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Whitehead Institute
June 5, 2020
Kristina Lopez, a first-year graduate student at the Massachusetts Institute of Technology working in Whitehead Fellow Kristin Knouse’s lab, has received the Ford Foundation Fellowship, an award designated by the National Academy of Sciences and funded by the Ford Foundation to encourage diversity in education.
Lopez, a native of the mid-size South Texas city of McAllen is the first person in her family to go to college. When she graduated from high school, she moved to Cambridge to study biology at MIT.
During her undergraduate years, Lopez worked in the lab of Angelika Amon. There she met Kristin Knouse, a graduate student at the time. When Knouse joined Whitehead Institute’s Fellows Program, Lopez joined her lab, which focuses on how mammals sense and respond to organ injury.
Now in the first year of her PhD, Lopez is interested in how the body senses liver injury. “It’s well known that the liver is the only organ in the mammalian body that has the ability to regenerate,” she says. “However, it is entirely unclear how the body senses liver insufficiency in order to drive regeneration. My work aims to uncover this critical first step.”
The Ford Foundation Fellowship, which aims to increase the diversity of college and university faculties in the United States, will provide Lopez with $27,000 a year for three years of her graduate education. When she finishes her graduate work, Lopez plans to complete a postdoc and ultimately run her own research program.
“We are thrilled that the Ford Foundation has recognized Tina’s unique background and perspectives and the fearlessness, resilience, and passion with which she approaches science,” says Knouse.
Lopez is the first researcher at Whitehead Institute to receive this fellowship. “I’m very fortunate to be able to do what I love for a living,” she says. “I’m honored to receive a Ford Foundation Fellowship to support my research and look forward to using this as an opportunity to connect with other scientists who share this passion.”
Education
- PhD, 1993, MIT
- AB, 1988, Physics, Harvard
Research Summary
We study how cells ensure that proteins fold into their correct shape, as well as the role of protein misfolding in disease and normal physiology. We also build innovative tools for broadly exploring organizational principles of biological systems. These include ribosome profiling, which globally monitors protein translation, CRIPSRi/a for controlling the expression of human genes and rewiring the epigenome, and lineage tracing tools, to record the history of cells.
Awards
- Ira Herskowitz Award, Genetic Society of America, 2020
- European Molecular Biology Organization, Member, 2017
- National Academy of Sciences Award for Scientific Discovery, 2015
- American Academy of Microbiology, Fellow, 2010
- National Academy of Sciences, Member, 2009
- Raymond and Beverly Sackler International Prize in Biophysics, Tel Aviv University, 2008
- Protein Society Irving Sigal Young Investigator’s Award, 2004
- Howard Hughes Medical Institute, Assistant Investigator, 2000
- Searle Scholars Program Fellowship, 1997
- David and Lucile Packard Fellowship, 1996
June 4, 2020
Whitehead Institute announced today that the internationally renowned developmental biologist Yukiko Yamashita will join the Institute as its newest Member in September 2020. Yamashita has also been appointed a Professor of Biology at Massachusetts Institute of Technology (MIT), and will be the inaugural incumbent of the Susan Lindquist Chair for Women in Science at Whitehead Institute.
Currently, Yamashita holds multiple academic and research roles at the University of Michigan: James Playfair McMurrich Collegiate Professor of the Life Sciences; Professor of Cell and Developmental Biology; Research Professor in the Life Sciences Institute; and Director of the Michigan Life Sciences Fellows Program. She is also a Howard Hughes Medical Institute (HHMI) Investigator, and was named a MacArthur Foundation Fellow in 2011.
“Yukiko’s work has been extraordinarily creative and productive,” says David C. Page, Whitehead Institute Director and Member. “Her approach is to take curious observations that cannot easily be explained, and consider them as hints given by nature. It’s a high-risk, courageous approach to science that has led to a series of important discoveries. Her creativity and her bold vision will find a welcoming environment at Whitehead Institute.”
Yamashita’s research focuses on the process by which stem cells are renewed, in normal and diseased contexts. A balance between differentiated daughter cells and self-renewing stem cells is critical for life, and asymmetric cell division creates problems: an excess of self-renewal can lead to cancer; an excess of differentiation can deplete the stem cell pool necessary for long-term health. Yamashita seeks to understand the mechanisms underlying asymmetric stem cell division, which are now poorly understood, using Drosophila male germline stem cells (GSCs) as a model system. Among her lab’s current research focuses are the orientation of GSCs’ mitotic spindle during cell division; stem cell-specific centrosomal components and their roles in asymmetric division; and the mechanisms of non-random sister chromatid segregation. Yamashita’s research is also expanding into new territories—such as functions of satellite DNA, a little-understood constituent of the genome—prompted by curious observations made in her investigations.
“I find that pursuing the unexpected results and anomalous hints that we find in our studies is both exciting and anxiety-provoking—like riding a rollercoaster,” Yamashita says. “I look forward to sharing this experience with my new colleagues at Whitehead Institute and MIT, who are fearless in their pursuit of new and often unanticipated opportunities.”
“I am delighted that Yukiko is joining our community,” says Alan D. Grossman, Praecis Professor of Biology and Department Head at MIT. “She is remarkably creative and her passion for science and service is infectious.”
Yamashita earned both her B.S. in Biology (1994) and her Ph.D. in Biophysics (1999) from Kyoto University, where she conducted her graduate research in the lab of Mitsuhiro Yanagida. From 2001 to 2006, she did postdoctoral research in developmental biology in Margaret Fuller’s lab at Stanford University. She was appointed to the Michigan faculty in 2007 and was named an HHMI Investigator in 2014.
A prolific author and speaker, Yamashita has published more than 80 peer-reviewed studies, research review articles, and book chapters; and has delivered more than 100 invited lectures and addresses around the world. She also serves as an advisory board member for the Searle Scholars Program; as Associate Editor of Molecular Biology of the Cell; and as an editorial board member for eLife, Scientific Reports, and PLoS Biology. A committed mentor and educator, she has guided the work and career development of 32 undergraduate, graduate, and postdoctoral researchers.
In addition to being named a MacArthur Foundation Fellow, Yamashita has been a Searle Scholar and received a Keck Foundation Award. She has also received the Tsuneko and Reiji Okazaki Award from Nagoya University, the Rackham Faculty Recognition Award and the Dean’s Basic Science Research Award from University of Michigan, and the Women in Cell Biology Junior Career Recognition Award from the American Society for Cell Biology.
National Medal of Science recipient Susan Lindquist—who was a Member and former director of Whitehead Institute and a Professor of Biology at MIT—served on the Johnson & Johnson Board of Directors from 2004 to 2016. Johnson & Johnson endowed the Susan Lindquist Chair for Women in Science to honor Lindquist’s achievements as a researcher, scientific leader, mentor, and wise counselor. “We established this Chair in Sue’s name to recognize a greatly respected and beloved scientist and a passionate advocate for women in science,” says Paul Stoffels, M.D., Vice Chairman of the Executive Committee and Chief Scientific Officer, Johnson & Johnson. “Sue was a prolific scientific pioneer who changed fundamental understanding of the biology of human health. As part of the Johnson & Johnson Board of Directors, she challenged us to use science and technology in new ways to help improve the health and lives of people all around the world.”
“The Susan Lindquist Chair for Women in Science is to be held by a distinguished female scientist who is advancing biomedical research,” Page explains. “And I believe that Sue would be very proud that Yukiko Yamashita is its first incumbent.”
Picower Institute
June 1, 2020
We are free to wander but usually when we go somewhere it’s for a reason. In a new study, researchers at The Picower Institute for Learning and Memory show that as we pursue life’s prizes a region of the brain tracks our location with an especially strong predilection for the location of the reward. This pragmatic bias of the lateral septum suggests it’s a linchpin in formulating goal-directed behavior.
“It appears that the lateral septum is, in a sense, ‘prioritizing’ reward-related spatial information,” said Hannah Wirtshafter, lead author of the study in eLife and a former graduate student in the MIT lab of senior author Matthew Wilson, Sherman Fairchild Professor of Neurobiology. Wirtshafter is now a postdoc at Northwestern University.
Last year, Wirtshafter and Wilson, a professor of biology and of brain and cognitive sciences, analyzed measurements of the electrical activity of hundreds of neurons in the LS and the hippocampus, a region known for encoding many forms of memory including spatial maps, as rats navigated a maze toward a reward. In Current Biology they reported that the LS directly encodes information about the speed and acceleration of the rats as they navigated through the environment.
The new study continued this analysis, finding that while the LS dedicates a much smaller proportion of its cells to encoding location than does the hippocampus, a much larger proportion of those cells respond when the rat is proximate to where the reward lies. Moreover, as rats scurried toward the reward point and back again within the H-shaped maze, the pace of their neural activity peaked closest to those reward locations, skewing the curve of their activity in association with where they could find a chocolate treat. Finally, they found that neural activity between the hippocampus and the LS was most highly correlated among cells that represented reward locations.
“Understanding how reward information is linked to memory and space through the hippocampus is crucial for our understanding of how we learn from experience, and this finding points to the role the lateral septum may play in that process,” Wilson said.
Specifically, Wilson and Wirtshafter interpret the results of the two studies to suggest that the LS plays a key role in helping to filter and convert raw information about location, speed and acceleration coming in from regions such as the hippocampus, into more reward-specific output for regions known to guide goal-directed behavior, such as the ventral tegmental area. In the paper they discuss ways in which the hippocampus and the LS might be wired together to do so. They theorize that the LS may dedicate neurons to receiving reward-related location information from the hippocampus and may blend non-reward location information within neurons also tasked for processing other information such as motion.
“This is supported by our previous work that shows somewhat overlapping populations of place-encoding and movement-encoding LS cells,” Wirtshafter said.
Though it’s easy for most of us to take the brain’s ability to facilitate navigation for granted, scientists study it for several reasons, Wirtshafter said.
“Elucidating brain mechanisms and circuits involved in navigation, memory and planning may identify processes underlying impaired cognitive function in motor and memory diseases,” she said. “Additionally, knowledge of the principles of goal directed behavior can also be used to model context-dependent brain behavior in machine models to further contribute to artificial intelligence development.”
The National Defense Science & Engineering Graduate Fellowship Program and the JPB Foundation provided funding for the study.
An unconventional geneticist uses cryogenic electron microscopy and crystallography to understand gene expression and cell fate.
Lucy Jakub
June 1, 2020
Seychelle Vos arrived in September 2019 as the Department of Biology’s newest assistant professor. Her lab in Building 68 uses cryogenic electron microscopy (cryo-EM), X-ray crystallography, biochemistry, and genetics to study how DNA and its associated proteins are organized inside the cell. Vos received her PhD from the University of California at Berkeley and completed her postdoctoral research at the Max Planck Institute for Biophysical Chemistry in Germany. She sat down to discuss her structural biology research, and why it’s so important to understand DNA as a physical structure.
Q: Your research is on the proteins that compress DNA so it can fit inside a cellular organelle called the nucleus. How does the genome organize itself in different shapes to perform different functions in the cell, and why is this an important process for us to understand?
A: If we take all the DNA inside of one human cell and stretch it out end to end, it extends 2 meters in length. But it needs to fit into the nucleus, which is only a few microns wide. It’s essentially like stringing a fishing line from here to New Haven and trying to put it in a soccer ball. That’s not an easy thing to do. There are lots of proteins that compact the genome either by wrapping the DNA around themselves or by forming loops in the DNA.
In order to replicate DNA or transcribe it to make a protein, the cell’s molecular machinery needs to be able to access and read it. Depending on how the DNA is wrapped and organized, different genes will be more accessible than others. In a stem cell, essentially any gene can be turned on. But as cells begin to differentiate into kidney cells, liver cells, and so on, only the genes specific to those functions can be turned on. Every cell has its own set of proteins that make it special, and most of that regulation happens at the level of RNA expression.
Our lab wants to understand how DNA organization impacts gene expression at the atomic level. This gets to the crux of how a stem cell becomes a specific cell type, and what happens when those programs go wrong. Without the right kind of compaction you can have cancer phenotypes, because things get turned on that shouldn’t be, or a cell thinks it’s a stem cell again and divides really fast. Many of the proteins we study are involved either in developmental disorders or cancers. If we don’t understand their basic biology, it’s very hard to come up with reasonable ways of treating these diseases.
Q: What was it about structural biology that hooked you during your early career?
A: When I started my PhD at UC Berkeley, I didn’t have much of an interest in structural biology. I thought that I wanted to study the immunology of nucleic acids, and I did my first lab rotation with Jennifer Doudna, one of the biochemists who was instrumental in developing CRISPR-Cas9 as a gene-editing tool. She might seem like a funny first person to do a rotation with if you were doing immunology, but CRISPR is essentially a bacterial immune system, and I went to her lab just to see a completely different way of viewing immunology. During that rotation, I fell in love with crystallography. What’s so beautiful about this technique is that it shows us how different atoms are communicating with each other, and how one molecule might be engaging with another molecule.
For the rest of my rotations as a graduate student, I did research in biochemistry and structural biology labs, and ended up joining James Berger’s lab, which did a combination of both. I worked on a class of enzymes called topoisomerases that bind to DNA and uncoil the DNA when it gets tangled. I was able to solve a number of very interesting structures, and do biochemistry and genetics all at the same time.
During my postdoc I studied RNA polymerase II, the enzyme that makes all the RNAs that turn into proteins in the cell and determine the cell’s identity. I wanted to know how it is regulated after the initiation stage of transcription. One of the proteins I was working with wouldn’t crystallize, and we had to come up with some other ways of seeing it. So we turned to cryo-EM, which had just become a very high-resolution technology — we could actually see the atoms touching each other! That was a game-changer for me. If you told me at the beginning of my PhD that these technologies could become central to my research, I would have told you there’s no way that would happen. But life has surprises.
Q: How does your expertise in genetics and biochemistry help you solve structural problems?
A: I’m definitely not your average structural biologist — I use structural tools to advance the genetics I want to do. My lab uses genetics to inform which protein complexes we want to look at, and then we use cryo-EM and X-ray crystallography to understand how those proteins actually affect RNA polymerase II. With what we learn about the structure, we can go back and use targeted genetic approaches to remove those proteins from the genome and see what happens to gene expression in particular cells. I also have projects where we’ll do a genetic screen first, and then use structural biology and chemistry techniques to get more information. The research is like a giant feedback loop. You need all of those perspectives to really understand the whole system.
American Association for Cancer Research
May 28, 2020
PHILADELPHIA — The American Association for Cancer Research (AACR) is recognizing Phillip A. Sharp, PhD, Fellow of the AACR Academy and Nobel Laureate, with the 17th AACR Award for Lifetime Achievement in Cancer Research.
Sharp, an Institute professor at Massachusetts Institute of Technology’s David H. Koch Institute for Integrative Cancer Research, is being honored for his exceptional body of groundbreaking and high-impact basic research, including his seminal co-discovery of RNA splicing. For this discovery, Sharp was awarded the 1993 Nobel Prize in Physiology or Medicine, along with Sir Richard J. Roberts, PhD. This body of research fundamentally changed scientists’ understanding of the structure of genes, shaping our understanding of RNA biology and our knowledge of the genetic causes of cancer and other diseases.
“Dr. Sharp is a luminary in the fields of molecular biology and biochemistry who has dedicated his research career to advancing our understanding of the molecular biology of gene expression as it pertains to cancer and the mechanisms of RNA splicing,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “He is one of the most creative scientific thinkers of our time, always looking to push the boundaries to address the enormous challenges that cancer still poses. We are very proud to honor him with this special award.”
The AACR Award for Lifetime Achievement in Cancer Research was established in 2004 to honor individuals who have made significant fundamental contributions to cancer research, either through a single scientific discovery or a collective body of work. These contributions, whether they have been in research, leadership, or mentorship, must have had a lasting impact on the cancer field and must have demonstrated a lifetime commitment to progress against cancer.
After first describing the phenomenon of RNA splicing, Sharp’s work focused on elucidating the biochemical mechanisms of RNA splicing and mammalian transcription. Today, his research continues to enhance our understanding of RNA structure and function and has been particularly focused on defining the biology of small RNAs and other types of noncoding RNAs. Additionally, his research has led the emerging field of convergence science for many years, resulting in the generation of the first CAS9 mouse model, which has proven vital to in vivo screening experiments dedicated to identifying genes involved in metastasis. To date, Sharp’s career publications in peer-reviewed journals total more than 440.
Sharp’s scientific influence extends far beyond his research accomplishments and has informed public policies and funding decisions at the nation’s highest level. Additionally, he has been an inspiration and mentor to more than 90 postdoctoral fellows and almost 40 graduate students, many of whom are now preeminent scientists in their respective areas of expertise.
Sharp, an AACR member since 1986, was elected to the inaugural class of the Fellows of the AACR Academy in 2013 and has been Chair of the Stand Up To Cancer (SU2C) Scientific Advisory Committee for more than a decade, leading the selection of 26 “Dream Teams” of top researchers and other SU2C research groups. The AACR is the Scientific Partner of SU2C. Further he served as program chair of the AACR’s Inaugural Special Conference in 1988. That conference, “Gene Regulation and Oncogenes,” has been characterized as a watershed meeting that stimulated novel, transformative thinking about the molecular biology of cancer. Sharp has provided steadfast support for the AACR Special Conferences Program over the past three decades, and served as co-chair for the 30th Anniversary Special Conference, “Convergence: Artificial Intelligence, Big Data, and Prediction in Cancer,” in 2018. In 2006, Sharp received the AACR-Irving Weinstein Foundation Distinguished Lectureship award, and in 2010, Sharp was honored with the AACR-Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research. In 2018, Sharp was presented with the AACR’s Distinguished Service Award for Extraordinary Scientific Innovation and Exceptional Leadership in Cancer Research and Biomedical Science.
Sharp has received countless scientific awards over his brilliant career in addition to the Nobel Prize, including the Gairdner Foundation International Award (1986), the Albert Lasker Basic Medical Research Award (1988), the Louisa Gross Horwitz Prize (1988), and the 2004 National Medal of Science, among many others. He is an elected member of the National Academy of Sciences and the American Academy of Arts and Sciences. He also holds more than 18 honorary Doctor of Science degrees from institutions of higher learning around the world. Sharp has a distinguished record of public service, serving as cochair of the National Cancer Advisory Board (2000-2002) and as a member of both the President’s Council of Advisors on Science and Technology (1994-1997) and the Committee on Science, Engineering, and Public Policy (1992-1995).
Outside of his academic research, Sharp cofounded two successful biotech companies, Biogen and Alnylam, both of which have developed therapeutics including rituximab and obinutuzumab for lymphoma, natalizumab and peginterferon for multiple sclerosis, and the first small interfering RNA-based therapy for transthyretin-mediated amyloidosis.
American Association for Cancer Research
May 28, 2020
PHILADELPHIA – The American Association for Cancer Research (AACR) is recognizing Tyler Jacks, PhD, Fellow of the AACR Academy, with the 2020 AACR Princess Takamatsu Memorial Lectureship.
Jacks is director of the David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT), co-director of the Ludwig Center at MIT, and a Howard Hughes Medical Institute Investigator. He is being recognized for transforming cancer research and the development of therapeutic treatments through his remarkable advancement of genetically engineered mouse models and for his seminal discoveries related to oncogenes, tumor suppressor genes, cell death, and immune system regulation of tumor progression.
“Dr. Jacks is a highly esteemed cancer scientist, and we are delighted to recognize his exceptional body of innovative work,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “His groundbreaking research has provided deep insights into cancer initiation and progression and has led to the identification of promising new treatments for cancer patients worldwide. He is revered for his tremendous research achievements as well as for his commitment to collaborative research across the world. He is richly deserving of this prestigious accolade, which honors the life and work of Princess Takamatsu.”
The AACR Princess Takamatsu Memorial Lectureship is awarded to a scientist whose novel and significant fundamental scientific work has had or may have a far-reaching impact on the detection, diagnosis, treatment, or prevention of cancer, and who embodies the dedication of the Princess to outstanding cancer research and advances that emanate from multinational collaborations. Her Imperial Highness Princess Kikuko Takamatsu was personally instrumental in promoting progress against cancer. She became a champion of these causes following her mother’s death from bowel cancer in 1933 at the young age of 43.
Jacks is a world-renowned researcher whose career has focused on understanding the genetic events that drive the development of cancer by applying the most advanced techniques of genetic engineering to develop mouse models of disease. He and researchers in his laboratory have engineered mice to carry mutations in many genes known to be involved in human cancer, including tumor suppressor genes such as Rb; oncogenes such as K-Ras; and genes involved in oxidative stress, DNA damage and repair, and epigenetic control of gene expression. These preclinical models have since enabled researchers to further investigate the fundamental initiation and progression mechanisms of colon, lung, pancreatic, and ovarian cancers as well as astrocytomas, peripheral nervous system tumors, retinoblastoma, and soft tissue sarcomas. Furthermore, these mice have been used as essential tools for the testing of novel approaches to cancer prevention, early detection, interception, and treatment. Recently, Jacks has used new genetic engineering techniques to study additional cancer processes, including metastasis and tumor-immune cell interactions.
An active AACR member since 1994, Jacks was elected to the inaugural class of Fellows of the AACR Academy in 2013, served as AACR President from 2009 to 2010, served as a member of the AACR Board of Directors from 2001 to 2004, and is a Trustee Emeritus of the AACR Foundation. Jacks has further served the AACR as chair of the AACR Membership Development Task Force and a member of the AACR Academy Steering Committee; Science Policy and Government Affairs Committee; Cancer Prevention, Early Detection, and Interception Committee; the AACR Team Science Award Committee; and the AACR Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research Committee. Jacks was honored with the AACR Award for Outstanding Achievement in Cancer Research in 1997.
Jacks’ scientific accomplishments have been recognized with numerous honors throughout his career, including the MIT James R. Killian Jr. Faculty Achievement Award (2015), Sergio Lombroso Award in Cancer Research (2015), the Simon M. Shubitz Award (2005), the Paul Marks Prize for Cancer Research (2005), the Chestnut Hill Award for Excellence in Cancer Research (2002), and the Amgen Award (1998). In addition, Jacks is an elected Fellow of the American Academy of Arts and Sciences, member of the National Academy of Sciences, and member of the National Academy of Medicine.
Jacks received his undergraduate degree in Biology from Harvard University and completed his doctorate in Biochemistry under the tutelage of Nobel Laureate Harold Varmus at the University of California, San Francisco.
Greta Friar | Whitehead Institute
May 27, 2020
In order to understand our biology, researchers need to investigate not only what cells are doing, but also more specifically what is happening inside of cells at the level of organelles, the specialized structures that perform unique tasks to keep the cell functioning. However, most methods for analysis take place at the level of the whole cell. Because a specific organelle might make up only a fraction of an already microscopic cell’s contents, “background noise” from other cellular components can drown out useful information about the organelle being studied, such as changes in the organelle’s protein or metabolite levels in response to different conditions.
Whitehead Institute Member David Sabatini and Walter Chen, a former graduate student in Sabatini’s lab and now a pediatrics resident at Boston Children’s Hospital and Boston Medical Center and a postdoctoral researcher at Harvard Medical School, developed in recent years a method for isolating organelles for analysis that outstrips previous methods in its ability to purify organelles both rapidly and specifically. They first applied the method to mitochondria, the energy-generating organelles known as the “powerhouses of the cell,” and published their study in Cell in 2016. Subsequently, former Sabatini lab postdoctoral researcher Monther Abu-Remaileh and graduate student Gregory Wyant applied the method to lysosomes, the recycling plants of cells that break down cell parts for reuse, as described in the journal Science in 2017. In collaboration with former Sabatini lab postdoctoral researcher Kivanc Birsoy, Sabatini and Chen next developed a way to use the mitochondrial method in mice, as described in PNAS in 2019. Now, in a paper published in iScience on May 22, Sabatini, Chen, and graduate student Jordan Ray have extended the method for use on peroxisomes, organelles that play essential roles in human physiology.
“It’s gratifying to see this toolkit expand so we can use it to gain insight into the nuances of these organelles’ biology,” Sabatini says.
Using their organellar immunoprecipitation techniques, the researchers have uncovered previously unknown aspects of mitochondrial biology, including changes in metabolites during diverse states of mitochondrial function. They also uncovered new aspects of lysosomal biology, including how nutrient starvation affects the exchange of amino acids between the organelle and the rest of the cell. Their methods could help researchers gain new insights into diseases in which mitochondria or lysosomes are affected, such as mitochondrial respiratory chain disorders, lysosomal storage diseases, and Parkinson’s Disease. Now that Sabatini, Chen, and Ray have extended the method to peroxisomes, it could also be used to learn more about peroxisome-linked disorders.
DEVELOPING A POTENT METHOD
The researchers’ method is based on “organellar immunoprecipitation,” which utilizes antibodies, immune system proteins that recognize specific perceived threats that they are supposed to bind to and help remove from the body. The researchers create a custom tag for each type of organelle by taking an epitope, the section of a typical perceived threat that antibodies recognize and bind to, and fusing it to a protein that is known to localize to the membrane of the organelle of interest, so the tag will attach to the organelle. The cells containing these tagged organelles are first broken up to release all of the cell’s contents, and then put in solution with tiny magnetic beads covered in the aforementioned antibodies. The antibodies on the beads latch onto the tagged organelles. A magnet is then used to collect all of the beads and separate the bound organelles from the rest of the cellular material, while contaminants are washed away. The resulting isolated organelles can subsequently be analyzed using a variety of methods that look at the organelles’ metabolites, lipids, and proteins.
With their method, Chen and Sabatini have developed an organellar isolation technique that is both rapid and specific, qualities that prior methods have typically lacked. The workflow that Chen and Sabatini developed is fast—this new iteration for peroxisomes takes only 10 minutes to isolate the tagged organelles once they have been released from cells. Speed is important because the natural profile of the organelles’ metabolites and proteins begins to change once they are released from the cell, and the longer the process takes, the less the results will reflect the organelle’s native state.
“We’re interested in studying the metabolic contents of organelles, which can be labile over the course of an isolation,” Chen says. “Because of their speed and specificity, these methods allow us to not only better assess the original metabolic profile of a specific organelle but also study proteins that may have more transient interactions with the organelle, which is very exciting.”
PEROXISOMES TAKE THE LIMELIGHT
Peroxisomes are organelles that are important for multiple metabolic processes and contribute to a number of essential biological functions, such as producing the insulating myelin sheaths for neurons. Defects in peroxisomal function are found in various genetic disorders in children and have been implicated in neurodegenerative diseases as well. However, compared to other organelles such as mitochondria, peroxisomes are relatively understudied. Being able to get a close-up look at the contents of peroxisomes may provide insights into important and previously unappreciated biology. Importantly, in contrast to traditional ways of isolating peroxisomes, the new method that Sabatini, Chen, and Ray have developed is not only fast and specific, but also reproducible and easy to use.
“Peroxisomal biology is quite fascinating, and there are a lot of outstanding questions about how they are formed, how they mature, and what their role is in disease that hopefully this tool can help elucidate,” Ray says.
An exciting next step may be to adapt the peroxisome isolation method so it can be used in a mammaliam model organism, such as mice, something the researchers have already done with the mitochondrial version.
“Using this method in animals could be especially helpful for studying peroxisomes because peroxisomes participate in a variety of functions that are essential on an organismal rather than cellular level,” Chen says. Going forward, Chen is interested in using the method to profile the contents of peroxisomes in specific cell types across a panel of different mammalian organs.
While Chen sets out to discover what unknown biology the peroxisome isolation method can reveal, researchers in Sabatini’s lab are busy working on another project: extending the method to even more organelles.
Written by Greta Friar
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David Sabatini’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.
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Citations:
G. Jordan Ray, Elizabeth A. Boydston, Emily Shortt, Gregory A. Wyant, Sebastian Lourido, Walter W. Chen, David M. Sabatini, “A PEROXO-Tag Enables Rapid Isolation of Peroxisomes from Human Cells,” iScience, May 22, 2020.
Bayraktar et al., “MITO-Tag Mice enable rapid isolation and multimodal profiling of mitochondria from specific cell types in vivo,” PNAS, Jan 2, 2019.
Abu-Remaileh et al., “Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes,” Science, Nov 10, 2017.
Chen et al., “Absolute quantification of matrix metabolites reveals the dynamics of mitochondrial metabolism,” Cell, August 25, 2016.
Multi-institutional MassCPR initiative announces more than $16.5 million to support 62 Boston-area projects.
Mindy Blodgett | Institute for Medical Engineering and Science
May 22, 2020
As the world grapples with the continuing challenges of the Covid-19 pandemic, a multi-institutional initiative has been formed to support a broad range of research aimed at addressing the devastation to global public health, including projects by six MIT faculty.
Called the Massachusetts Consortium on Pathogen Readiness (MassCPR), and based at Harvard Medical School (HMS), it was conceived to both battle the myriad effects of SARS-CoV-2 and prepare for future health crises. Now, MassCPR has announced more than $16.5 million in funding to support 62 research projects, all with the potential for significant impact in fighting the pandemic on several fronts.
MassCPR includes scientists and clinicians from Harvard, MIT, Boston University, Tufts University, and the University of Massachusetts, as well as local biomedical research institutes, biotech companies and academic medical centers. The projects selected in the initial round of funding were based on the MassCPR’s primary scientific and clinical focus areas: the development of vaccines, therapies and diagnostic tools, clinical management, epidemiology and understanding how SARS-CoV-2 causes disease.
Of the projects selected, six are led by MIT faculty:
Lee Gehrke, the Hermann von Helmholtz Professor of Health Sciences and Technology, MIT Institute for Medical Engineering and Science (IMES), a professor at HMS and a member of the faculty at the Harvard-MIT Health Sciences and Technology program (HST), will receive funding for work to develop a “simple and direct antigen rapid test for SARS-CoV-2 infections.” A Cambridge-based startup, E25Bio, which is using technology developed by Gerhke, has been working on a paper-based test that can deliver results in under half an hour. Gehrke, the CTO of E25Bio, says that the funding will help to accelerate the final stages of producing and introducing this test into patient care. “We have been working on diagnostic tests overall for over 10 years,” Gehrke says. “We started working on a Covid test as soon as the news came of potential danger back in January.” Gehrke says that the test is “manufacturing-ready” and that they have conducted small-scale manufacturing runs with a local Massachusetts-based company that will be able to scale up once clinical tests are complete. E25Bio has submitted the test to the FDA for emergency use authorization.
Angela Belcher, head of the Department of Biological Engineering, the James Mason Crafts Professor of Biological Engineering and Materials Science and Engineering, and a member of the Marble Center for Cancer Nanomedicine at the Koch Institute for Integrative Cancer Research, will also receive support for her research proposal, “Novel nanocarbon materials for life-development of distributable textiles that filtrate/neutralize dangerous viruses/bacteria to protect medical professional and civilians from virus pandemic disease.”
Jianzhu Chen, a professor in the Department of Biology, also a member of the Koch Institute and a co-director of the Center for Infection and Immunity at the Chinese Academy of Sciences, was selected for a project focusing on “enhancing mRNA-based coronavirus vaccines with lymph node-targeted delivery and neutralizing antibody-inducing adjuvant.” Chen says that the grant will help fund proposed research aimed at devising an effective vaccine, and that the money will “help us to jumpstart our research on SARS-CoV-2,” as well as vaccines to address other pathogens.
Bruce Walker, professor of the practice at IMES and the Department of Biology, founding director of the Ragon Institute of MGH, MIT, and Harvard, and Phillip T and Susan M Ragon Professor of Medicine at Harvard Medical School, will receive support for research on “A highly networked, exosome-based SARS-CoV-2 vaccine.”
Feng Zhang’s project, “Development of a point-of-care diagnostic for COVID-19,” was also selected. Zhang is the James and Patricia Poitras Professor of Neuroscience and a professor of brain and cognitive sciences and biological engineering at MIT, and a core member of the Broad Institute of MIT and Harvard.
Siqi Zheng, the Samuel Tak Lee Associate Professor in the Department of Urban Studies and Planning and faculty director of the Center for Real Estate will receive funding for research on quantifying “the role of social distancing in shaping the Covid-19 curve: incorporating adaptive behavior and preference shifts in epidemiological models using novel big data in 344 Chinese cities.” Zheng calls the funding “crucial” in research that will compare different regions and how people react to social and physical distancing during a pandemic, and will examine various government policies aimed at controlling the spread of the virus.