viruses do instead is hedge their bets between crowding up around sharp peaks and spreading out over “plateaus” of fitness. When the immune system comes around, it’s more like trying to play whack-a-mole than taking out all the viruses at once, and some of the virus strains can escape, leading to new waves of infection.
This analogy of peaks and plateaus of fitness describes how physicists and theoretical chemists think about evolutionary fitness landscapes, which are used to visualize the relationship between genes and reproductive success. Connections and analogies between fitness landscapes and other systems in physics, such as magnetic systems and spin glasses, make it easier to translate the math from the physical sciences to biology.
Here at Harvard, my goal is to make this physics-based perspective on evolution practically useful for treating disease. For example, if these viruses spread around a fitness plateau, can we build a fence around it through new vaccination strategies designed to trap the evolving population? Right now, I am trying to build what I call “mutational traps” for these diseases using the tools of computational chemistry and theoretical physics to try to slow down evolution, so our immune systems have the opportunity to adapt to the disease.
This is not my first time at Harvard Griffin GSAS. I was an undergraduate student in the joint AB/AM program working in the same department I’m in now, albeit on very different problems involving quantum mechanics in graphene (a material made of a one-atom-thick layer of carbon atoms arranged in a honeycomb pattern). It was my time in that program that confirmed my plans to pursue an MD-PhD. In my senior year at the College, I won a Marshall Scholarship and went to Oxford in 2019 for a PhD in theoretical physics. That’s where I started working on this overlap with evolutionary biology, which suddenly became relevant when the pandemic broke out in 2020. I finished my dissertation in 2021 and returned to Harvard to join the Harvard/MIT MD-PhD Program.
During my clinical rotations, I saw firsthand the impacts of infectious disease and cancer. The sheer number of people affected by rapidly evolving diseases is astoundingly high. The desire to prevent and treat them is what drives my research and clinical goals. The joint MD-PhD training has provided a bridge between my background in theoretical physics and its practical application in the field of medicine.
Making Memories, Making Music
I lived in Quincy House when I was an undergraduate at Harvard. Now that I’m at the Medical School and Harvard Griffin GSAS, I’ve returned to Quincy as a resident tutor. I hoped that I could join the staff there if I came back for graduate school, and it has been really rewarding to be a part of the Quincy community again. It’s a chance to give back to the house that gave me so much as an undergraduate student.
Most of the tutors are fellow Harvard Griffin GSAS students, and we’ve made amazing memories supporting the undergraduates and participating in Quincy House life. It’s exciting to be there for students as an advisor and to help them apply to graduate school and fellowships. This is my first year as a PhD student, but I’ve already made so many great friends and memories with my cohort. As a composer and jazz pianist and saxophonist, I’ve especially enjoyed making music with my graduate school peers.
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Other physics-related phd track programs, biophysics .
The primary objective of the program is to educate and train individuals with background in physical or quantititative science, especially chemistry, physics, computer science, or mathematics, to apply the concepts and methods of the physical sciences to the solution of biological problems. Owing to the interdepartmental nature of the program, a student's research options are increased greatly. Research programs may be pursued in any of the departments or hospitals mentioned.
Molecules, Cells and Organisms (MCO)
MCO is an innovative doctoral program that trains future leaders of scientific research in all areas of modern biology. MCO hosts faculty members from five departments on Harvard University's Cambridge campus - Molecular and Cellular Biology, Organismic and Evolutionary Biology, Chemistry and Chemical Biology, Stem Cell and Regenerative Biology, and Physics.
Applied Physics John A. Paulson School of Engineering and Applied Sciences (SEAS)
Applied Physics at Harvard School of Engineering is at the intersection of physics and engineering. Applied physicists explore the phenomena that become the foundation of quantum and photonic devices and novel materials. They also study the fundamentals of complex systems, including living organisms. Applied physicists are problem solvers by nature, and our PhDs find employment not only in academia but also in non-profits and industry, including startups.
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Dr. Charles Hong named Department of Medicine chairOctober 17, 2023  Yet here is Detroit native Charles (aka “Chaz”) Hong, after earning multiple degrees from MIT and Yale and teaching medicine at Harvard, Vanderbilt, and the University of Maryland, back in Michigan as chair of the College of Human Medicine’s Department of Medicine. “I never imagined I’d be coming back to Michigan,” said Hong, MD, PhD. “I’m not coming here for a homecoming. I came here because of Michigan State. It has an extraordinarily deep and broad base of fundamental research with equity woven into the fabric of everything we do. The opportunity to really make an impact is what attracted me here.” Hong assumed the job in September after what Dean Aron Sousa described as “a national search yielding a remarkably strong pool.” "One of the most impressive parts of Hong’s experience is his dedicated work as a mentor of students, residents, fellows, post-docs, and faculty,” Sousa wrote. After growing up in the Detroit area, Hong earned his bachelor’s degree at MIT followed by an MD and PhD at Yale School of Medicine and a cardiology fellowship at Massachusetts General Hospital. He completed a research fellowship in chemical biology at Harvard Medical School, where he also taught before joining the faculty at the Vanderbilt University School of Medicine. Immediately before joining Michigan State, he was Melvin Sharoky Professor and co-chief of cardiovascular medicine at the University of Maryland School of Medicine. Hong’s research combines chemical biology, cell and molecular biology, stem cell biology, genetics, and cardiology. His work has led to a possible treatment for glioblastoma, an aggressive form of brain cancer. Hong described his vision for the Department of Medicine as similar to the “Medici Effect,” the idea that creative sparks and disruptive innovations occur when talented people of diverse backgrounds come together. In addition to chairing the department, he will mentor clinician scientists through MSU’s partnership with Henry Ford Health. “The opportunity exists for me to make it (the Department of Medicine) into a translational powerhouse in conjunction with our clinical partners,” quickly bringing new treatments from the lab to patients, Hong said. “We want to make the Department of Medicine into a biomedical equivalent of Renaissance Florence. We want to be at the heart of all these intersections between scientists, clinicians and entrepreneurs to make Michigan State a dynamic innovator of academic medicine. “It’s a big task,” he said, but added: “I’m totally excited about this.” See More about the Department of Medicine 2024-2025 MSTP Student DirectoryA-B C-D E-F G-H I-J K-L M-N O-P Q-R S-T U-V W-X Y-Z  Aiduk, Michael/GS4 Email: [email protected] Alma Mater: Syracuse University Research Interests: Pediatric cancer, CRISPR technologies, Genetics PhD Department/Program: Molecular Cancer Biology Mentor: Kris Wood, PhD  Alway, Emily/GS4 Email: [email protected] Alma Mater: Johns Hopkins Research Interests: The role of environmental factors in neuropsychiatric illness progression PhD Department/Program: Neurobiology Mentor: Diego Bohorquez, PhD  Anderson, Preston/GS5 Email: [email protected] Alma Mater: University of Iowa Research Interests: Investigating Airway Stem Cell Biology and Progression of Lung Cancer PhD Department/Program: Biochemistry Mentor: Sudarshan K Rajagopal, MD, PhD  Beaman, Mary Makenzie/MS4 Email : [email protected] Alma Mater: Vanderbilt University Research Interests: Cancer genetics and precision medicine PhD Department/Program: University Program in Genetics and Genomics Mentor: Greg Crawford  Behrer, Christopher/GS6 Email: [email protected] Alma Mater: Harvard University Research Interests: Health Policy, economics, and global health, specifically public, labor and development economics applications to health care markets PhD Department/Program: Sanford School of Public Policy Mentor: Manoj Mohanan, PhD  Bidzimou, Minu/GS5 Email: [email protected] Alma Mater : Grinnell College Research Interests: Therapeutic discovery and development PhD Department/Program: Cell Biology Mentor: Andrew Landstrom, MD, PhD  Blackmer, Jane/GS3 Email: [email protected] Alma Mater: Tufts University Research Interests: Genome Instability, Molecular Genetics and Cancer PhD Department/Program: Molecular Cancer Biology Mentor: Don Fox, PhD  Brown, Erin/MS2 Email: [email protected] Alma Mater: Duke University Research Interests: Infectious disease, immunology, host-pathogen interactions, vaccinology PhD Department/Program: Mentor:  Burner, Danielle/GS3 Email: [email protected] Alma Mater: University of California - San Diego Research Interests: Urology, oncology and regenerative medicine PhD Department/Program: Molecular Cancer Biology Mentor : Micha Luftig, PhD  Cano, Reuben Ryan/GS2 Email: [email protected] Alma Mater: The University of Utah Research Interests: Immunology, Functional Genomics PhD Department/Program: Mentor:  Castellano, Steven/LOA Email: [email protected] Alma Mater: Columbia University Research Interests: Neuroscience and Biophysics PhD Department/Program: External PhD, NIH Oxford/Cambridge Scholars Program  Chen, Reed/MS1 Email: [email protected] Alma Mater: Duke University Research Interests: PhD Department/Program: Mentor:  Chen, Reid/MS1 Email: [email protected] Alma Mater: Duke University Research Interests: PhD Department/Program: Mentor:  Chew, Lindsey/GS5 Email: [email protected] Alma Mater: University of Arizona Research Interests: Visual neuroscience and the molecular basis of ophthalmological conditions that cause visual impairment PhD Department/Program: Mentor: Catherine Bowes-Rickman, PhD  Chakraborty, Nishma/MS2 Email: [email protected] Alma Mater: University of California - Los Angeles Research Interests: Cancer cell metabolism and signaling pathways in cancer PhD Department/Program: Mentor:  Chung, David/MS2 Email: [email protected] Alma Mater: University of California - Los Angeles Research Interests: Computational and Systems Neuroscience PhD Department/Program: Mentor:  Corredera-Wells, Kayla/MS1 Email: [email protected] Alma Mater: Duke University Research Interests: PhD Department/Program: Mentor:  Dalapati, Trisha/GS4 Email: [email protected] Alma Mater: University of Georgia Research Interests: Infectious diseases and immunology, maternal-fetal interactions PhD Department/Program: Molecular genetics and Microbiology Mentor: Dennis Ko, MD, PhD  Dale, Jahrane/GS5 Email: [email protected] Alma Mater: Columbia University Research Interests: Biomedical Engineering, Neuroscience PhD Department/Program: Biomedical Engineering Mentor: Warren Grill, PhD  D'Anniballe, Vincent/GS1 Email: [email protected] Alma Mater: Xavier University Research Interests: Initiation and modulation of adaptive immune responses PhD Department/Program: Mentor:  De Albuquerque, Daniela /GS6 Email: [email protected] Alma Mater: Duke University Research Interest s: Computational Neuroscience/Neuroengineering, Machine learning applications to imaging, bioinformatics and genomics PhD Department/Program: Electrical and Computer Engineering Mentor: John Pearson, PhD  Delaney, Christopher /GS6 Email: [email protected] Alma Mater : University of Chicago Research Interests: Molecular Genetics and Cancer Biology PhD Department/Program : Molecular Cancer Biology Mentor: Kris Wood, PhD  DiPalma, Devon/GS5 Email: [email protected] Alma Mater: Duke University Research Interests: Immunology and Cell Biology PhD Department/Program: Integrative Immunobiology Mentor: Mari Shinohara, PhD  Finlay, John (Jack)/MS4 Email: [email protected] Alma Mater: Princeton University Research Interests: Neural Stem Cell Biology and Cancer Biology PhD Department/Program: Cell and Molecular Biology Mentor: Bradley Goldstein, MD, PhD  Frye, William/MS1 Email: [email protected] Alma Mater: University of Louisville Research Interests: PhD Department/Program: Mentor:  Gerlus, Nimesha/GS4 Email: [email protected] Alma Mater: Brown University Research Interests: Cognitive and systems neuroscience PhD Department/Program: Psychology and Neuroscience Mentor: Kevin LaBar, PhD  Gilles, Casey/MS1 Email: [email protected] Alma Mater: University of California - Los Angeles Research Interests: PhD Department/Program: Mentor:  Granger, Abra/MS1 Email: [email protected] Alma Mater: University of Richmond Research Interests: PhD Department/Program: Mentor:  Haarer, Elena/MS2 Email: [email protected] Alma Mater: University of Connecticut Research Interests: Targeted therapy, epigenetics, and genomic instability in cancer PhD Department/Program: Mentor:  Heo, Helen/GS2 Email: [email protected] Alma Mater: University of Wisconsin - Madison Research Interests: Neurobiology, Stem Cells and Regenerative Medicine PhD Department/Program: Cell and Molecular Biology Mentor: Cagla Eroglu, PhD  Herche, Jesse/MS4 Email: [email protected] Alma Mater: University of the Pacific Research Interests: Neural Sound Processing PhD Department/Program: Neurobiology Mentor: Jennifer Groh, PhD  Huang, Ouwen/LOA Email: [email protected] Alma Mater: Duke University Research Interests: Health informatics, machine learning, computer vision, and natural language processing PhD Department/Program: Biomedical Engineering Mentor: Mark L Palmeri, MD, PhD  Jeffs, Sydney/GS4 Email: [email protected] Alma Mater: Duke University Research Interests: Biomedical Engineering, Immunology and Cell Biology PhD Department/Program: Biomedical Engineering Mentor: Tatiana Segura, PhD  Karpurapu, Anish/GS1 Email: [email protected] Alma Mater: Duke University Research Interests: Biomedical engineering, data science. PhD Department/Program: Mentor:  Killarney, Shane/MS4 Email: [email protected] Alma Mater: University of Nevada- Las Vegas Research Interests: Pharmacology and Cancer Biology PhD Department/Program: Molecular Cancer Biology Mentor: Kris Wood, PhD  Labib, David/GS1 Email: [email protected] Alma Mater: Cornell University Research Interests: Neurobiology; developmental and cell biology; neuro-immune interactions PhD Department/Program: Mentor:  Lai, Austin/GS1 Email: [email protected] Alma Mater: Emory University Research Interests: Genetics and mechanisms of rare diseases, biotechnology development PhD Department/Program:  LaRosa, Alexis/MS2 Email: [email protected] Alma Mater: Tulane University Research Interests: Genomic instability, molecular genetics, repetitive and non-coding sequences PhD Department/Program: Mentor:  Larson, Travis/GS2 Email: [email protected] Alma Mater: University of Iowa Research Interests: Biomedical Engineering, Neuroscience PhD Department/Program: Neurobiology Mentor: Marty Woldorff, PhD  Lawrence, Elijah/GS1 Email: [email protected] Alma Mater: University of California - 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Ann Arbor Research Interests: PhD Department/Program: Mentor:  Scherba, Jacob/GS4 Email: [email protected] Alma Mater: Harvard University Research Interests: Designing biologically inspired materials and devices to instruct tissue behavior, particularly in modulating stem cell differentiation and stimulating angiogenesis PhD Department/Program: Biomedical Engineering Mentor: Nenad Bursac, PhD  Seas, Andreas/GS6 Email: [email protected] Alma Mater: University of Maryland Research Interests: Biomedical engineering and data science with applications in surgery. 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CHARMed collaboration creates a potent therapy candidate for fatal prion diseasesPress contact :.  Previous image Next image Drug development is typically slow: The pipeline from basic research discoveries that provide the basis for a new drug to clinical trials and then production of a widely available medicine can take decades. But decades can feel impossibly far off to someone who currently has a fatal disease. Broad Institute of MIT and Harvard Senior Group Leader Sonia Vallabh is acutely aware of that race against time, because the topic of her research is a neurodegenerative and ultimately fatal disease — fatal familial insomnia, a type of prion disease — that she will almost certainly develop as she ages. Vallabh and her husband, Eric Minikel, switched careers and became researchers after they learned that Vallabh carries a disease-causing version of the prion protein gene and that there is no effective therapy for fatal prion diseases. The two now run a lab at the Broad Institute, where they are working to develop drugs that can prevent and treat these diseases, and their deadline for success is not based on grant cycles or academic expectations but on the ticking time bomb in Vallabh’s genetic code. That is why Vallabh was excited to discover, when she entered into a collaboration with Whitehead Institute for Biomedical Research member Jonathan Weissman, that Weissman’s group likes to work at full throttle. In less than two years, Weissman, Vallabh, and their collaborators have developed a set of molecular tools called CHARMs that can turn off disease-causing genes such as the prion protein gene — as well as, potentially, genes coding for many other proteins implicated in neurodegenerative and other diseases — and they are refining those tools to be good candidates for use in human patients. Although the tools still have many hurdles to pass before the researchers will know if they work as therapeutics, the team is encouraged by the speed with which they have developed the technology thus far. “The spirit of the collaboration since the beginning has been that there was no waiting on formality,” Vallabh says. “As soon as we realized our mutual excitement to do this, everything was off to the races.” Co-corresponding authors Weissman and Vallabh and co-first authors Edwin Neumann, a graduate student in Weissman’s lab, and Tessa Bertozzi, a postdoc in Weissman’s lab, describe CHARM — which stands for Coupled Histone tail for Autoinhibition Release of Methyltransferase — in a paper published today in the journal Science . “With the Whitehead and Broad Institutes right next door to each other, I don’t think there’s any better place than this for a group of motivated people to move quickly and flexibly in the pursuit of academic science and medical technology,” says Weissman, who is also a professor of biology at MIT and a Howard Hughes Medical Institute Investigator. “CHARMs are an elegant solution to the problem of silencing disease genes, and they have the potential to have an important position in the future of genetic medicines.” To treat a genetic disease, target the gene Prion disease, which leads to swift neurodegeneration and death, is caused by the presence of misshapen versions of the prion protein. These cause a cascade effect in the brain: the faulty prion proteins deform other proteins, and together these proteins not only stop functioning properly but also form toxic aggregates that kill neurons. The most famous type of prion disease, known colloquially as mad cow disease, is infectious, but other forms of prion disease can occur spontaneously or be caused by faulty prion protein genes. Most conventional drugs work by targeting a protein. CHARMs, however, work further upstream, turning off the gene that codes for the faulty protein so that the protein never gets made in the first place. CHARMs do this by epigenetic editing, in which a chemical tag gets added to DNA in order to turn off or silence a target gene. Unlike gene editing, epigenetic editing does not modify the underlying DNA — the gene itself remains intact. However, like gene editing, epigenetic editing is stable, meaning that a gene switched off by CHARM should remain off. This would mean patients would only have to take CHARM once, as opposed to protein-targeting medications that must be taken regularly as the cells’ protein levels replenish. Research in animals suggests that the prion protein isn’t necessary in a healthy adult, and that in cases of disease, removing the protein improves or even eliminates disease symptoms. In a person who hasn’t yet developed symptoms, removing the protein should prevent disease altogether. In other words, epigenetic editing could be an effective approach for treating genetic diseases such as inherited prion diseases. The challenge is creating a new type of therapy. Fortunately, the team had a good template for CHARM: a research tool called CRISPRoff that Weissman’s group previously developed for silencing genes. CRISPRoff uses building blocks from CRISPR gene editing technology, including the guide protein Cas9 that directs the tool to the target gene. CRISPRoff silences the targeted gene by adding methyl groups, chemical tags that prevent the gene from being transcribed, or read into RNA, and so from being expressed as protein. When the researchers tested CRISPRoff’s ability to silence the prion protein gene, they found that it was effective and stable. Several of its properties, though, prevented CRISPRoff from being a good candidate for a therapy. The researchers’ goal was to create a tool based on CRISPRoff that was just as potent but also safe for use in humans, small enough to deliver to the brain, and designed to minimize the risk of silencing the wrong genes or causing side effects. From research tool to drug candidate Led by Neumann and Bertozzi, the researchers began engineering and applying their new epigenome editor. The first problem that they had to tackle was size, because the editor needs to be small enough to be packaged and delivered to specific cells in the body. Delivering genes into the human brain is challenging; many clinical trials have used adeno-associated viruses (AAVs) as gene-delivery vehicles, but these are small and can only contain a small amount of genetic code. CRISPRoff is way too big; the code for Cas9 alone takes up most of the available space. The Weissman lab researchers decided to replace Cas9 with a much smaller zinc finger protein (ZFP). Like Cas9, ZFPs can serve as guide proteins to direct the tool to a target site in DNA. ZFPs are also common in human cells, meaning they are less likely to trigger an immune response against themselves than the bacterial Cas9. Next, the researchers had to design the part of the tool that would silence the prion protein gene. At first, they used part of a methyltransferase, a molecule that adds methyl groups to DNA, called DNMT3A. However, in the particular configuration needed for the tool, the molecule was toxic to the cell. The researchers focused on a different solution: Instead of delivering outside DNMT3A as part of the therapy, the tool is able to recruit the cell’s own DNMT3A to the prion protein gene. This freed up precious space inside of the AAV vector and prevented toxicity. The researchers also needed to activate DNMT3A. In the cell, DNMT3A is usually inactive until it interacts with certain partner molecules. This default inactivity prevents accidental methylation of genes that need to remain turned on. Neumann came up with an ingenious way around this by combining sections of DNMT3A’s partner molecules and connecting these to ZFPs that bring them to the prion protein gene. When the cell’s DNMT3A comes across this combination of parts, it activates, silencing the gene. “From the perspectives of both toxicity and size, it made sense to recruit the machinery that the cell already has; it was a much simpler, more elegant solution,” Neumann says. “Cells are already using methyltransferases all of the time, and we’re essentially just tricking them into turning off a gene that they would normally leave turned on.” Testing in mice showed that ZFP-guided CHARMs could eliminate more than 80 percent of the prion protein in the brain, while previous research has shown that as little as 21 percent elimination can improve symptoms. Once the researchers knew that they had a potent gene silencer, they turned to the problem of off-target effects. The genetic code for a CHARM that gets delivered to a cell will keep producing copies of the CHARM indefinitely. However, after the prion protein gene is switched off, there is no benefit to this, only more time for side effects to develop, so they tweaked the tool so that after it turns off the prion protein gene, it then turns itself off. Meanwhile, a complementary project from Broad Institute scientist and collaborator Benjamin Deverman’s lab, focused on brain-wide gene delivery and published in Science on May 17, has brought the CHARM technology one step closer to being ready for clinical trials. Although naturally occurring types of AAV have been used for gene therapy in humans before, they do not enter the adult brain efficiently, making it impossible to treat a whole-brain disease like prion disease. Tackling the delivery problem, Deverman’s group has designed an AAV vector that can get into the brain more efficiently by leveraging a pathway that naturally shuttles iron into the brain. Engineered vectors like this one make a therapy like CHARM one step closer to reality. Thanks to these creative solutions, the researchers now have a highly effective epigenetic editor that is small enough to deliver to the brain, and that appears in cell culture and animal testing to have low toxicity and limited off-target effects. “It’s been a privilege to be part of this; it’s pretty rare to go from basic research to therapeutic application in such a short amount of time,” Bertozzi says. “I think the key was forming a collaboration that took advantage of the Weissman lab’s tool-building experience, the Vallabh and Minikel lab’s deep knowledge of the disease, and the Deverman lab’s expertise in gene delivery.” Looking ahead With the major elements of the CHARM technology solved, the team is now fine-tuning their tool to make it more effective, safer, and easier to produce at scale, as will be necessary for clinical trials. They have already made the tool modular, so that its various pieces can be swapped out and future CHARMs won’t have to be programmed from scratch. CHARMs are also currently being tested as therapeutics in mice. The path from basic research to clinical trials is a long and winding one, and the researchers know that CHARMs still have a way to go before they might become a viable medical option for people with prion diseases, including Vallabh, or other diseases with similar genetic components. However, with a strong therapy design and promising laboratory results in hand, the researchers have good reason to be hopeful. They continue to work at full throttle, intent on developing their technology so that it can save patients’ lives not someday, but as soon as possible. Share this news article on:Related links.
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Co-corresponding authors Weissman and Vallabh and co-first authors Edwin Neumann, a graduate student in Weissman's lab, and Tessa Bertozzi, a postdoc in Weissman's lab, describe CHARM — which stands for Coupled Histone tail for Autoinhibition Release of Methyltransferase — in a paper published today in the journal Science.
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