Rudolf Jaenisch

Education

  • MD, 1967, University of Munich

Research Summary

We aim to understand the epigenetic regulation of gene expression in mammalian development and disease. Embryonic stem cells are important because they have the potential to generate any cell type in the body and, therefore, have great potential for regenerative medicine. We study the way somatic cells reprogram to an embryonic pluripotent state, and use patient specific pluripotent cells to study complex human diseases.

Awards

  • German Society for Biochemistry and Molecular Biology, Otto Warburg Medal, 2014
  • New York Academy, Medicine Medal, 2013
  • Franklin Institute, Benjamin Franklin Medal, 2013
  • National Science Foundation, National Medal of Science, 2011
  • National Science Foundation, National Medal of Science, 2010
  • National Academy of Sciences, Member, 2003
Susumu Tonegawa

Education

  • PhD, 1968, University of California, San Diego
  • BS, 1963, Chemistry, Kyoto University

Research Summary

We are interested in the molecular, cellular and neural circuit mechanisms underlying learning and memory in rodents. We generate genetically engineered mice, and analyze them through multiple methods including molecular and cellular biology, electrophysiology, microscopic imaging, optogenetic engineering, and behavioral studies. Ultimately, we aim to detect the effects of our manipulations at multiple levels in the brain — deducing which behaviors or cognitions are causally linked to specific processes and events taking place at the molecular, cellular, and neuronal circuit levels.

Awards

  • The Nobel Foundation, Nobel Prize in Physiology or Medicine, 1987
  • Albert and Mary Lasker Award in Basic Research, 1987
  • National Academy of Sciences, Member, 1986
Troy Littleton

Education

  • PhD, 1994, Baylor College of Medicine; MD, 1997, Baylor College of Medicine
  • BS, 1989, Biochemistry, Louisiana State University

Research Summary

Using Drosophila, we study how neurons form synaptic connections, as well as how synapses transmit information and change during learning and memory. We also investigate how alterations in neuronal signaling underlie several neurological diseases, including epilepsy, autism, and Huntington’s Disease. We hope to bridge the gap between the molecular components of the synapse and the physiological responses they mediate.

Of highways, engines, and chromosomes

Whitehead researchers unravel fundamental molecular machinery that propels chromosome movement

November 16, 2017

Each day, billions of cells in the human body undergo a vital ritual, wherein one cell divides to form two. This process, known as cell division, is as beautiful as it is essential, undergirding the body’s growth in times of both health and disease. Despite the fact that cell division (or “mitosis”) has been a basic topic in high school biology classes for the past 70 years, the mechanisms by which cells conduct this critical event remain poorly understood. In particular, there are lingering uncertainties about how chromosomes — large units of DNA that include our genes — get properly allocated so that both daughter cells receive intact, complete copies of their genetic blueprint.

“People have been watching chromosomes move, align, and segregate for more than a century — it’s such a fundamental aspect of biology,” says Iain Cheeseman, a member of the Whitehead Institute for Biomedical Research and an associate professor of biology at Massachusetts Institute of Technology. “It’s also much more elegant and complicated than we ever anticipated.”

Cheeseman and members of his Whitehead laboratory have discovered many of the molecular movers and shakers that ensure chromosomes get to the right place at the right time. These components assemble together — like the parts of an engine — to establish robust connections with chromosomes and ultimately power their movement within cells. “The most important unanswered question in the field is how do these components work together? That is, how do you build a machine that is more than the sum of its parts?” he says.

Now, in two recent papers in the journals eLife and Current Biology, Cheeseman and his colleagues help shed light on this central question.

Back to the drawing board

As recently as 15 years ago, scientists assumed that in dividing cells, chromosomes move the way many other cellular objects move — transported by tiny molecular motors. These mini-motors are specifically designed to travel along roads made from rod-like structures called microtubules. Like a car cruising on a highway, they can carry cargo over long distances. Although such microtubule-based vehicles seemed a logical suspect, when scientists inactivate them in human cells, chromosomes can still move and segregate just fine. So something else must contribute the necessary molecular muscle.

“We basically had to throw out the major hypothesis that was out there and go back to the drawing board,” says Cheeseman.

Over the last several years, he and other scientists in the field have helped develop a clearer view of how this process works and who the key players are that enable a very different type of movement. Consider a car sitting motionless on a highway. Rather than revving its own engine to generate motion, the highway itself moves, shrinking or growing while the car hangs on. “It is a radically different way of imagining this movement process,” says Cheeseman. “An important part of my lab’s mission has been to figure out how do you build a motor like that? What are the factors required and how do they act?”

Of course, the highway — or more precisely, the microtubule — must grow and shrink as needed. But even more important, there must also be an apparatus that can enable chromosomes to hold on to such a dynamic structure. As Cheeseman and his colleagues have uncovered, this coupling requires a suite of highly sophisticated molecular players.

Building an unusual machine

Cheeseman and his laboratory have focused on three key groups or complexes of proteins that play essential roles in chromosome segregation in human cells. These components assemble together to form a kind of molecular tether point on chromosomes (called the kinetochore) where microtubules attach.

Diagram of the kinetochore/microtube interface
Diagram of the kinetochore/microtube interface
Courtesy: David Kern/Whitehead Institute

Among this trio of parts, the most critical is the Ndc80 complex. “It is the major connection between the kinetochore and the microtubule,” says Cheeseman. As a postdoc, he discovered the biochemical properties that enable this Ndc80 complex to grab on to microtubules, research that sparked his lab’s quest to study the various pieces of the kinetochore machinery and how they work.

While Ndc80 forms a critical linkage, it lacks some key capabilities, like processivity — the ability to keep ahold of something while it moves. In a series of papers, one published in 2009, another in 2012, and a new one in Current Biology, Cheeseman’s team revealed that Ska1 can perform this crucial function. That is, it has the biochemical capacity to enable chromosomes to hang onto microtubules while they grow and as they shrink, an activity that it can impart to the Ndc80 complex. “These are pretty powerful properties,” says Cheeseman.

Diving even deeper into Ska1’s bag of tricks, Julie Monda and Ian Whitney, lead authors of the Current Biology paper, went on to decipher the precise molecular features that enable the complex’s dynamic capabilities, uncovering multiple surfaces that associate with microtubules and enable Ska1 to undergo something akin to molecular somersaults. These somersaults are what allow it to maintain its association with microtubules.

The third complex, Astrin-SKAP, also plays a unique role. As Cheeseman’s team described in their recent eLife paper, led by first author David Kern, it serves as a master stabilizer — like a final drop of superglue to secure everything in place. “It’s the last thing that comes in and helps lock down these interactions, so you can stabilize and maintain them,” says Cheeseman.

Uncovering its role was no easy feat. Astrin-SKAP proved to be rather temperamental biochemically, complicating Kern’s efforts to purify and manipulate it in the laboratory. Also, as he and his colleagues discovered, a tiny piece of the structure had previously gone undetected; it works alongside the rest of the complex and is required for its normal function. Perhaps the most important revelation was that Astrin-SKAP doesn’t just work alone — it also coordinates with Ndc80. “This is an important finding for how we think about these components as a whole,” saysCheeseman.

Although questions remain about how all of these parts work together and how other pieces may come into play, Cheeseman believes these studies provide an exciting start. “The first human kinetochore component wasn’t identified until 1987, when many of the other key processes in the cell had already been intensively studied,” he says. “There are so many exciting questions that are accessible now that we have these tools and knowledge.”

Now, he and his colleagues will continue to meld approaches in cell biology and biochemistry to decode the inner workings of the kinetochore. That includes understanding how the various components operate not only in individual cells, but also in multicellular organisms.

“We are currently thinking a lot about the physiological context— that is, what matters to cells and to an organism,” says Cheeseman. “The work that our lab and others have conducted over the past two decades has given us a molecular handle on this problem. I’m excited to be able to apply these finding to understanding the ways that cell division is altered in development and in disease states.”

Written by Nicole Davis
* * *
Iain Cheeseman’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also an associate professor of biology at Massachusetts Institute of Technology.
* * *
Full citations:
“Astrin-SKAP complex reconstitution reveals its kinetochore interaction with microtubule-bound Ndc80”
eLife 2017;6:e26866 August 25, 2017. DOI: 10.7554/eLife.26866
David M Kern (1,2), Julie K Monda (1,2), Kuan-Chung Su (1), Elizabeth M Wilson-Kubalek (3), and Iain M Cheeseman (1,2).
1. Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
3. Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
“Microtubule tip tracking by the spindle and kinetochore protein Ska1 requires diverse tubulin-interacting surfaces”
Current Biology, online November 16, 2017. DOI: 10.1016/j.cub.2017.10.018
Julie K. Monda (1,2,6), Ian P. Whitney (1,6), Ekaterina V. Tarasovetc (3,4), Elizabeth Wilson-Kubalek (5), Ronald A. Milligan (5), Ekaterina L. Grishchuk (3), and Iain M. Cheeseman (1,2).
1. Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
3. Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
4. Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia
5. Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
6. These authors contributed equally
Alan D. Grossman

Education

  • PhD, 1984, University of Wisconsin, Madison
  • BS, 1979, Biochemistry, Brown University

Research Summary

We use a variety of approaches to investigate several of the fundamental and conserved processes used by bacteria for propagation and growth, adaptation to stresses, and acquisition of new genes and traits via horizontal gene transfer. Our long term goals are to understand many of the molecular mechanisms and regulation underlying basic cellular processes in bacteria. Our organism of choice for these studies is usually the Gram positive bacterium Bacillus subtilis.

Our current efforts are focused in two important areas of biology: 1) The control of horizontal gene transfer, specifically the lifecycle, function, and control of integrative and conjugative elements (ICEs). These elements are widespread in bacteria and contribute greatly to the spread of antibiotic resistances between organisms. 2) Regulation of the initiation of DNA replication and the connections between replication and gene expression, with particular focus on the conserved replication initiator and transcription factor DnaA. This work is directly related to mechanisms controlling bacterial growth, survival, and stress responses.

Awards

  • National Academy of Sciences, 2014
  • American Academy of Arts and Sciences, 2008
  • American Academy of Microbiology 1998
  • Eli Lilly Company Research Award, 1997
A scientific approach to writing fiction

Megan Miranda '02 graduated from MIT intent on pursuing a career in biotechnology. Instead, she became a New York Times best-selling author.

Jay London | MIT Alumni Association
November 15, 2017

Megan Colpitts Miranda ’02, who graduated from MIT with a degree in biology, intended to pursue a career in biotechnology. Instead, she became a successful fiction author whose book, “All the Missing Girls,” is a New York Times best-seller. Both careers share a trial-and-error approach to achieving success, she believes.

“There are a lot of similarities in the process,” Miranda says. “Each book draft is an experiment where I can assess what’s working and what’s not. You start with a blank slate; then each step gets you closer to a solution.”

Miranda worked in biotech in Boston for two years after graduation before moving with her husband, Luis Miranda ’01, to North Carolina, where she spent two years as a high school science teacher.

“Teaching put me back in touch with the elements that made me initially fall in love with science,” she says. “That love of science kind of funneled into writing my first books, which all contained weird scientific elements in their plots.”

Miranda began writing full time after the birth of her two children. After a few years of proposals, rewrites, and revisions, her first book, the young-adult thriller “Fracture,” was released in 2012. Six other books quickly followed, including “Hysteria,” “Vengeance,” “Soulprint,” and “The Safest Lies.” But the one to make the biggest impact has been “All the Missing Girls,” a story about the disappearance of two young women that was named editors’ choice by The New York Times Book Review and one of The Wall Street Journal’s “5 Killer Books for 2016.”

Miranda’s most recent work, “The Perfect Stranger,” was published by Simon and Schuster this year. And her next young-adult book, “Fragments of the Lost,” is due out in early 2018.

Miranda credits the thematic elements of her young-adult books, in part, to her coursework at MIT, where she mixed bioengineering with a steady dose of anthropology and literature.

“My first books combined biology and anthropology,” she says. “They are different sides of the same interests. Biology is the science element, confirmed by process of experiment, while anthropology is the human element.”

MIT’s “fail-forward” mentality also helped lay the groundwork for her literary career. “At MIT, I learned not to fear failure,” Miranda says. “MIT is the type of place where you need self-discipline and a willingness to take risks and try a different approach. Writing is no different.”

Miranda lives near Charlotte with her husband, a senior manager at Accenture, and their 11-year-old daughter and nine-year-old son. She enjoys connecting with readers through school and library visits, and she offers Skype Q&A sessions to book clubs and classes.

This article originally appeared in the September/October 2017 issue of MIT Technology Review.

Mary Clare Beytagh: Finding poetry in medicine

MIT senior and aspiring physician aims to tell stories that humanize the patients behind medical statistics.

Fatima Husain | MIT News correspondent
November 12, 2017

When MIT senior Mary Clare Beytagh isn’t performing research at the Koch Institute for Integrative Cancer Research or writing poetry, she can be found in ballet class at the Harvard Dance Center, continuing her 15 years of intensive dance training.

For Beytagh, ballet provides a reprieve from the hustle and bustle of academics and research. Her twice-a-week classes are “a nice way to de-stress and think about things,” including flashbacks to exciting moments on stage as a preprofessional ballerina, and fond memories with friends.

On days without dance class, Beytagh goes running. The two activities are “sort of antithetical to each other,” she notes. However, she makes it work. Beytagh is majoring in biology and literature at MIT — two fields that, like running and ballet, rarely intersect. But Beytagh aims to change that.

Running start on research

The summer before Beytagh’s senior year in high school, her teachers encouraged her to apply to a research program at the University of Texas Southwestern Medical Center.

The eight-week program took Beytagh out of the the classroom and into to the lab of Kathryn O’Donnell-Mendell, a cancer researcher studying B-cell lymphoma. The program was Beytagh’s first experience with scientific and medical research, and she was hooked.

She continued the research into her senior year of high school and submitted a paper to the prestigious Siemens Competition in Math, Science, and Technology.

While working in the lab, she met an MD-PhD student who opened Beytagh’s eyes to the possibility of pursuing medicine and cancer research simultaneously. When Beytagh applied to college, she looked for schools that emphasized undergraduate research. MIT topped her list.

“MIT rises above everyone else in that aspect,” she says. During an on-campus visit, she took part in a tour that allowed her to learn about the different types of research performed at the Institute. By the end of the tour, Beytagh knew MIT was the right fit. “These are my people,” she recalls thinking.

Upon the advice of her research advisor at UT Southwestern, after Beytagh arrived at MIT she sought out Tyler Jacks, professor of biology and director of the Koch Institute.

Beytagh has worked in the Jacks Lab since her second semester at the Institute. She and the other researchers are developing mouse models for cancer that recapitulate more aspects of the human disease. One goal, for example, is to have the tumors grow in the same locations in the animals as they do in humans.

Last year, Beytagh was invited to speak at the American Association for Cancer Research meeting. There, she presented her research alongside postdocs and early-career cancer biologists.

“That was a cool experience,” she says, “But then, it was back to the lab immediately!”

Documenting experiences

Outside of the lab, Beytagh enjoys expressing herself through her writing as a literature major.

During her sophomore Independent Activities Period (IAP), she traveled to Madrid to study Spanish literature. Her class was taught by MIT professors Stephen Tapscott and Margery Resnick. It examined post-Spanish Civil War novels and poetry — and captivated Beytagh.

After IAP ended, Beytagh continued studying poetry in Tapscott’s course 21L.487 (Modern Poetry). During the class, distinguished American poet Martha Collins visited and performed a poetry reading.

The visit had such an impact on Beytagh that she embarked upon an exercise inspired by one of Collins’ poetry series. The experiment lasted 21 days, during which Beytagh wrote poetic snapshots of each day within a set of predetermined rules.

“I’m a person who likes rules, but within those rules finds creativity,” Beytagh says.

On the 21st day, poetry morphed from hobby to emotional necessity. She found out her good friend had been diagnosed with Hodgkin’s lymphoma. At that moment, her poetry “became catharsis.”

She decided to declare literature as her second major.

“I had been flirting with the idea, but I had never committed,” she says, “Then, at the end of [sophomore] year, I committed.”

“This is it,” she says, recounting her reasoning, “These professors are amazing. I’m having a great time. It’s enriching me as a person.”

Bringing backstories to the forefront

Beytagh often integrates her research and other undergraduate experiences into her writing.

During her junior year IAP, she did an externship in the Yale School of Medicine’s emergency medicine department, with Charles Wira, III. She worked on developing a new risk score system for patients experiencing sepsis, but it was what she witnessed while shadowing in the emergency room that transformed her outlook.

“The most timely and impactful thing I saw there was the nature of the opioid epidemic,” she says, “You can read all you want in The New York Times and look at graphs — but that’s just statistics.”

That winter, she witnessed two to three patients coming into the emergency room for opioid overdoses each day she was there.

“What you don’t get in a graph,” she points out, “are the backstories of all these people.”

After that experience, she began to write about patients she saw and interacted with, in her poetry. In the long term, Beytagh hopes to become a science writer as well as a physician-scientist, telling stories that humanize patients and focus on the social and economic determinants of health.

Though she plans to study cancer biology in an MD-PhD program, she hopes to end up at an institution that allows her to take on other projects such as epidemiological research on opioid addiction.

Facilitating leadership

After a recommendation from her roomates freshman year, Beytagh joined the Leadership Training Institute, an organization which provides leadership training and mentorship to underprivileged Boston area high school students. The institute runs a 12-week program for 50 students each spring.

As the director of the program, Beytagh aims to reach students who are shy but passionate about community service and leadership, and works to provide them with transformative experiences.

“It’s always very gratifying when the students [graduate from the program],” she says. “They say, ‘You guys have made me realize that I not only want to keep service as a part of high school, but as a part of my career and onward.’”

“That gives you chills,” Beytagh says. “If you can spark that in someone and make them realize having an others-focused heart is the way to live life, it can only be good for our world.”

New player in cellular signaling

Researchers have identified a key nutrient sensor in the mTOR pathway that links nutrient availability to cell growth.

Nicole Giese Rura | Whitehead Institute
November 9, 2017

To survive and grow, a cell must properly assess the resources available and couple that with its growth and metabolism — a misstep in that calculus can potentially cause cell death or dysfunction. At the crux of these decisions is the mTOR pathway, a cellular pathway connecting nutrition, metabolism, and disease.

The mTOR pathway incorporates input from multiple factors, such as oxygen levels, nutrient availability, growth factors, and insulin levels to promote or restrict cellular growth and metabolism. But when the pathway runs amok, it can be associated with numerous diseases, including cancer, diabetes, and Alzheimer’s disease. Understanding the various sensors that feed into the mTOR pathway could lead to novel therapies for these diseases and even aging, as dialing down the mTOR pathway is linked to longer lifespans in mice and other organisms.

Although the essential amino acid methionine is one of the key nutrients whose levels cells must carefully sense, researchers did not know how it fed into the mTOR pathway — or if it did at all. Now, Whitehead Institute Member David Sabatini and members of his laboratory have identified a protein, SAMTOR, as a sensor in the mTOR pathway for the methionine derivative SAM (S-adenosyl methionine). Their findings are described in the current issue of the journal Science.

Methionine is essential for protein synthesis, and a metabolite produced from it, SAM, is involved in several critical cellular functions to sustain growth, including DNA methylation, ribosome biogenesis, and phospholipid metabolism. Interestingly, methionine restriction at the organismal level has been linked to increased insulin tolerance and lifespan, similar to the antiaging effects associated with inhibition of mTOR pathway activity. But the connection between mTOR, methionine, and aging remains elusive.

“There are a lot of similarities between the phenotypes of methionine restriction and mTOR inhibition,” says Sabatini, who is also a Howard Hughes Medical Institute investigator and a professor of biology at MIT. “The existence of this protein SAMTOR provides some tantalizing data suggesting that those phenotypes may be mechanistically connected.”

Sabatini identified mTOR as a graduate student and has since elucidated numerous aspects of its namesake pathway. He and his lab recently pinpointed the molecular sensors in the mTOR pathway for two key amino acids: leucine and arginine. In the current line of research, co-first authors of the Science paper Xin Gu and Jose Orozco, both graduate students Sabatini’s lab, identified a previously uncharacterized protein that seemed to interact with components of the mTOR pathway. After further investigation, they determined that the protein binds to SAM and indirectly gauges the pool of available methionine, making this protein — SAMTOR — a specific and unique nutrient sensor that informs the mTOR pathway.

“People have been trying to figure out how methionine was sensed in cells for a really long time,” Orozco says. “I think that this is the first time in mammalian cells a mechanism has been found to describe the way methionine can regulate a major signaling pathway like mTOR.”

The current research indicates that SAMTOR plays a crucial role in methionine sensing. Methionine metabolism is vital for many cellular functions, and the Sabatini lab will further investigate the potential links between SAMTOR and the extended lifespan and increased insulin sensitivity effects that are associated with low methionine levels.

“It is very interesting to consider mechanistically how methionine restriction might be associated in multiple organisms with beneficial effects, and identification of this protein provides us a potential molecular handle to further investigate this question,” Gu says. “The nutrient-sensing pathway upstream of mTOR is a very elegant system in terms of responding to the availability of certain nutrients with specific mechanisms to regulate cell growth. The currently known sensors raise some interesting questions about why cells evolved sensing mechanisms to these specific nutrients and how cells treat these nutrients differently.”

This work was supported by the National Institutes of Health, the Department of Defense, the National Science Foundation, and the Paul Gray UROP Fund.

Retinoic acid regulates transitions in mouse sperm production
November 7, 2017

CAMBRIDGE, MA – Sperm production requires progression through a well-orchestrated series of transitions in the testes that move diploid spermatogonia cells, with two complete sets of chromosomes, through a series of transitions to produce haploid sperm, with one copy of each chromosome, poised to swim and fertilize an available egg. There are four major transitions in sperm production, or spermatogenesis. The first is spermatogonial differentiation, during which spermatogonia differentiate, losing their stem-cell like qualities. The resulting spermatocytes then initiate meiosis and undergo two rounds of cell division to generate haploid spermatids. The spermatids undergo elongation and then the resulting sperm are released.

The signals that control progression through these transitions were poorly understood until 2015, when David Page, Member and Director of Whitehead Institute, professor of biology at Massachusetts Institute of Technology, and investigator with Howard Hughes Medical Institute and colleagues determined that retinoic acid (RA), a derivative of vitamin A that has been shown to play a key role in a number of developmental processes, was responsible for coordinating the first two stages of spermatogenesis-differentiation and meiosis. Now, in a paper published this week in the journal Proceedings of the National Academy of Sciences, Page, first author Tsutomu Endo, and colleagues extend those findings to show that RA signaling in mice coordinates the second two transitions as well.

Diagram of model by which retinoic acid coordinates spermatogenesisThe researchers used chemical manipulation of RA levels to determine that RA controlled the second two transitions, spermatid elongation and sperm release, in addition to the first two. With this knowledge in hand, the researchers were then able to drill down and get a better picture of how RA regulates male gamete production. One outstanding question has been how males are able to continually produce sperm throughout their lifetime, in contrast with females whose egg production and maturation is limited. Page and colleagues measured RA levels in the testes and discovered that it is cyclically produced, driving production of sperm during the male lifetime. In addition to the timing of RA production, the researchers also examined its source. From which cells was the RA signal coming? During the first two transitions, they determined that the RA was coming from the somatic Sertoli cells, the support cells of the testes, and in the second two transitions they determined that it was being released by the germ cells themselves-the meiotic (pachytene-stage) spermatocytes were found to be secreting RA to other germ cells in the testes.

These findings not only contribute to our fundamental understanding of male gamete formation, they also provide important clues for the field of reproductive technology. For years, scientists have been working on making gametes in the laboratory, but have had difficulty making functional sperm. This discovery of the role of RA in spermatogenesis adds important tools to the toolbox of assisted reproduction. The work shows that RA is required in both the early and late transitions of spermatogenesis and sheds light on an important component of laboratory efforts for sperm production.

Other researchers involved include Elizaveta Freinkman and Dirk G. de Rooij.

This research was supported by Howard Hughes Medical Institute (HHMI) and the United States Department of Defense (DoD W81XWH-15-1-0337)

Written by Lisa Girard
****
David Page’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 the Massachusetts Institute of Technology.
 ****
Paper cited: Endo, T et al.  Periodic production of retinoic acid by meiotic and somatic cells coordinates four transitions in mouse spermatogenesis. Proc Natl Acad Sci. DOI: 10.1073/pnas.1710837114. Epub 2017 Nov 6.
Other work cited: Endo T et al. Periodic retinoic acid-STRA8 signaling intersects with periodic germ-cell competencies to regulate spermatogenesis. Proc Natl Acad Sci. DOI: 10.1073/pnas.1505683112. Epub 2015 Apr 20.
A new workflow for natural product characterization comes ashore with red algae
October 30, 2017

CAMBRIDGE, Mass. – A few years ago while paddling off the coast near La Jolla, California, avid surfer Roland Kersten noticed a piece of red algae (Laurenica pacifica) bobbing alongside his surfboard. Kersten, whose background is in natural product chemistry, was intrigued.

Natural products—chemicals from living organisms such as plants and algae—represent a rich source of potential therapeutics. A majority of anti-cancer drugs are natural product-based or inspired. One such well-known natural product—the potent anti-cancer drug Taxol—was identified in the bark of a yew tree.

Marine algae, like the red algae Kersten found, are often rich in compounds called sesquiterpenes, some of which have been shown to have potential medicinal attributes. Since the 1970s, scientists identified many sesquiterpenes produced by Laurencia species with anti-cancer properties. The identification techniques usually required about tens of milligrams of purified compounds, which were obtained from more than a kilogram of algae. Because Laurencia and the reef ecosystems in which it thrives are protected, and such large-scale harvesting for scientific or medicinal purposes is no longer tenable, Kersten had to devise a different approach to analyze its sesquiterpenes.

Kersten received a collection permit to clamber over the rocky shore at deep low tide to collect a hand-sized sample of the red algae. Now a postdoctoral fellow in the lab of Whitehead Member and Massachusetts Institute of Technology assistant professor of biology Jing-Ke Weng, Kersten’s first task was to search the RNA sequences of all genes expressed in his red algae sample to find those whose product seemed likely to be enzymes that make sesquiterpenes.  In order to determine the product generated by these enzymes, he engineered them in yeast and isolated its sesquiterpene products.

In order to define the first step in the biogenesis of sesquiterpenes in red algae, Kersten wanted to see the precise 3-D structure of the isolated sesquiterpene. But the small handful of algae he had obtained produced only a fraction of the amount required for x-ray crystallography, the established method for determining a compound’s absolute structure. So Kersten tried a method recently developed by collaborator Makoto Fujita at the University of Tokyo that requires only a few nanograms of material: soaking extracted compounds into a special crystalline sponge, which supports the sample’s molecular shape while it is bombarded with x-rays to accurately determine the 3-D conformation of a molecule. A new combination of the crystalline sponge method and nuclear magnetic resonance spectroscopy by the Fujita group revealed the structure of prespatane.

With the compound’s structure in hand, Kersten is closer to understanding how Laurenciabiosynthesizes its sesquiterpenes and how to engineer yeast to produce the same molecules for medicinal research at scale—without touching the red algae flourishing on protected reefs. And the novel workflow—spanning genomics, metabolomics, synthetic biology, and x-ray crystallography with crystalline sponges—established by Weng, Kersten, and their collaborators may expedite the identification of other promising compounds produced by organisms from both land and sea.

Other contributors to this work include Shoukou Lee of Tokyo University, Daishi Fujita of Tokyo University and Whitehead Institute, Tomáš Pluskal of Whitehead Institute.  The team also collaborated with researchers from Scripps Institution of Oceanography and Salk Institute of Biological Sciences.

This work was supported by Howard Hughes Medical Institute, the Simons Foundation, the Helen Hay Whitney Foundation, the Pew Scholars Program in the Biomedical Sciences, the Searle Scholars Program, and the Japan Science and Technology Agency.

 Written by Nicole Giese Rura
* * *
Jing-Ke Weng’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also an assistant professor of biology at Massachusetts Institute of Technology.
* * *
Full Citation:
“A Red Algal Bourbonane Sesquiterpene Synthase Defined by Microgram-scale NMR-coupled Crystalline Sponge XRD Analysis”
Journal of the American Chemical Society, online October 30, 2017.
Roland D. Kersten (1,6), Shoukou Lee (2,6) , Daishi Fujita (1,2) , Tomáš Pluskal (1) , Susan Kram (3), Jennifer E. Smith (3) , Takahiro Iwai (2) , Joseph P. Noel (4) , Makoto Fujita (2), Jing-Ke Weng (1,5).
1. Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA, United States
2. Graduate School of Engineering, The University of Tokyo, JST-ACCEL, Tokyo, Japan
3. Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, United States
4. Howard Hughes Medical Institute, Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA, United States
5. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, United States
6. These authors contributed equally