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Intrigued by immortality
Eva Frederick | Whitehead Institute
March 16, 2021

New Whitehead Institute director Ruth Lehmann and new Member Yukiko Yamashita study opposite sides of the germ cell life cycle. Yamashita’s work in male germ cells shows how the cells are formed and maintained; Lehmann studies female germ cells to understand their fates. At the Whitehead Institute, they join Member and former director David Page in painting a fuller picture of how these seemingly immortal cell lines pass instructions uninterrupted from generation to generation.

All other cells in the body — neurons, muscle cells, the stem cells that replenish other tissue types — are made anew in each embryo and go away when organisms die. But not the germ cells. “The germ cell passes its DNA to the next generation, then that DNA is used to build up to a new germ cell,” says Yamashita. “That means that germ cells never cease to exist.”

In this way, an unbroken chain of germ cells stretches back to our most distant ancestor. Scientists study this never-ending link for insights into the fundamentals of biology and evolution. Yamashita began studying germ cells as a model to investigate other questions, but as her research progressed, she grew more and more intrigued by the cells’ special properties.

“This is one thing Ruth and I have in common,” Yamashita says. “There are many biologists that study germ cells, but not many are acutely interested or fascinated by this immortality. We want to know, where does it come from?”

Yamashita, also an Investigator of the Howard Hughes Medical Institute, joined Whitehead Institute in September. Work in her laboratory at Whitehead Institute will focus on two areas, using the fruit fly Drosophila melanogaster as a model. First, she will continue her focus from previous projects on the mechanics of asymmetric cell division using male germline stem cells. These cells, like other stem cells in the body, must undergo a series of asymmetric divisions — instead of simply dividing into two identical daughter cells, the cells must create daughters with different cell fates and programming.

“This balance — maintaining the stem cell number while making some differentiating cells — is considered to be a very important process,” she says. “If you end up making too many stem cells, it can become cancerous; but if you commit too much to the differentiation, you lose the stem cell count, and that means you cannot continue sperm production.”

A newer project in her lab centers on the long sequences of nucleotides within organisms’ genomes that don’t code for any genes. They’re often nonsensical, gibberish combinations or long strings of certain bases. This “genomic junk” has long been dismissed as meaningless filler between essential genes, but Yamashita proposes that the junk is essential for the overall structure of the genome. Much like the binding of a book holds together its contents in an organized fashion, the genomic junk may provide a blueprint for how genetic material is held together and eventually read.

Ultimately, it is the germline cells that are responsible for maintaining this DNA framework. Yamashita hypothesizes that slow changes in junk DNA could provide some explanation for why different species are reproductively incompatible.

“If you look at the chimpanzee genome and the human genome, the protein coding regions are, like, 98 percent, 99 percent identical,” she says. “But the junk DNA part is very, very different. We think this divergence might explain what happens when one species splits into two.”

Yamashita’s research team will share lab space with Lehmann’s group. Both researchers use fruit flies for their experiments, but Lehmann’s research focuses on egg cells, not sperm. “Germ cells are special; you don’t need them for survival, but you need them to keep the species going,” she says. “How are they initially specified and set aside? What makes them different, how are they set aside from somatic cells, and how do they maintain their cell fate?”

One project Lehmann is carrying over from her work at New York University’s Skirball Institute of Biomolecular Medicine involves phase transition condensates — small, membraneless granules that bring together the components needed for complex cellular functions. Lehmann studies a specific type of condensate called a germ granule, an aggregation of small RNAs and RNA binding proteins found only in germline cells, which helps determine the cells’ fate.

Lehmann is also investigating the female germline cells’ role in maternal inheritance. After fertilization, the maternal cell imparts not only its nuclear DNA but also components of its cytoplasm, including mitochondria, RNAs, and even bacteria. “This whole idea of cytoplasmic inheritance and the transgenerational continuum of the cytoplasm is something I’m just starting to think about,” she says.

Yamashita and Lehmann share a large open space on the third floor of the Institute, with researchers from each lab integrated throughout. They will also share a fly room and computational room. The researchers hope the communal setup will allow a flow of ideas between their labs. “By sharing this kind of basic space, we are hoping to let our people interact with each other and for discussions to happen,” Yamashita says.

“This is a new concept for Whitehead, and we’ll see how it works,” Lehmann says. “It’s an exciting experiment in lab sociology.”

“Selfish” DNA helps bacteria cheat and grow in densely-packed microbial communities
Raleigh McElvery
March 12, 2021

Scientists have a term for genes that spread themselves throughout a population at any cost: “selfish” DNA. One way that these genes transmit through bacterial communities is via a type of bacterial sex called conjugation. When one bacterium makes contact with another, DNA from the host cell can be injected into a recipient cell.

Alan Grossman’s lab at the MIT Department of Biology studies a small but selfish chunk of DNA called ICEBs1. His group has identified several ways in which this so-called mobile genetic element actually benefits its host bacterium as it fights to spread. Building off this body of work, Grossman’NetBet sports lab collaborated with colleagues at Tel Aviv University on a new study recently published in eLife. The international team found that ICEBs1 contains one gene in particular, which allows the host cell to continue dividing in densely-packed microbial communities. This helps the host to grow in conditions where nutrients are scarce, while also potentially helping ICEBs1 to propagate.

“Mobile genetic elements like ICEBs1 are found in the chromosomes of many different types of bacteria,” says Grossman, department head and co-senior author on the study. “Studying these elements — how they spread and how they affect their host cells — is critical for understanding the evolution of bacteria, engineering some types of bacteria to do useful things, and possibly preventing the deleterious effects caused by harmful bacteria.”

Like many DNA segments on the move, ICEBs1 includes genes that encode the molecular machinery required to transfer itself from one cell to the next. But mobile genetic elements can also contain “cargo” genes that bestow the host bacterium with new traits, such as antibiotic resistance. However, in many cases, the properties a cargo gene will endow are hard to predict.

“The host cell can get a lot of new genes in a hurry through mobile genetic elements like ICEBs1, and there’s a lot we still don’t know about the types of phenotypes cargo genes confer,” says the study’s first author, Joshua Jones PhD ’20. “The array of possible traits is probably a lot more diverse than we currently appreciate.”

To investigate the changes that ICEBs1 triggers in the host cell, Jones and colleagues examined large microbial communities called biofilms. These form when many bacteria aggregate on a surface and secrete a slimy “glue” made of sugar, proteins, and DNA that encases the population. Common examples of biofilms include dental plaque, the sludge that coats the inside of pipes, or the deleterious infections that form on surgical implants in patients’ bodies.

Because there are so many bacteria in close contact, biofilms are hot spots for exchanging mobile genetic elements like ICEBs1. However, secreting the materials needed to produce the slimy glue can rapidly deplete resources. As a result, bacteria in a biofilm do not always have the capacity to grow, divide, and potentially spread ICEBs1. Instead, certain types of rod-shaped bacteria begin to produce spores that are analogous to plant seeds. This process, called sporulation, enables these bacteria to become dormant and survive extreme conditions.

Jones found that Bacillus subtilis bacteria containing ICEBs1 were delayed in contributing to the biofilm glue, and also delayed in producing dormant spores. As a result, these bacteria could continue dividing for longer than bacteria without ICEBs1 — increasing the number of bacteria with ICEBs1 and the likelihood that ICEBs1 would spread. The researchers were able to pinpoint one ICEBs1 cargo gene in particular, called Development Inhibitor (devI), that triggered this delay in both biofilm development and sporulation.

“In a way, the cells with ICEBs1 are ‘cheating’ by delaying sporulation and not contributing to the greater good of the biofilm community,” Jones says. But, he explains, they can get away with it because the devI pathway only initiates when ICEBs1-containing cells are the minority in a microbial population. In order to spread as widely as possible, it’s best for ICEBs1 to transfer to new cells that don’t already contain existing copies. Furthermore, accumulating duplicate copies can have detrimental effects on ICEBs1 itself.

“It’s a very clever system for assessing the situation around the cell, and deciding whether it’s worthwhile for ICEBs1 to attempt to transfer,” Jones adds.

Next, the Grossman lab plans to determine precisely how devI exerts its effects on biofilm formation and sporulation. They suspect that other ICEBs1-like elements may also use genes analogous to devI to execute similar propagation strategies. Probing such “cheating” tactics orchestrated by selfish genes will help scientists better understand microbial evolution and, eventually, perhaps even inspire drugs to disrupt harmful biofilms, like those that form around surgical implants.

Linda Griffith and Douglas Lauffenburger honored for contributions to biological engineering education

Professors awarded the National Academy of Engineering's prestigious Bernard M. Gordon Prize for Innovation in Engineering and Technology Education.

School of Engineering
March 11, 2021

The National Academy of Engineering (NAE) has announced that two MIT professors have been jointly awarded the Bernard M. Gordon Prize for Innovation in Engineering and Technology Education, the most prestigious engineering education award in the United States.

Linda G. Griffith, the School of Engineering Professor of Teaching Innovation in the Department of Biological Engineering, and Douglas A. Lauffenburger, the Ford Professor of Biological Engineering, Chemical Engineering and Biology, were recognized for their respective contributions to “the establishment of a new biology-based engineering education, producing a new generation of leaders capable of addressing world problems with innovative biological technologies,” according to an NAE statement.

“We are absolutely delighted that professors Griffith and Lauffenburger received this prestigious prize from the NAE,” says Angela Belcher, head of the Department of Biological Engineering. “Anyone who knows Doug Lauffenburger and Linda Griffith knows that educating and mentoring in engineering, particularly biological engineering, is at the core of who they are.”

Griffith and Lauffenburger spearheaded the establishment of the biological engineering discipline at MIT, which revolves around teaching students how to translate innovations in the molecular life sciences into therapeutics, and a range of non-medical products in agriculture, materials, energy, and nutrition.

“Professor Griffith and Professor Lauffenburger have made incredible contributions to education in biological engineering,” says Anantha P. Chandrakasan, dean of the MIT School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. “They have both been fundamental in establishing and shaping the biological engineering curriculum at MIT, and continue to inspire current and former students in this space.”

Griffith championed the biological engineering BS degree program, while Lauffenburger focused his efforts on the graduate level. Students who have participated in the curriculum have gone on to found innovative startups, such as Gingko Bioworks.

“The award is really in recognition of the power of MIT students to create change,” says Griffith. “The creation of a new discipline of engineering was a lot of effort, but it was done in partnership with students who were brave enough to imagine what could be.”

In addition to her achievements in education, Griffith directs the Center for Gynepathology Research and has championed novel approaches in tissue engineering. She is also responsible for establishing the field of physiomimetics.

She holds more than a dozen patents, has over 200 publications, and has chaired multiple scientific conferences, including the annual TED conference-like Open Endoscopy Forum that assembles gynecology scientists, surgeons, and engineers at MIT for a weekend of talks.

Lauffenburger is affiliated with multiple biomedical organizations including the Center for Gynepathology Research, Center for Biomedical Engineering, and Koch Institute for Integrative Cancer Research at MIT. He is a past president of the Biomedical Engineering Society and currently the chair of the College of Fellows of American Institute for Medical and Biological Engineering.

Both Griffith and Lauffenburger hope that their accomplishments at MIT will help propel biological engineering forward on a global level.

“The world needs biology-based technologies to address a broad spectrum of critical NetBet sportchallenges that have not been satisfactorily met by physics- and chemistry-based technologies,” says Lauffenburger. “Our aspiration, and expectation, is that what we’ve created here will catalyze adoption of biology-based engineering at many other institutions worldwide in the coming years.”

Established in 2001, the Gordon Prize includes a cash award of $500,000, of which Griffith and Lauffenburger will receive half. The other half will go to support biological engineering education efforts at MIT. Griffith and Lauffenburger will also each receive a gold-plated, sterling silver medal and a hand-scribed certificate.

2021 MacVicar Faculty Fellows named

Professors Guth, Olivetti, Short, and Yaffe are honored for exceptional undergraduate teaching.

Registrar’s Office
March 11, 2021

The Office of the Vice Chancellor and the Registrar’s Office have announced this year’s Margaret MacVicar Faculty Fellows: professor of mathematics Larry Guth, associate professor of materials science and engineering Elsa Olivetti, associate professor of nuclear science and engineering professor Michael Short, and professor of biology and biological engineering Michael Yaffe.

For nearly three decades, the MacVicar Faculty Fellows Program has recognized exemplary and sustained contributions to undergraduate education at MIT. The program was named after Margaret MacVicar, the first dean for undergraduate education and founder of the Undergraduate Research Opportunities Program (UROP). Departments must submit nominations along with recommendation letters from the nominees’ colleagues, students, or alumni. The selection process is highly competitive. Award recipients are appointed to a 10-year term and receive $10,000 per year of discretionary funds. Junior faculty are eligible for an initial three-year term with the possibility of conversion to a 10-year term if tenure is granted.

The 2021 fellows join an elite group of scholars from across the Institute who are committed to curricular innovation, scientific research, and improving the student experience through teaching, mentoring, and advising. Within each of their departments, Guth, Olivetti, Short, and Yaffe have made groundbreaking discoveries, created new subjects, breathed life into longstanding MIT subjects and programs, and gone the extra mile to support and connect with their students.

They will be recognized at a private, virtual gathering on March 12 along with the 2020 fellows — associate professor of materials science and engineering Polina Anikeeva, professor of literature Mary Fuller, associate professor of chemical engineering William Tisdale, and professor of electrical engineering and computer science Jacob White — whose celebration was canceled last spring due to Covid-19.

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A Claude E. Shannon Professor of Mathematics, Larry Guth received his PhD from MIT in 2005 and became a professor in the mathematics department in 2012. He received both the Maryam Mirzakhani Prize in Mathematics and the American Mathematical Society’s Bocher Prize last year.

Guth’s research combines mathematics and mathematical analysis (metric geometry and harmonic analysis specifically), but his special talent lies in his ability to gracefully translate complex information into succinct and digestible terms and communicate these principles to individuals of all levels.

Professor of mathematics Gigliola Staffilani says, “for most of us theoretical mathematicians, our advancement in our research does not make its way into our undergraduate classes. For Larry, it is different. He is capable of distilling the thought process that goes into his most sophisticated papers and present it to his students in an incredibly effective way.”

Junior Dina Atia wrote, “It turned out that Guth’s approach to advising is the same as his approach to integration. Whenever I came to him with a problem that felt huge and complicated, he did the same thing: cut it into small pieces and added them all up.”

Students say his classes are challenging, yet approachable and inclusive. One notes, “He has an incredible ability to place himself in his students’ shoes and make them feel heard.” Another student nominator remarks that Guth’s approach changed her relationship with mathematics as a discipline: “Before coming to MIT, I had decided that mathematics was not for me, and it was through Professor Guth’s instruction I was able to once more realize a passion I thought I had lost.”

Mathematics Research Affiliate Sanjoy Mahajan calls Larry Guth “a wonderful colleague [and a] deep mathematical thinker” and affirms that he “teaches students how to think like a mathematician.”

“There is no one more deserving of such an exceptional award,” concludes Atia. “Throughout my undergraduate career … Professor Guth has been a source of knowledge, passion, and reassurance. He is a model educator and I cannot imagine someone more qualified to be a Margaret MacVicar Faculty Fellow.”

Elsa Olivetti

“It is an overwhelming honor to be selected as a MacVicar Faculty Fellow, particularly in this year when each of us has had to transform both our teaching and our learning in profound and unprecedented ways,” says Elsa Olivetti, the Esther and Harold E. Edgerton Career Development Associate Professor.

Innovation is a key tenet of education at MIT and is a critical part of professor Olivetti’s subjects. Department of Materials Science and Engineering (DMSE) head Jeffrey Grossman remarks of her experimentation in lecturing, curriculum building, mentoring, and more, “[She] is in a class by herself … a brilliant teacher with an uncanny ability to keep the students on the edge of their seats.”

Olivetti received her PhD in materials science and engineering from MIT in 2007 before securing a position of postdoc a few months later. She subsequently worked as a research scientist in the Materials Systems Lab from 2009 to 2013 and began teaching in 2014.

Olivetti’s research addresses environmental issues such as sustainability, recycling-friendly materials, and waste disposition, which have significant real-world implications. After joining Course 3, she was tasked with creating a new subject in the area of industrial ecology and materials from “scratch,” which rolled out with flying colors in 2014.

Elsa Olivetti’s work underscores the importance of caring for undergraduates as a whole, and what most stands out from their testimonials is her positive spirit and compassionate demeanor. “Professor Olivetti’s classroom was one of the most supportive learning environments at MIT,” says Rahul Ramakrishnan, a recent Course 3 alumnus. Another calls her “universally loved by all undergraduates.”

2020 MacVicar Faculty Fellow and DMSE Associate Professor Polina Anikeeva confirms that while Olivetti’s high teaching scores speak to her gift as an educator, “what makes her absolutely unique is the extra mile (more like an extra marathon…) [she] goes to advance undergraduate education and well-being at the level of the department and the Institute.”

Olivetti received the Earll M. Murman Award for Excellence in Undergraduate Advising in 2017, the award for “best DMSE advisor” in 2019, and the Paul Gray Award for Public Service in 2020.

In order to assist students in finding employment, Olivetti established the Course 3 Industry Seminars, pairing undergraduates with individuals working in careers related to 3D printing, environmental consulting, and manufacturing. Olivetti also champions the issues of diversity, equity, and inclusion and incorporates them into her curriculum.

“Her approach is visionary,” says materials science and engineering Associate Professor James LeBeau, “The result of her work serves as the model for materials science and engineering across the country and the world.” Moreover, Olivetti has continued to innovate during the pandemic by spearheading a pilot community on Canvas for faculty to share strategies, recommendations, and best practices for digital and remote learning.

On working with MIT students, she is full of optimism and inspiration: “their humble, creative persistence gives me hope that we netbet online sports bettingactually have a shot to take on the pressing challenges we face today.”

Michael Short

Creative, dedicated, and enthusiastic, Michael Short is an associate professor in nuclear science and engineering (NSE) and, according to his colleagues, “a leader in the field of nuclear materials.”

He received his BS, MS, and PhD from MIT, joined the department in 2005, and became an assistant professor in 2013. He has been recognized with the Joel and Ruth Spira Award, the Junior Bose Award from the School of Engineering, and the Earll M. Murman Award for Excellence in Undergraduate Advising.

Short’s research interests include fouling and its prevention, nondestructive evaluation (NDE), and radiation damage and effects, and he has spent more than a decade in the fields of nuclear materials, microstructural characterization, and alloy development.

A unique element of Short’s classes is his imaginative, hands-on approach. For example, in 22.01 (Ionizing Radiation and Nuclear Engineering), students have the ability to irradiate their toenails in the MIT Nuclear Reactor Laboratory to learn how much arsenic they have in their bloodstream.

Short’s students say that his teaching impacts are nothing “short” of inspirational, musing that he “never sets ‘ceilings’ for the performance of his students” and gives them space to fail. Third-year PhD student Jonathan Paras remarks that Short is “among the very few at the Institute who embody integrity, student-centric focus, and the eccentric hacker spirit that MIT has become known for.”

Michael Short is also deeply committed to curricular innovation and solving complex environmental issues. He is currently working on the problems of climate change and renewable energy through a NEET thread. He also developed the 22-ENG major to provide curricular flexibility, implemented a new prototyping focus to 22.033 (Nuclear Systems Design Project), and substantially revamped 22.01 (Introduction to Nuclear Engineering and Ionizing Radiation).

Much of Short’s work in these two subjects set the stage for wide-ranging improvements to the Course 22 curriculum by “futurizing” undergraduate education through a “context-first” approach that additionally addressed the problem of low enrollment within the major itself.

Associate Provost Richard K. Lester says, “He is a force of nature, and his impact on the NSE undergraduate program has been transformative.”

Among his most impressive accomplishments is his expansion of the department’s UROP program. Professor of nuclear science and engineering Jacopo Buongiorno notes, “[Short] stimulated the faculty to develop and continuously update a rich portfolio of UROP projects and made it easy for students to connect with the faculty through the online UROP system that he created.”

Buongiorno goes on to say that Short’s “energy and creativity, as well as intellectual and emotional connection to UG [undergraduate] students, are second to no one. Simply put … [he] is an unstoppable, inexhaustible machine.”

On being named a 2021 fellow, Short says, “I was absolutely thrilled to be selected, since as an undergrad and grad at MIT I had the distinct pleasure to take courses from a great number of MacVicar Fellows … To be selected to join their ranks … is an enormous honor.”

Michael Yaffe

Michael Yaffe is the David H. Koch Professor of Science, professor of biology and biological engineering, and director of the MIT Center for Precision Cancer Medicine.

After completing his undergraduate degree at Cornell University, he received his MD and PhD from Case Western Reserve University. He has been a member of the Course 7 faculty since 2000 and a member of the biological engineering faculty since its inception.

Yaffe has taught 7.05 (General Biochemistry), an important core subject, since 2001. He also developed 7.10 (Physical Chemistry of Biomolecular Systems), and his work on a 9th edition of “Molecular Cell Biology” has become a primary textbook used by several undergraduate courses.

Yaffe’s research extends across multiple disciplines including materials science, biophysical chemistry, and medicine. He also runs a highly esteemed cell biology and cancer laboratory and serves as physician and trauma surgeon.

“He offered to let me shadow him on his surgeries,” writes one student. “I have not had another professor before or since who was so invested in helping me explore the entirety of my academic interests.” MacVicar Faculty Fellow and professor in the department of biological engineering Linda G. Griffith additionally praises Yaffe’s “unusual ability to straddle the basic science and clinical universes and to translate science into practice.”

Associate professor of biology Matthew Vander Heiden applauds Yaffe’s ability to do it all: “It is difficult to balance … the demands of a research laboratory and teaching responsibilities, but somehow Michael finds a way to take care of some of the sickest patients in Boston … and is among the best educators at any university.”

Michael Yaffe’s teaching style draws on this twin — academic and clinical — expertise, and his classes often include physical props such as Styrofoam balls, colored balloons, and cardboard constructs to help students visualize different structures.

Department head and professor of biology Alan Grossman remarks that Yaffe “mixes rigor and showmanship while presenting cutting-edge findings and science history, all combined into a pedagogy that is captivating and effective. He is an educator in the style of some of MIT’s most magnificent professors who have raised the level of lecturing to an art form.”

In addition to serving as a professor and physician, he is actively involved in MIT’s ROTC program and served in the Middle East as a member of the medical corps of the armed forces reserve. ROTC colleagues called him an “exemplar of the intersection of the military and academia.”

“Yaffe is one of the select few professors at MIT that everyone should get a chance to know,” confirms another student, “as he truly changes the way you understand, view, and approach the world.”

Members of MIT Biology came together with alumni, industry representatives, and supporters to review the department’s challenges and accomplishments.

March 9, 2021
Eyeless roundworms sense color

C. elegans compares the ratio of wavelengths in its environment to avoid dangerous bacteria that secrete colorful toxins.

Raleigh McElvery | Department of Biology
March 4, 2021

Roundworms don’t have eyes or the light-absorbing molecules required to see. Yet, new research shows they can somehow sense color. The study, published on March 5 in the journal Science, suggests worms use this ability to assess the risk of feasting on potentially dangerous bacteria that secrete blue toxins. The researchers pinpointed two genes that contribute to this spectral sensitivity and are conserved across many organisms, including humans.

“It’s amazing to me that a tiny worm — with neither eyes nor the molecular machinery used by eyes to detect colors — can identify and avoid a toxic bacterium based, in part, on its blue color,” says H. Robert Horvitz, the David H. Koch Professor of Biology at MIT, a member of the McGovern Institute for Brain Research and the Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute Investigator, and the co-senior author of the study. “One of the joys of being a biologist is the opportunity to discover things about nature that no one has ever imagined before.”

The roundworm in question, Caenorhabditis elegans, is only about a millimeter long. Despite their minute stature and simple nervous system, these nematodes display a complex repertoire of behaviors. They can smell, taste, sense touch, react to temperature, and even escape or change their feeding patterns in response to bright, blue light. Although researchers once thought that these worms bury themselves deep in soil, it’s becoming increasingly clear that C. elegans prefers compost heaps above ground that offer some sun exposure. As a result, roundworms may have a need for light- and color-sensing capabilities after all.

netbet sports bettingThe decomposing organic matter where C. elegans resides offers an array of scrumptious microbes, including bacteria like Pseudomonas aeruginosa, which secretes a distinctive blue toxin. Previous studies showed that worms in the lab feed on a lawn of P. aeruginosa for a few hours and then begin avoiding their food — perhaps because the bacteria continue to divide and excrete more of the colorful poison. Dipon Ghosh, Horvitz lab postdoc and the study’s first author, wondered whether the worms were using the distinctive color to determine if their meal was too toxic to consume.

Over the course of his experiments, Ghosh noticed that his worms were more likely to flee the colorful bacterial lawn if it was bathed in white light from a nearby LED bulb. This finding was curious on its own, but Ghosh wanted know if the blue toxin played a role as well.

To test this theory, he first exchanged the blue toxin for a harmless dye of the same color, and then for a clear, colorless toxin. On its own, neither substitute was sufficient to spur avoidance. Only together did they prompt a response — suggesting the worms were assessing both the toxic nature and the color of the P. aeruginosa secretions simultaneously. Once again, this behavioral pattern only emerged in the presence of the LED’s white light.

Intrigued, Ghosh wanted to examine what it was about the blue color that triggered avoidance. This time, he used two colored LED lights, one blue and one amber, to tint the ambient light. In doing so, he could control the ratio of wavelengths without changing the total energy delivered to the worms. The beam had previously contained the entire visible spectrum, but mixing the amber and blue bulbs allowed Ghosh to tweak the relative amounts of short-wavelength blue light and long-wavelength amber light. Surprisingly, the worms only fled the bacterial lawn when their environment was bathed in light with specific blue:amber ratios.

“We were able to definitively show that worms aren’t sensing the world in grayscale and simply evaluating the levels of brightness and darkness,” Ghosh says. “They’re actually comparing ratios of wavelengths and using that information to make decisions — which was thoroughly unexpected.”

It wasn’t until Ghosh ran his experiments again, this time using various types of wild C. elegans, that he realized the popular laboratory strain he’d been using was actually less color-sensitive compared to its close relatives. After analyzing the genomes of these worms, he was able to identify two genes in particular (called jkk-1 and lec-3) that contributed to these variations in color-dependent foraging.

Although the two genes play many important functions in a variety of organisms, including humans, they are both involved in molecular pathways that help cells respond to stress caused by damaging ultraviolet light.

“We’ve discovered that the color of light in the worm’s environment can influence how the worm navigates the world,” Ghosh says. “But our work suggests that many genes, in addition to the two we’ve already identified, can affect color sensitivity, and we’re now exploring how.”

The notion that worms can sense color is “astounding” and showcases nature’s innovation, according to Leslie Vosshall, Robin Chemers Neustein Professor and Howard Hughes Medical Institute Investigator at The Rockefeller University, who was not involved in the study. “These worms are sliding around in a dim muck with colorful, toxic bacteria. It would be helpful to see and avoid them, so the worms somehow evolved a completely new way to see.”

Vosshall is curious about which cells in C. elegans help discriminate light, as well as the specific roles that the jkk-1 and lec-3 genes play in mediating light perception. “This paper, like all important papers, raises many additional questions,” she says.

Ghosh suspects the lab’s findings could generalize to other critters besides roundworms. If nothing else, it’s clear that light-sensitivity does not always require vision — or eyes. C. elegans are seeing the light, and now so are the biologists.

This research was funded by the Howard Hughes Medical Institute and National Institute of General Medical Sciences.

Study reveals how egg cells get so big

Oocyte growth relies on physical phenomena that drive smaller cells to dump their contents into a larger cell.

Anne Trafton | MIT News Office
March 10, 2021

Egg cells are by far the largest cells produced by most organisms. In humans, they are several times larger than a typical body cell and about 10,000 times larger than sperm cells.

There’s a reason why egg cells, or oocytes, are so big: They need to accumulate enough nutrients to support a growing embryo after fertilization, plus mitochondria to power all of that growth. However, biologists don’t yet understand the full picture of how egg cells become so large.

A new study in fruit flies, by a team of MIT biologists and mathematicians, reveals that the process through which the oocyte grows significantly and rapidly before fertilization relies on physical phenomena analogous to the exchange of gases between balloons of different sizes. Specifically, the researchers showed that “nurse cells” surrounding the much larger oocyte dump their contents into the larger cell, just as air flows from a smaller balloon into a larger one when they are connected by small tubes in an experimental setup.

“The study shows how physics and biology come together, and how nature can use physical processes to create this robust mechanism,” says Jörn Dunkel, an MIT associate professor of physical applied mathematics. “If you want to develop as an embryo, one of the goals is to make things very reproducible, and physics provides a very robust way of achieving certain transport processes.”

Dunkel and Adam Martin, an MIT associate professor of biology, are the senior authors of the paper, which appears this week in the Proceedings of the National Academy of Sciences. The study’s lead authors are postdoc Jasmin Imran Alsous and graduate student Nicolas Romeo. Jonathan Jackson, a Harvard University graduate student, and Frank Mason, a research assistant professor at Vanderbilt University School of Medicine, are also authors of the paper.

A physical process

In female fruit flies, eggs develop within cell clusters known as cysts. An immature oocyte undergoes four cycles of cell division to produce one egg cell and 15 nurse cells. However, the cell separation is incomplete, and each cell remains connected to the others by narrow channels that act as valves that allow material to pass between cells.

Members of Martin’s lab began studying this process because of their longstanding interest in myosin, a class of proteins that can act as motors and help muscle cells contract. Imran Alsous performed high-resolution, live imaging of egg formation in fruit flies and found that myosin does indeed play a role, but only in the second phase of the transport process. During the earliest phase, the researchers were puzzled to see that the cells did not appear to be increasing their contractility at all, suggesting that a mechanism other than “squeezing” was initiating the transport.

“The two phases are strikingly obvious,” Martin says. “After we saw this, we were mystified, because there’s really not a change in myosin associated with the onset of this process, which is what we were expecting to see.”

cluster of cells

Martin and his lab then joined forces with Dunkel, who studies the physics of soft surfaces and flowing matter. Dunkel and Romeo wondered if the cells might be behaving the same way that balloons of different sizes behave when they are connected. While one might expect that the larger balloon would leak air to the smaller until they are the same size, what actually happens is that air flows from the smaller to the larger.

This happens because the smaller balloon, which has greater curvature, experiences more surface tension, and therefore higher pressure, than the larger balloon. Air is therefore forced out of the smaller balloon and into the larger one. NetBet live casino“It’s counterintuitive, but it’s a very robust process,” Dunkel says.

Adapting mathematical equations that had already been derived to explain this “two-balloon effect,” the researchers came up with a model that describes how cell contents are transferred from the 15 small nurse cells to the large oocyte, based on their sizes and their connections to each other. The nurse cells in the layer closest to the oocyte transfer their contents first, followed by the cells in more distant layers.

“After I spent some time building a more complicated model to explain the 16-cell problem, we realized that the simulation of the simpler 16-balloon system looked very much like the 16-cell network. It is surprising to see that such counterintuitive but mathematically simple ideas describe the process so well,” Romeo says.

The first phase of nurse cell dumping appears to coincide with when the channels connecting the cells become large enough for cytoplasm to move through them. Once the nurse cells shrink to about 25 percent of their original size, leaving them only slightly larger than their nuclei, the second phase of the process is triggered and myosin contractions force the remaining contents of the nurse cells into the egg cell.

“In the first part of the process, there’s very little squeezing going on, and the cells just shrink uniformly. Then this second process kicks in toward the end where you start to get more active squeezing, or peristalsis-like deformations of the cell, that complete the dumping process,” Martin says.

Cell cooperation

The findings demonstrate how cells can coordinate their behavior, using both biological and physical mechanisms, to bring about tissue-level behavior, Imran Alsous says.

“Here, you have several nurse cells whose job it is to nurse the future egg cell, and to do so, these cells appear to transport their contents in a coordinated and directional manner to the oocyte,” she says.

Oocyte and early embryonic development in fruit flies and other invertebrates bears some similarities to those of mammals, but it’s unknown if the same mechanism of egg cell growth might be seen in humans or other mammals, the researchers say.

“There’s evidence in mice that the oocyte develops as a cyst with other interconnected cells, and that there is some transport between them, but we don’t know if the mechanisms that we’re seeing here operate in mammals,” Martin says.

The researchers are now studying what triggers the second, myosin-powered phase of the dumping process to start. They are also investigating how changes to the original sizes of the nurse cells might affect egg formation.

The research was funded by the National Institute of General Medical Sciences, a Complex Systems Scholar Award from the James S. McDonnell Foundation, and the Robert E. Collins Distinguished Scholarship Fund.

Grace Johnson earns Harold M. Weintraub Graduate Student Award
March 3, 2021

Grace Johnson, a graduate student in Gene-Wei Li’s lab, has received a 2021 Harold M. Weintraub Graduate Student Award from the Fred Hutchinson Cancer Research Center. Johnson is one of 13 recipients who were honored for the quality, originality, and significance of their work in the biological sciences.

The Weintraub Graduate Student Award was established in 2000, and since then more than 300 graduate students have been recognized for their research contributions. The 2021 awardees study a spectrum of topics, including immunology, molecular biology, neurobiology, and cancer.

Johnson’s research focuses on bacterial gene expression. In bacteria such as Escherichia coli — a widely-studied model organism — the RNA polymerase, which transcribes DNA into RNA, is followed in close pursuit by the ribosome, which translates the RNA into proteins. However, Johnson recently helped to show that the Bacillus subtilis bacterium does not display this common “coupled” transcription-translation. She demonstrated that, rather than working in tandem with the ribosome, the polymerase in B. subtilis speeds ahead. This system of “runaway” transcription creates alternative mechanisms for RNA quality control, and provides insights into the range of molecular processes present in bacteria.

“To me, this work is really exciting because it provides a glimpse into how differences in basic biological properties can shape the evolution of diverse bacteria,” Johnson says. “I was extremely humbled when I heard I had received the Weintraub Award and recognized alongside 12 other graduate students. It is always great to learn that others find my work as exciting as I do.”

“Grace’s thesis work, in collaboration with physics graduate student Jean-Benoît Lalanne, provides an excellent example of how interdisciplinary approaches can generate new knowledge and challenge our understanding of biological mechanisms,” says Li, Johnson’s advisor. “What’s remarkable about Grace is not just her science, but also her deep devotion to make research institutions safer and more inclusive places.”

The Weintraub Award is supported by the Weintraub/Groudine Fellowship for Science and Human Disease, which was established to foster intellectual exchange by promoting programs for graduate students, fellows, and visiting scholars.

Cells are known by the company they keep
Eva Frederick
March 2, 2021

In the paper, published online March 1 in the journal Cell Metabolism, researchers at Whitehead Institute and the Morgridge Institute for Research performed CRISPR-based genetic screens of cells cultured in either traditional media or a new physiologic medium previously designed in the Sabatini Lab at Whitehead Institute designed to more closely reflect the nutrient composition of human blood. The screen revealed that different genes became essential for survival and reproduction in the various conditions.

“This work underscores the importance of using more human-like, physiologically relevant media for culturing human cancer cell lines,” said Whitehead Institute Member and co-senior author David Sabatini, who is also a professor of biology at the Massachusetts Institute of Technology and an investigator of the Howard Hughes Medical Institute. “The information we can learn from screens in human plasma-like media — or media designed to mimic other fluids throughout the body — may inform new therapeutic methods down the line.”

The widespread use of a human plasma-like medium could open the door for many researchers to conduct experiments in the lab that could have more relevance to human disease, but without complicated methods or prohibitive costs.

“Medium composition is both relatively accessible and quite flexible,” said co-senior author Jason Cantor, an Investigator at the Morgridge Institute for Research and an assistant professor of biochemistry at the University of Wisconsin-Madison, and a former postdoc in Sabatini’s lab. “Not all researchers have access to specialized tissue culture incubators, nor can everyone easily pursue some of the more complex 3D and co-culture methods, but most can get their hands on a bottle of media.”

The big screen

The idea that different environmental conditions may lead to different genes being essential is not a new one. “People have done this in microorganisms, and shown that if you throw [bacteria] into different growth conditions — the contributions of different genes to cell fitness can change,” Cantor said.

With this reasoning in mind — that medium composition could affect which genes become necessary for human cells to grow — the researchers set up screens to identify essential genes in a single leukemia cell line in different kinds of culture media. One batch was grown in a traditional medium, and another cultured in the lab’s new medium called Human Plasma-Like netbet sports betting appMedium, or HPLM, which has a metabolic composition more reflective of that in human blood.

The approach they used — called a CRISPR screen —  takes advantage of CRISPR-Cas9 gene editing technology to systematically snip and knock out genes across the genome, with the goal of creating a population of cells in which every possible gene knockout is represented. The expression of some genes is essential to survival, and cells grow substantially slower or die when those genes are deleted. Other cells may have trouble functioning, and some may grow even faster. Once the pooled cells have had a chance to grow and proliferate, researchers sequence the genetic material of the entire population to determine which genes were critical for survival within the given screen.

Once they completed the initial screens, the researchers identified hundreds of genes that were conditionally essential — that is, necessary for cell growth in one medium versus another. Interestingly, these medium-dependent essential genes collectively had roles in a number of different biological processes.

To determine how much these genes were dependent on the type of cells studied, the researchers then ran similar screens across a panel of human blood cancer cell lines, and then pursued follow-up work to understand why certain genes were identified as conditionally essential.

Ultimately, they uncovered the underlying gene-nutrient interactions, and specifically for these hit genes, traced the effects to availability of certain metabolites — the nutrients and small molecules necessary for metabolism — that are uniquely defined in HPLM versus the traditional media.

The next steps

CRISPR screens can help scientists identify potential drug targets and map out important cellular interactions to inform cancer therapies. “There are so many ways that people use CRISPR screens right now,” said Cantor. “What this study is showing is that the availability metabolites can have a major impact on which genes are important for cell growth, and so I think there are a lot of implications here in terms of how these types of screens could be performed in the future in order to potentially increase the fidelity of what we see in the lab and what might happen in the body.”

The research also establishes more nuanced relationships between cells’ genes and their environment. “What this allows us to do down the line, theoretically, is to tune how important a gene is — how important the encoded protein is — by manipulating metabolite levels in the blood,” said Cantor. “That’s one of our bigger-picture ideas.”

In the future, these relationships could inform cancer treatments. For example, if scientists could “tune” the importance of a specific gene for cancer cell growth, then the protein encoded by that gene could become a more promising drug target — in effect, tricking cancer cells into revealing possible context-dependent vulnerabilities. “The idea of targeting metabolites to treat cancer isn’t itself new — in fact, it [underlies] a well-established anti-cancer therapeutic enzyme still in use today — but I think our work maybe enables us to look for ways to couple this type of approach with other targeted therapies.”

“At our core, we are a basic cell biology lab,” added Nicholas Rossiter, a technician in Cantor’s lab and the first author of the study. “But whenever you’re studying basic cell biology, there’s the potential to translate it into therapeutic strategy. Our plan is just to keep on chugging along in our lab and studying how exactly cell biology can be influenced by these environmental factors. We do the basics, and then there will hopefully be some auspicious findings that can be carried on into therapeutics.”