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School of Science announces 2019 Infinite Mile Awards

Ten staff members in the School of Science are recognized for going above and beyond their job descriptions to support a better Institute.

School of Science
April 2, 2019

The MIT School of Science has announced the winners of the 2019 Infinite Mile Award, which is presented annually to staff members within the school who demonstrate exemplary dedication to making MIT a better place.

Nominated by their colleagues, these winners are notable for their unrelenting and extraordinary hard work in their positions, which can include mentoring fellow community members, innovating new solutions to problems big and small, building their communities, or going far above and beyond their job descriptions to support the goals of their home departments, labs, and research centers.

The 2019 Infinite Mile Award winners are:

Christine Brooks, an administrative assistant in the Department of Chemistry, nominated by Mircea Dincă and several members of the Dincă, Schrock, and Cummins groups;

Annie Cardinaux, a research specialist in the Department of Brain and Cognitive Sciences, nominated by Pawan Sinha;

Kimberli DeMayo, a human resources consultant in the Department of Mathematics, nominated by Nan Lin, Dennis Porche, and Paul Seidel, with support from several other faculty members;

Arek Hamalian, a technical associate at the Picower Institute for Learning and Memory, nominated by Susumu Tonegawa;

Jonathan Harmon, an administrative assistant in the Department of Mathematics, nominated by Pavel Etingof and Kimberli DeMayo, with support from several other faculty members;

Tanya Khovanova, a lecturer in the Department of Mathematics, nominated by Pavel Etingof, David Jerison, and Slava Gerovitch;

Kelley Mahoney, an SRS financial staff member in the Kavli Institute for Astrophysics and Space Research, nominated by Sarah Brady, Michael McDonald, Anna Frebel, Jacqueline Hewitt, Jack Defandorf, and Stacey Sullaway;

Walter Massefski, the director of instrumentation facility in the Department of Chemistry, nominated by Timothy Jamison and Richard Wilk;

Raleigh McElvery, a communications coordinator in the Department of Biology, nominated by Vivian Siegel with support from Amy Keating, Julia Keller, and Erika Reinfeld; and

Kate White, an administrative officer in the Department of Brain and Cognitive Sciences, nominated by Jim DiCarlo, Michale Fee, Sara Cody-Larnard, Rachel Donahue, Federico Chiavazza, Matthew Regan, Gayle Lutchen, and William Lawson.

The recipients will receive a monetary award in addition to being honored at a celebratory reception, along with their peers, family and friends, and the recipients of the 2019 Infinite Kilometer Award this month.

Biologists find a way to boost intestinal stem cell populations

Study suggests that stimulating stem cells may protect the gastrointestinal tract from age-related disease.

Anne Trafton | MIT News Office
March 28, 2019

Cells that line the intestinal tract are replaced every few days, a high rate of turnover that relies on a healthy population of intestinal stem cells. MIT and University of Tokyo biologists have now found that aging takes a toll on intestinal stem cells and may contribute to increased susceptibility to disorders of the gastrointestinal tract.

The researchers also showed that they could reverse this effect in aged mice by treating them with a compound that helps boost the population of intestinal stem cells. The findings suggest that this compound, which appears to stimulate a pathway that involves longevity-linked proteins known as sirtuins, could help protect the gut from age-related damage, the researchers say.

“One of the issues with aging is organ dysfunction, accompanied by a decline in the activity of the stem cells that nurture and replenish that organ, so this is a potentially very useful intervention point to either slow or reverse aging,” says Leonard Guarente, the Novartis Professor of Biology at MIT.

Guarente and Toshimasa Yamauchi, a professor at the University of Tokyo, are the senior authors of the study, which appears online in the journal Aging Cell on March 28. The lead author of the paper is Masaki Igarashi, a former MIT postdoc who is now at the University of Tokyo.

Population growth

Guarente’s lab has long studied the link between aging and sirtuins, a class of proteins found in nearly all animals. Sirtuins, which have been shown to protect against the effects of aging, can also be stimulated by calorie restriction.

In a paper published in 2016, Guarente and Igarashi found that in mice, low-calorie diets activate sirtuins in intestinal stem cells, helping the cells to proliferate. In their new study, they set out to investigate whether aging contributes to a decline in stem cell populations, and whether that decline could be reversed.

By comparing young (aged 3 to 5 months) and older (aged 2 years) mice, the researchers found that intestinal stem cell populations do decline with age. Furthermore, when these stem cells are removed from the mice and grown in a culture dish, they are less able to generate intestinal organoids, which mimic the structure of the intestinal lining, compared to stem cells from younger mice. The researchers also found reduced sirtuin levels in stem cells from the older mice.

Once the effects of aging were established, the researchers wanted to see if they could reverse the effects using a compound called nicotinamide riboside (NR). This compound is a precursor to NAD, a coenzyme that activates the sirtuin SIRT1. They found that after six weeks of drinking water spiked with NR, the older mice had normal levels of intestinal stem cells, and these cells were able to generate organoids as well as stem cells from younger mice could.

To determine if this stem cell boost actually has any health benefits, the researchers gave the older, NR-treated mice a compound that normally induces colitis. They found that NR protected the mice from the inflammation and tissue damage usually produced by this compound in older animals.

“That has real implications for health because just having more stem cells is all well and good, but it might not equate to anything in the real world,” Guarente says. “Knowing that the guts are actually more stress-resistant if they’re NR- supplemented is pretty interesting.”

Protective effects

Guarente says he believes that NR is likely acting through a pathway that his lab previously identified, in which boosting NAD turns on not only SIRT1 but another gene called mTORC1, which stimulates protein synthesis in cells and helps them to proliferate.

“What we would hypothesize is that the NAD replenishment in old mice is driving this pathway of growth that’s working through SIRT1 and TOR to reverse the decline that has occurred with aging,” he says.

The findings suggest that NAD might have a protective effect against diseases of the gut, such as colitis, in older people, he says. Guarente and his colleagues have previously found that NAD precursors can also stimulate the growth of blood vessels and muscles and boost endurance in aged mice, and a 2016 study from researchers in Switzerland found that boosting NAD can help replenish muscle stem cell populations in aged mice.

In 2014, Guarente started a company called Elysium Health, which sells a dietary supplement containing NR combined with another natural compound called pterostilbene, which is an activator of SIRT1.

The research was funded, in part, by the National Institutes of Health and the Glenn Foundation for Medical Research.

Whitehead Institute’s David Page to conclude term as director

Search committee chaired by MIT President Emerita Susan Hockfield will identify new director for eminent biomedical institute.

Lisa Girard | Whitehead Institute
March 27, 2019

Whitehead Institute, the world-renowned nonprofit research institution dedicated to improving human health through basic biomedical research, has announced that Institute Director David C. Page — a Whitehead Institute member since 1988 and director since 2004 — will complete his current term as director and president in summer 2020. An international search has been launched for Page’s successor.

“David’s tenure as director has been a period of incredible richness for Whitehead Institute,” says Charles D. Ellis, chair of the Whitehead Institute Board of Directors. “It has been rich in the path-breaking science that our researchers have done; in the intellectual ferment and creative environment that Whitehead members have fostered; and in the sense of community and common purpose that David has nurtured. He has led us with great skill and vision through a dynamic period of growth and continuous exploration, and he will pass to his successor an organization primed to tackle the challenges offered by a swiftly evolving bioscience landscape.”

Since its founding in 1982, Whitehead Institute has been one of the world’s most influential biomedical research centers — producing a continual stream of significant discoveries and new research tools and approaches. Whitehead Institute is a legally and financially independent organization closely affiliated with MIT, and Whitehead Institute members hold MIT faculty appointments. The 17 Whitehead Institute members include two National Medal of Science winners, nine National Academy of Sciences members, four National Academy of Medicine members, and four Investigators of the Howard Hughes Medical Institute. In addition, the institute’s prestigious Whitehead Fellows Program has fostered generations of biomedical science leaders — including Harvard Medical School Dean George Daley, celebrated MIT cancer researcher and professor of biology Angelika Amon, Broad Institute President and Founding Director Eric Lander, and NASA astronaut and space biologist Kate Rubins.

Whitehead Institute and MIT have been Page’s professional home since he earned an MD from Harvard Medical School and the Harvard-MIT Health Sciences and Technology Program and completed research in David Botstein’s lab at MIT in 1984. After serving as the institute’s first Whitehead Fellow, he became a Whitehead member and MIT faculty member in 1988. Page was appointed associate director of the institute in 2002, interim director in 2004, and director in 2005.

Throughout his 35 years at Whitehead Institute, Page has run a thriving and productive research lab. His groundbreaking studies on the Y chromosome changed the way biomedical science views the function of sex chromosomes. That work earned him wide recognition, including a Macarthur Foundation Fellowship and a Searle Scholar Award; and he has been an Investigator of the Howard Hughes Medical Institute since 1990. His research twice earned inclusion in Science magazine’s “Top 10 Breakthroughs of the Year,” first for mapping a human chromosome and then for sequencing the human Y chromosome. Today, his lab is pursuing a deep understanding of the role of sex chromosomes in health and disease — work with the potential to fundamentally change the practice of medicine and improve the quality of care for women and men alike.

As director, Page has made a mark on all facets of the Whitehead Institute organization. During his tenure, he oversaw the creation of the Institute’s Intellectual Property Office; strengthened its core facilities; and established new platforms, such as the Metabolomics Center. He also enhanced the leadership structure by appointing three associate directors; and he supported the creation of the child care center. Perhaps most important for the long run, Page has guided a robust renewal of faculty and has helped to prepare the organization for the eventual retirement of the Institute’s founding generation of members.

The search for Page’s successor will be guided by a committee of noted leaders in education, biomedical research, and nonprofit organizations, including Susan Hockfield (chair), MIT professor of neuroscience and president emerita; Laurie H. Glimcher, president and CEO of the Dana-Farber Cancer Institute and former dean of Weill Cornell Medical College; Alan Grossman, the Praecis Professor of Biology and head of the MIT Department of Biology; Paul L. Joskow, former president and CEO of Alfred P. Sloan Foundation and the Elizabeth and James Killian Professor of Economics Emeritus at MIT; Amy E. Keating, professor in the departments of Biology and Biological Engineering at MIT; David Sabatini, Whitehead Institute member and associate director, and professor of biology at MIT; Phillip A. Sharp, Nobel laureate and MIT Institute professor and professor of biology; and Sarah Williamson, CEO of FCLT Global and former partner at Wellington Management Company (Joskow, Sharp, and Williamson are also members of the Whitehead Institute Board of Directors.)

The committee will be assisted by global executive search firm Russell Reynolds Associates.

“Whitehead Institute is one of the world’s premier research institutions,” says Hockfield. “It possesses an innovative and collaborative culture; rich talent and intellectual capital; a robust relationship with MIT; and a place at the heart of the Kendall Square innovation community. These factors make it an ideal opportunity for a director with vision, scientific courage, and a passion to address basic biomedical science’s most significant challenges.”

“The scientists of Whitehead Institute have helped to drive biomedical research forward and onto exciting new paths,” says Page. “In coming years, the Institute itself will experience a generational evolution, and my successor will help define the organization’s future — and by extension, help shape the direction of biomedical research for decades to come.”

The new director will have an impressive line of predecessors: Whitehead Institute’s founding director was Nobel laureate and former Caltech president David Baltimore; he was succeeded by globally respected researcher and science enterprise leader Gerald Fink, and then by National Medal of Science recipient Susan Lindquist — Page’s immediate predecessor.

Life unfolding

Graduate student Marlis Denk-Lobnig investigates the biological forces that shape developing tissue to dictate form and function.

Raleigh McElvery
March 22, 2019

A few hours after fertilization, the fruit fly embryo is just a hollow sphere, slightly oblong in shape, until a band of cells on its surface furrows inward to form a new layer. This folding process takes only 15 minutes, but it’s critical for determining where the cells will go and what roles they will eventually play. In humans, errors in tissue folding can result in diseases like spina bifida, where the spine never fully closes.

Fourth-year graduate student Marlis Denk-Lobnig watches this gastrulation process occurring in fly embryos in real time, tagging molecules with fluorescent proteins to probe the forces that eventually shape a fully-formed organism. Every day, she gets to witness new life unfold — literally.

Denk-Lobnig spends most of her time with her eye to a microscope or generating genetic crosses in the “fly room” where she keeps her stocks — rows of tubes containing light brown insect food that emits an unmistakable odor, despite being corked with cotton swabs. Inside each neatly labeled container, scores of tiny flies mill around as they lay eggs and feast.

Given that her mother trained in chemistry and her father in physics, “it didn’t take much creativity to get into science early on.” Denk-Lobnig enjoyed physics throughout high school, but also maintained a keen interest in biology, which became more pronounced after she was diagnosed with an autoimmune disease affecting her thyroid and adrenal glands.

“In some ways, the question of how your own body works is the most tangible question to ask,” she says. “It’s fascinating to connect everyday experiences with mechanisms, and studying biology and medicine seemed like a powerful way to have a direct impact on life.”

She majored in molecular medicine at Georg August University in Göttingen, Germany, located several hours from her childhood home in Heidelberg. Inspired by a summer internship with MIT Biology alum and Rockefeller professor Cori Bargmann PhD ’87, Denk-Lobnig centered her undergraduate thesis on the role glial cells play in disease.

She graduated after only three years, the typical duration in Germany, and spent the next several months traveling and applying to graduate schools. She also visited Nepal, where she taught visual and performing arts — and a bit of gymnastics — at a local boarding school.

When she began at MIT in 2015, Denk-Lobnig took the opportunity to blend her expertise in biology with a renewed enthusiasm for physics. Although she is a full-fledged member of the Department of Biology, she is simultaneously enrolled in the interdepartmental Biophysics Certificate Program.

“Not many people know that MIT has a thriving biophysics community,” she says. “It’s a mix of mechanical engineers, chemists, biologists, and physicists. There are specific course requirements, and we go on retreats and participate in seminars to share our research and discuss collaborations.”

As a member of Adam Martin’s lab, Denk-Lobnig studies the cellular forces that shape tissue form and function. Martin is also affiliated with the certificate program, and was one of the faculty members who initially interviewed Denk-Lobnig for the graduate program.

“Biophysics is all about finding elegant explanations for everyday phenomena, and I really enjoy thinking about physical principles and how they apply to biological problems,” Denk-Lobnig says. “The methods we use in the Martin lab are also incredibly visual. You can literally see a fruit fly embryo fold, and watch as a sheet of cells furrows inside the embryo to form a second layer, which is important for development. It’s both informative and aesthetically pleasing.”

Denk-Lobnig began by focusing on a single molecule called Cumberland-GAP (C-GAP), which regulates one of the many proteins in charge of tissue folding: myosin. Myosin is responsible for muscle contraction, among other duties. With its characteristic forked shape — two “heads” protruding from string-like “tail” domain — myosin can appear to walk along the cell’s scaffolding, sometimes transporting cargo. Denk-Lobnig, though, is most interested in myosin’s ability to pull on developing tissue and create a fold.

Right before graduating, one of Denk-Lobnig’s former labmates noticed that depleting C-GAP seemed to alter the concentration (or “gradient”) of myosin across the tissue. Since this finding pertained to the very regulator she was studying, it piqued Denk-Lobnig’s interest. She wanted to know how molecules like C-GAP might influence myosin and impact folding, and her scope widened from the molecular level to include the entire tissue.

It’s unlikely, she says, that myosin is pulling with equal force across the tissue — “that wouldn’t constrict the sheet of cells very efficiently.” Instead, there’s probably more myosin in middle and less towards the edges, which contracts the cells in the middle of the sheet to a greater degree and creates the curvature that forms the crease of the fold. In the fruit fly, gastrulation occurs just three hours after the eggs are laid. Because the folding happens at the surface of the embryo, there’s no need for dissection to witness the entire event through a microscope.

Denk-Lobnig has begun exploring other regulators besides C-GAP to analyze their effects on the myosin gradient and cell curvature. She was one of the first members of the lab to introduce CRISPR-Cas9 into their testing protocol, and is currently the only one experimenting with optogenetic techniques. She also regularly participates in the lab book club, which features classics like The Bell Jar and One Hundred Years of Solitude.

Outside of lab, Denk-Lobnig serves as the president of MIT’s women’s club gymnastics team, volunteers to help run weekly Gymnastics Special Olympics events, and sings in a graduate student choir. She is also a member of the department’s peer support program, bioREFs.

Long-term, she plans to stay in academia and delve further into physics-based methods, like modeling and coding. If she could find a project that’s just as visual as her current work in the Martin lab, “that would definitely be a plus.”

Posted 3.21.19
Meenakshi Chakraborty named 2019 Churchill Scholar

Senior majoring in computer science and molecular biology will pursue an MPhil at Cambridge University.

Office of Distinguished Fellowships
March 18, 2019

Meenakshi Chakraborty, a senior from Cambridge, Massachusetts, has been named a 2019 Churchill Scholar and will pursue an MPhil at Cambridge University.

Chakraborty is expected to graduate this spring with a BS in computer science and molecular biology. As a Churchill scholar she aims to pursue a master’s degree in genetics at Cambridge. When she returns to the U.S. she plans to pursue a PhD in biology with a focus on genetics.

Chakraborty realized a passion for scientific research when still in high school. After a trip to a South African hospital, she realized the devastation caused by the AIDS epidemic, and discovered a desire to participate in scientific research that could lead to medical breakthroughs. Upon her return, she learned of the work of Bruce Walker, director of the Ragon Institute of MGH, MIT, and Harvard, and a professor at MIT’s Institute for Medical Engineering and Science. Despite the fact that Chakraborty was still in high school, Walker agreed to mentor her work on a study of epidemiology of HIV.

Chakraborty next began research under the tutelage of Institute Professor Phil Sharp. Jeremy Wilusz, a former Sharp Lab postdoc and current professor of biochemistry at the University of Pennsylvania, says, “It was clear long ago that Meena was a superstar in the making. As a 15-year-old, she reached out to Phil about writing an independent report on RNA over the summer. (I believe you had to be at least 16 to do actual research in a lab at MIT, so this was her way of getting her feet wet.) She asked to meet with one of the postdocs in the lab every couple of weeks to make sure she was heading in the right direction, and I became that postdoc. We decided to have her write a report on the history and functions of circular RNAs, which had recently been the subject of several prominent papers in Nature. She would go off, read a ton of papers, write extensive outlines, and bring very thoughtful questions to my attention that we would talk about. This effort ultimately resulted in the first Wikipedia page on circular RNAs (completely her idea) that others have built upon as the field has evolved.”

When Chakraborty matriculated at MIT, she began conducting research in the Sharp Lab at the Koch Institute for Integrative Cancer Research, as an Undergraduate Research Opportunities Program (UROP) student. During her time in the lab, she has investigated cell states, and how cells with identical genetic information and the same differentiation state vary. This issue is at the center of problems in developmental biology and the mechanisms of cancer. She has worked closely with research scientist Salil Garg on this work, who says, “Meena makes everything around her more fun. Her endless enthusiasm and positivity rub off on everyone in lab. Working with her has been an absolute joy. It’s hard to imagine what the lab will be like without her.”

Chakraborty has also participated in competitive summer research programs including MIT’s Johnson and Johnson UROP Scholars Program, which aims to support and increase the number of women in STEM, manufacturing, and design fields. With funding from Johnson and Johnson as part of its Women in Science, Technology, Engineering, Math, Manufacturing and Design (WiSTEM2D) initiative, Johnson and Johnson UROP Scholars conduct full-time summer research, in addition to attending faculty presentations, workshops, and networking events. Sarah Nelson, senior program coordinator of UROP and Johnson and Johnson UROP Scholars, says, “Meena was a great addition to this program not only because she is an outstanding student and researcher, but she is a true advocate for women in STEM.”

Chakraborty received a Goldwater scholarship last year due to her exceptional work as a student and researcher. She has continued to work in the Sharp lab while she finishes her degree at MIT.

During her time at MIT, she has also worked on science advocacy with MIT Effective Altruism (EA) Club. Chakraborty plans to explore working with Cambridge EA while studying in the U.K. She hopes to use this opportunity to develop her multidisciplinary approach to research and developing treatments for life-threatening conditions.

Chakraborty was advised in her application by Kim Benard in the Office of Distinguished Fellowships and by the Presidential Committee for Distinguished Fellowships, co-chaired by Professors William Broadhead and Rebecca Saxe. The Churchill Scholarship is a competitive program that annually offers 16 students an opportunity to pursue a funded graduate degree in science, mathematics or engineering at Churchill College within Cambridge University.

A Wide Net to Trap Cancer

Stefani Spranger is exploring multiple avenues for the next immunotherapy breakthrough

Pamela Ferdinand | Spectrum
March 12, 2019

A YOUNG LAB AT THE FOREFRONT OF IMMUNOTHERAPY DISCOVERIES is an exciting yet challenging place to be. MIT faculty member Stefani Spranger, an expert in cancer biology and immunology, understands that better than most people.

Spranger knows that new labs such as hers, which opened in July 2017 at the Koch Institute for Integrative Cancer Research at MIT, face distinct advantages and disadvantages when it comes to making their mark. While younger labs typically have startup grants, they lack the long-term funding, track record, and name recognition of established researchers; on the other hand, new labs tend to have smaller, close-knit teams open to tackling a wider array of investigative avenues to see what works, what doesn’t work, and where promise lies.

That’s when the funds and recognition of an endowed professorship can make a big difference, says Spranger, an assistant professor of biology who last year was named the Howard S. (1953) and Linda B. Stern Career Development Professor. “Not everything will work, so being able to test multiple approaches accelerates discovery and success,” she says.

Spranger is working to understand the mechanisms underlying interactions between cancer and the immune system—and ultimately, to find ways to activate immune cells to recognize and fight the disease. Cancer immunotherapies (the field in which this past year’s Nobel Prize in Physiology or Medicine was awarded) have revolutionized cancer treatment, leading to a new class of drugs called checkpoint inhibitors and resulting in lasting remissions, albeit for a very limited number of cancer patients. According to Spranger, there won’t be a single therapy, one-size-fits-all solution, but targeted treatments for cancers depending on their characteristics.

To discover new treatments, Spranger’s lab casts a wide net, asking big-picture questions about what influences anti-tumor immune response and disease outcome while also zooming in to investigate, for instance, specifically how cancer-killing T cells are excluded from tumors. In 2015, as a University of Chicago postdoc, Spranger made the novel discovery that malignant melanoma tumors with high beta-catenin protein lack T cells and fail to respond to treatment while tumors with normal beta-catenin do.

Her lab focuses on understanding lung and pancreatic cancers, employing a multidisciplinary research team with expertise ranging from immunology and biology to math and computation. One of her graduate students is using linear algebra to develop a mathematical model for translating mouse data into more accurate predictions about key signaling pathways in humans.

Another project involves exploring the relationship between homogenous tumors and immune response. Not every cancer cell is identical, nor does it have the same molecules on its surface that can be recognized by an immune cell; cancer patients with a more homogenous expression of those cells do better with immunotherapy. To investigate whether that homogeneity is due to the tumor or to the immune response to the tumor, Spranger is seeking to build a model system. The research involves a lot of costly sequencing—up to $3,000 per attempt, which is fairly expensive for a young lab—and each try has an element of what Spranger half-jokingly describes as “close your eyes and hope it worked.”

“Being able to generate preliminary proof of concept data for high-risk projects is of outstanding importance for any principal investigator,” she says. “However, it is particularly important to have freedom and flexibility early on.”

Boosting potential

Advancing cancer research and supporting the careers of promising faculty were the intentions of Linda Stern and her late husband Howard Stern ’53, SM ’54, whose gift has supported a series of biology professors since 1993. The first appointee to the chair was Tyler Jacks, now director of the Koch Institute.

Linda Stern says her husband, the cofounder and chairman of E-Z-EM, Inc., and a pioneer in the field of medical imaging, gave thoughtfully to many charitable causes. Yet MIT, where he earned undergraduate and graduate degrees in chemical engineering, had a special place in his heart.

“He was very involved and loved MIT,” says Stern, whose own career path included working as a private detective for 28 years. “He made wonderful contacts and got a wonderful education. He was a real heavy hitter when it came to defending the university.”

MIT’s continued excellence in a competitive environment depends on its ability to recognize and retain faculty, nurture careers, support students, and allow for the pursuit of novel ideas. Like the full professorships awarded to tenured faculty members, career development professorships such as the one endowed by the Sterns fund salary, benefits, and a scholarly allowance. These shorter-term (typically three-year) appointments, however, are specifically meant to accelerate the research and career progression of junior professors with exceptional potential.

“The professorship showed me that MIT as a community is invested and interested in fostering my career,” says Spranger. The discretionary funds she receives from the chair can cover, without need for an approval process, expenses that are not paid for by grants or that suddenly arise from a new idea or opportunity. They can keep projects running in tough times, fund travel to conferences, and purchase equipment. “It gives you a little more traction,” Spranger says. “It’s probably the best invested money because you have a lot of ideas you want to test, and at the same time, you are still checking the pulse of where the field might go and where you want to build your niche.”

A “model” parasite

Whitehead Institute researchers unravel the unique biology of apicomplexans — the parasites responsible for malaria, toxoplasmosis, and other diseases impacting global health.

Whitehead Institute
February 19, 2019

Apicomplexa: A brood of parasites

Malaria, cryptosporidiosis, and toxoplasmosis affect millions of people each year, killing an estimated 600,000 annually, mostly children under five in developing countries. Billions of dollars are spent each year to control and eliminate these diseases, according to the World Health Organization (WHO). Each of these diseases is caused by a different apicomplexan, a group of parasites that infect almost all animal species.

Toxoplasma gondii (T. gondii), which causes the disease toxoplasmosis, has a unique physiology that has allowed it to parasitize its hosts, yet it retains many features in common with other apicomplexans. Using T. gondii as a “model parasite”, Whitehead Member Sebastian Lourido is deciphering apicomplexans’ unique biology and uncovering aspects that could be harnessed to disrupt the parasites’ ability to proliferate and infect their hosts.

Apicomplexans’ toll on humans is staggering:

· Malaria, caused by several Plasmodium species of Apicomplexa, was responsible for over 200 million infections and more than 400,000 deaths, primarily in young children, in 2017 (WHO).

· Severe diarrhea kills an estimated 525,000 children under five each year (WHO). Over 200,000 of those deaths can be attributed to cryptosporidiosis, which is caused by the species of the apicomplexan Cryptosporidium (Sow et al., 2016, PLoS Negl Trop Dis.).

· 25% of the global population is infected with T. gondii with rates reaching over 60% in some areas (Pappas et al. 2009, Int. J. Parasitol.). Toxoplasmosis can cause an array of serious neurological disorders in those with weakened immune systems and can be lethal or lead to birth defects in a developing fetus. In an estimated 2% of infected individuals, toxoplasmosis causes retinal lesions (Holland, 2003, Am J Ophthalmol.).

A parasitic relationship, separated by a billion years of evolution

The diagram above depicts the evolutionary relationships between organisms — species separated by many branches are more distantly related than those divided by fewer branches. Apicomplexans and humans are separated by multiple branches and more than a billion years of evolution. In fact, apicomplexans are actually more closely related to plants than animals, having evolved from a non-parasitic ancestor about 700 to 900 million years ago that, like green plants, used photosynthesis to generate energy from sunlight. So far, scientists have studied only about half of the known apicomplexan genes, leaving the rest of their 8,000 predicted protein-coding genes uncharacterized.

Although key genes important for fundamental processes have remained fairly stable over the billion years since apicomplexans and their hosts diverged, other parts of the apicomplexan genomes evolved as they adapted to a parasitic lifestyle. The genes that emerged as unique to apicomplexans, such as those encoding factors involved in entering or exiting host cells, potentially represent therapeutic targets because curtailing their expression could hamstring — or even eliminate — the parasites without harming the host.

Analyzing a unique biology

Understanding apicomplexans and their distinct biology has been challenging at least in part because the tools — genomic analysis, genetic engineering, and culture systems — that scientists use to study and understand more traditional model organisms in the lab, such as mice, are difficult to apply in apicomplexans. Moreover, apicomplexans may spend different stages of their lives in different hosts, so studying a parasite’s complete life cycle may require studying and culturing multiple organisms or their tissues. For example, Plasmodium falciparum, which causes malaria, spends part of its life cycle in mosquitoes and another in humans.

Unlike the Plasmodium parasites that cause malaria, T. gondii is relatively easy to culture in the lab. Lourido, who is also an assistant professor of biology at Massachusetts Institute of Technology (MIT), and his lab are using this organism to unravel many elemental questions about apicomplexans: How do they infect their host cells? What do they require to reproduce? How do they break out of their host cell to infect more cells?

Adapted CRISPR/Cas9 gene editing system reveals first genome-wide glimpse of apicomplexan genomic profile

Researchers in Lourido’s lab are working to decipher the 50% of the T. gondii’s genome that remains to be characterized. To do so, they adapted the CRISPR/Cas9 gene editing system to work in T. gondii. Using CRISPR/Cas9, researchers can cut T. gondii’s DNA at specific sites to disable particular genes. With this approach, they were able to efficiently conduct genome-wide screens to identify genes that are functionally important to the parasite.

For this screen the Lourido lab used their adapted CRISPR/Cas9 gene editing system to remove the function — one at a time — of each of T. gondii’s ~8,000 protein-coding genes. The resulting altered parasites were then cultured with human host cells. After a period of time, the scientists tallied the number of parasites present with each modification to assess how disabling a particular gene’s function affects the parasites’ reproduction and survival. Altered parasites that successfully proliferated despite missing a gene’s function were deemed to have alterations in a gene that is dispensable, whereas modified parasites that did not thrive were deemed to have alterations in genes that are important for fitness.

Screen identifies apixomplexan-specific proteins

The initial screen of the T. gondii genome, led by Lourido lab research assistant Saima Sidik and postdoctoral researcher Diego Huet, identified a number of genes that encode indispensable conserved apicomplexan proteins, called ICAPs for short (Sidik et al. 2016, Cell). One ICAP identified by Sidik and Huet is an invasion factor called the claudin-like apicomplexan microneme protein (CLAMP).

In the same Cell paper, researchers described how they determined that CLAMP is critical to the initiation of host cell invasion by T. gondii. Working with Jacquin Niles and members of his lab in the MIT Department of Biological Engineering, the Lourido team also showed that CLAMP is required for the parasites that cause malaria to survive when grown in red blood cells.

In a recent paper published in the journal eLife, Lourido and first author Huet, identified a protein in apicomplexans that is crucial for creating adenosine triphosphate (ATP), the universal energy storage unit of cells. ATP is essential for cells’ survival and without it, cellular processes would stall. Most organisms have an enzyme, called ATP synthase, that creates ATP by converting the energy of a proton gradient across a membrane into mechanical energy. As the protons move through the ATP synthase, it spins like a turbine. This movement powers the formation of ATP. For the enzyme to work properly, a portion of the ATP synthase acts as a scaffold, or stator, by counteracting the rotation of the turbine-like part of the enzyme.

Although most components of the ATP synthase are conserved between apicomplexans and humans, scientists had been unable to pinpoint the gene encoding the essential stator portion – no DNA sequence in the apicomplexan genome resembles the sequences of known stator genes. Using a genomic approach, Huet and Lourido analyzed the predicted function and structure of the ICAPs  present in the mitochondrion, the ATP synthase’s home in all organisms. To their surprise, the predicted shape of one of the ICAPs resembles a stator subunit found in yeast and mammals.

When Huet and Lourido mutated or removed the stator subunit, the parasite’s ATP synthase failed to function properly, damaging the structure and performance of its mitochondria and halting the the parasite’s growth.

The beginning of a parasitic relationship

For Lourido and his lab, T. gondii’s unique stator protein is just one example of how these extraordinary apicomplexan organisms have evolved and adapted. By tailoring current tools and inventing new ones, Lourido’s investigations into T. gondii’s biology have the potential to reveal important insights into this family of parasites that impacts millions of people each year.

Credits

Written and produced by Nicole Giese Rura and Whitehead Institute

Illustrations and animations by Andrew Tubelli

Cover image courtesy of Clare Harding/Whitehead Institute

Special thanks to Sebastian Lourido and his lab, especially Clare Harding, Diego Huet, and Saima Sidik

References

WHO: Global Health Observatory (GHO data) for number of malaria cases

UNICEF: Diarrhoea as a cause of death in children under 5

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Huet D, Rajendran E, van Dooren GG, Lourido S. (2018) Identification of Cryptic Subunits from an Apicomplexan ATP Synthase. eLife. 2018;7:e38097. https://doi:10.7554/eLife.38097

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