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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

netbet sports betting app 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 NetBet sportremissions, 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, netbet sports bettingspends 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

Holland GN. (2003) Ocular toxoplasmosis: a global reassessment. Part I: epidemiology and course of disease. Am J Ophthalmol. Dec;136(6): 973-988. https://doi.org/10.1016/j.ajo.2003.09.040

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

Pappas G, Roussos N, Falagas ME. (2009) Toxoplasmosis Snapshots: Global Status of Toxoplasma gondii Seroprevalence and Implications for Pregnancy and Congenital Toxoplasmosis. Int J Parasitol. Oct;39(12):1385-94. https://doi: 10.1016/j.ijpara.2009.04.003

Sidik SM, Huet D, Ganesan SM, Huynh MH, Wang T, Nasamu AS, Thiru P, Saeij JPJ, Carruthers VB, Niles JC, Lourido S. (2016) A Genome-wide CRISPR Screen in Toxoplasma Identifies Essential Apicomplexan Genes. Cell. Sep 8;166(6):1423-1435.e12. https://doi:10.1016/j.cell.2016.08.019

Sow SO, Muhsen K, Nasrin D, Blackwelder WC, Wu Y, Farag TH, et al. (2016) The Burden of Cryptosporidium Diarrheal Disease among Children < 24 Months of Age in Moderate/High Mortality Regions of Sub-Saharan Africa and South Asia, Utilizing Data from the Global Enteric Multicenter Study (GEMS). PLoS Negl Trop Dis. 10(5): e0004729. https://doi.org/10.1371/journal.pntd.0004729

Yahata K, Treeck M, Culleton R, Gilberger T-W, Kaneko O (2012) Time-Lapse Imaging of Red Blood Cell Invasion by the Rodent Malaria Parasite Plasmodium yoelii. PLoS ONE. 7(12): e50780. https://doi.org/10.1371/journal.pone.0050780

Start signal for sex cell creation
Greta Friar | Whitehead Institute
February 27, 2019

Cambridge, MA — Cells can divide and multiply in two ways: mitosis, in which the cell replicates itself, creating two copies identical to the original; or meiosis, in which the cell shuffles its DNA and divides twice, creating four genetically unique cells, each with half of the original cell’s number of chromosomes. In mammals, these latter cells become eggs and sperm.

How do germ line cells, the repository of cells that create eggs and sperm, know when to stop replicating themselves and undergo meiosis? Researchers had been aware that a protein called STRA8, which is only active in germ line cells, was involved in initiating meiosis, but they did not know how. New research from Whitehead Member and Institute Director David Page, also a professor of biology at Massachusetts Institute of Technology and an investigator with Howard Hughes Medical Institute; Mina Kojima, formerly a Massachusetts Institute of Technology graduate student and now a postdoctoral researcher at Yale; and visiting scientist Dirk de Rooij has revealed that in mice, STRA8 initiates meiosis by activating and amplifying a network of thousands of genes. This network includes genes involved in the early stages of meiosis, DNA replication, and other cell division processes. The research was published in eLife on February 27, 2019.

In the past, researchers have had difficulty collecting enough cells on the cusp of meiosis to investigate STRA8’s role. In mammals, germ line cells are inside the body, difficult to access, and they begin meiosis in staggered fashion so few cells are at the same stage during an extraction. Researchers in Page’s lab had previously come up with an approach to solve this problem using developmental synchronization, manipulating the cells’ exposure to the chemical that triggers their development in order to prompt all of the cells to begin meiosis simultaneously. Once the cells were synced up, first author Kojima could get a large enough sample to observe patterns in gene expression leading netbet sports betting appup to and during meiosis, and to figure out where STRA8 is binding.

She found that STRA8 binds to the regulatory portions of DNA called promoter regions, which initiate or increase transcription of adjacent genes, of most critical meiosis genes. With some exceptions, STRA8 does not switch genes from off to on. Rather, genes in the STRA8-regulated network are already expressed at low levels and STRA8 binding massively ramps up their production. The researchers posit that meiosis is then initiated once the genes reach a threshold of expression. This finding sheds light on instances in previous studies in which researchers found meiosis-related genes active in cells not yet undergoing meiosis.

The researchers were surprised to find that STRA8 also amplifies many genes involved in mitosis. However, they suggest that the meiosis-specific genes activated by STRA8 take precedence in determining which of the two cell-cycle processes the cell will undergo. STRA8 regulates certain critical genes, such as Meioc and Ythdc2, which help to establish a meiosis-specific cell-cycle program.

This research enriches our understanding of the process of sexual reproduction. Identifying the expansive STRA8-regulated network has elucidated the start of meiosis: the moment a cell commits to recombining and dividing, relinquishing its genetic identity for the chance to create something — or someone — new.

This work was supported by the National Science Foundation and the Howard Hughes Medical Institute.

 

Written by Greta Friar

***

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.

***

Full citation:

“Amplification of a broad transcriptional program by a common factor triggers the meiotic cell cycle in mice”

eLife, February 27, 2019, https://doi.org/10.7554/eLife.43738

Mina L. Kojima (1,2), Dirk G. de Rooij (1), and David C. Page (1,2,3)

1. Whitehead Institute, 455 Main Street, Cambridge, MA 02142, USA

2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA

3. Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142, USA

Pumping up red blood cell production
Greta Friar | Whitehead Institute
February 28, 2019

Cambridge, MA — Red blood cells are the most plentiful cell type in our blood and play a vital role transporting oxygen around our body and waste carbon dioxide to the lungs. Injuries that cause significant blood loss prod the body to secrete a one-two punch of signals – stress steroids and erythropoietin (EPO) – that stimulates red blood cell production in the bone marrow. These signals help immature cells along the path to becoming mature red blood cells. In a healthy individual, as much as half of their blood volume can be replenished within a week. Despite its importance, scientists are still working to unravel many aspects of red blood cell production. In a paper published online February 28 in the journal Developmental Cell, Whitehead Institute researchers describe work that refines our understanding of how stress steroids, in particular glucocorticoids, increase red blood cell production and how early red blood cell progenitors progress to the next stage of maturation toward mature red blood cells.

These findings are especially important for patients with certain types of anemia that do not respond to clinical use of EPO to stimulate the final stages of red cell formation, such as Diamond-Blackfan anemia (DBA). In this rare genetic disorder usually diagnosed in infants and toddlers, the bone marrow does not produce enough of early red blood cell progenitors, called burst forming unit-erythroids (BFU-Es), that respond to glucocorticoids. In both healthy people and DBA patients, these BFU-Es divide several times and mature before developing into colony forming unit-erythroids (CFU-Es) that that, stimulated by EPO, repeatedly divide and produce immature red blood cells that are released from the bone marrow into the blood. But the lack of BFU-Es in DBA patients means that the glucocorticoid signal has a limited target, and the cascade of cell divisions that should result in plentiful red blood cells is contracted and instead produces an insufficient amount.

One of the standard treatments for DBA is boosting red blood cell production with high doses of synthetic glucocorticoids, such as prednisone or prednisolone. But the mechanisms behind these drugs and their normal counterparts are not well understood. By deciphering the mechanisms by which glucocorticoids stimulate red cell formation, scientists may be able identify other ways to stoke CFU-E production – and ultimately red blood cell production – without synthetic glucocorticoids and the harsh side effects that their long-term use can cause, such as poor growth in children, brittle bones, muscle weakness, diabetes, and eye problems.

For more than two decades, Whitehead Institute Founding Member Harvey Lodish, has investigated glucocorticoids’ effects on red blood cell production. In his lab’s most recent paper, co-first authors and postdocs Hojun Li and Anirudh Natarajan, describe their research, which helps decipher how BFU-Es progress through their maturation process.

For more than 30 years, scientists have thought that glucocorticoids bestowed BFU-Es with a stem cell-like ability to divide until an unknown switch flipped and the cells matured to the CFU-E stage. By looking at gene expression in individual BFU-Es from normal mice, Li and Natarajan determined that the developmental progression from BFU-E to CFU-E is instead a smooth continuum. They also found that in mice glucocorticoids exert the greatest effect on the BFU-Es at the beginning of the developmental continuum by slowing their developmental progression without affecting their cell division rate. In other words glucocorticoids are able to effectively compensate for a decreased number of BFU-Es by allowing those that do exist, while still immature, to divide more times, producing in mice up to 14 times more CFU-Es than BFU-Es lacking exposure to glucocorticoids.

Li and Natarajan’s work reveals previously unknown aspects of the mechanism by which glucocorticoids stimulate red blood cell production. With this better understanding, scientists are one step closer toward pinpointing more targeted approaches to treat certain anemias such as DBA.

This work was supported by the National Institutes of Health (NIH grants DK06834813 and HL032262-25) and the American Society of Hematology and was performed with the assistance of Whitehead Institute’s Fluorescence Activated Cell Scanning (FACS) Facility and Genome Technology Core facility. Styliani Markoulaki, head of the Whitehead Genetically Engineered Models Center, and M. Inmaculada Barrasa of Bioinformatics and Research Computing (BaRC) are also co-authors of the paper.

 

Written by Nicole Giese Rura

***

Harvey Lodish’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 professor of biology and a professor of biological engineering at Massachusetts Institute of Technology (MIT). Lodish serves as a paid consultant and owns equity in Rubius, a biotech company that seeks to exploit the use of modified red blood cells for therapeutic applications.

***

Citation:

“Rate of Progression through a Continuum of Transit-Amplifying Progenitor Cell States Regulates Blood Cell Production”

Developmental Cell, online February 28, 2019, https://doi.org/10.1016/j.devcel.2019.01.026

Hojun Li*, Anirudh Natarajan*, Jideofor Ezike, M. Inmaculada Barrasa, Yenthanh Le, Zoë A. Feder, Huan Yang, Clement Ma, Styliani Markoulaki, and Harvey F. Lodish.

*These authors contributed equally

Committed to service and science

When senior Julia Ginder isn’t investigating the mystery of her own allergies, she’s volunteering to help young people reach their goals.

Gina Vitale | MIT News correspondent
February 25, 2019

Julia Ginder has to avoid a lot of foods due to allergies. From a young age, she got used to bringing her own snacks to birthday parties and group outings. But she didn’t really know the science behind her allergies NetBet sportuntil high school, when she read a chapter for class on immunology.

“I read it, and then I read it again, and I went running downstairs to tell my mom, ‘This is what’s wrong with me!’” she recalls.

From them on, Ginder was driven to learn about what made her body react so severely to certain stimuli. Now a biology major, she does research in the lab of Christopher Love, in the Koch Institute for Integrative Cancer Research, where she studies peanut allergies — one of the few food allergies she actually doesn’t have.

“I really enjoy figuring out, what’s the perspective from the biology side? What is the contributing chemistry? And how do those fit together?” she says. “And then, when you take a step back, how do you use that knowledge and perhaps the technology that comes out of it, and actually apply that in the real world?”

Nuts about research

In the Love lab, researchers look at how individual immune cells from people with peanut allergies react when stimulated with peanut extracts. More recently, they’ve been analyzing how the stimulated cells change over the course of treatment, evolving from one state to the next.

“You can watch the activation signals change over time in individual cells from peanut-allergic patients compared to healthy ones,” Ginder explains. “You can then dig deeper and look at distinct populations of cells at a single time point. With all of this information, you can start to get a sense of what critical cell types and signals are making the allergic person maintain a reaction.”

The researchers aim to figure out which cell types are associated with the development of tolerance so that more effective treatments can be developed. For instance, allergic people are sometimes given peanuts in small doses as a sort of biological exposure therapy, but perhaps if more key cell states are identified, targeted drug treatments can be added on top of that to induce those cell states.

Further pursuing her interest in health, Ginder spent the Independent Activities Period of her sophomore year volunteering for Boston Medical Center. The program she worked for helped families learn how to be advocates for their children with autism. For instance, it provided guidance on how to negotiate an appropriate accommodations agreement with their child’s school for their individual needs.

“It [the BMC experience] made it clear to me that for a child to succeed, they need to have support from both the educational side and the health side,” she says. “And it might seem obvious, but, especially for a child who might be coming from a less privileged background, those are two really important angles for ensuring that they are given the opportunity to reach their full potential.”

“The most helpful thing you can do is simply be there.”

Ginder became a swim coach and tutor for Amphibious Achievement in the fall of her first year, almost immediately after arriving at MIT. It’s a program that aims to help high schoolers reach both their athletic and academic goals. The high schoolers, often known as Achievers, are assigned a mentor like Ginder who helps with the academic and the athletic activities.

Local students come to MIT early Sunday morning to practice swimming or rowing, head to the Maseeh dining hall for lunch, participate in an afternoon academics lesson, reflect on their goals, and then spend a half an hour one-on-one with their mentor. It’s a big commitment for both the Achievers and mentors to spend almost six hours every Sunday with the program, but Ginder, who completed her two-year term as one of the co-executive directors this fall, has seen the importance of showing up week after week.

“The most helpful thing you can do is simply be there. Listen if they want to tell you anything, but really just being consistent — every single Sunday, being there.”

Ginder played on the field hockey team during her first year. However, when a practice during her sophomore year left her with a concussion and unable to play, she used the newfound spare time to start volunteering for Camp Kesem (CK). Having really enjoyed her experience at Amphibious Achievement, she was eager to be a counselor for the camp, which serves children whose parents are affected by cancer.

“Being there for someone, whether they are having a tough time or a great day, is really important to me. I felt that CK really aligned with that value I hold, and I hoped to meet even more people at MIT who felt that way. And so I joined, and I’ve loved it,” she says.

Management and moving west

Eventually, Ginder would like to become a physician, possibly in the fields of pediatrics and allergies. However, with a minor in public policy, she’s interested in developing areas outside of science as well. So, for the next couple of years, she’ll be moving westward to work as an associate consultant for Bain and Company in San Francisco.

“The reason I’m most interested in consulting is that there is this strong culture of learning and feedback. I want to improve my ability to be a strong team member, leader, and persuader. I think these are areas where I can continue to grow a lot,” she says. “It may sound silly, but I think for me, as someone who is 5’2” and hoping to become a pediatrician, it’s important to cultivate those professional skills early. I want to also serve as a leader and advocate outside of the clinic.”

As Ginder admits, the move is quite the geographic leap. Right now, her entire family is between a 20-minute and two-hour drive away. Moving to the opposite side of the country will be difficult, but she isn’t one to shy away from a challenge.

“I think it’ll be a bit sad because I’m not going to be as close to my family, but I think that it’ll really push me to be as independent as possible. I’ll need to look for my own opportunities, meet new people, build my network, and be my own person,” she says. “I’m really excited about that.”

Predicting sequence from structure

Researchers have devised a faster, more efficient way to design custom peptides and perturb protein-protein interactions.

Raleigh McElvery | Department of Biology
February 15, 2019

One way to probe intricate biological systems is to block their components from interacting and see what happens. This method allows researchers to better understand cellular processes and functions, augmenting everyday laboratory experiments, diagnostic assays, and therapeutic interventions. As a result, reagents that impede interactions between proteins are in high demand. But before scientists can rapidly generate their own custom molecules capable of doing so, they must first parse the complicated relationship between sequence and structure.

Small molecules can enter cells easily, but the interface where two proteins bind to one another is often too large or lacks the tiny cavities required for these molecules to target. Antibodies and nanobodies bind to longer stretches of protein, which makes them better suited to hinder protein-protein interactions, but their large size and complex structure render them difficult to deliver and unstable in the cytoplasm. By contrast, short stretches of amino acids, known as peptides, are large enough to bind long stretches of protein while still being small enough to enter cells.

The Keating lab at the MIT Department of Biology is hard at work developing ways to quickly design peptides that can disrupt protein-protein interactions involving Bcl-2 proteins, which promote cancer growth. Their most recent approach utilizes a computer program called dTERMen, developed by Keating lab alumnus, Gevorg Grigoryan PhD ’07, currently an associate professor of computer science and adjunct associate professor of biological sciences and chemistry at Dartmouth College. Researchers simply feed the program their desired structures, and it spits out amino acid sequences for peptides capable of disrupting specific protein-protein interactions.

“It’s such a simple approach to use,” says Keating, an MIT professor of biology and senior author on the study. “In theory, you could put in any structure and solve for a sequence. In our study, the program came up with new sequence combinations that aren’t like anything found in nature — it deduced a completely unique way to solve the problem. It’s exciting to be uncovering new territories of the sequence universe.”

Former postdoc Vincent Frappier and Justin Jenson PhD ’18 are co-first authors on the study, which appears in the latest issue of Structure.

Same problem, different approach

Jenson, for his part, has tackled the challenge of designing peptides that bind to Bcl-2 proteins using three distinct approaches. The dTERMen-based method, he says, is by far the netbet sports betting appmost efficient and general one he’s tried yet.

Standard approaches for discovering peptide inhibitors often involve modeling entire molecules down to the physics and chemistry behind individual atoms and their forces. Other methods require time-consuming screens for the best binding candidates. In both cases, the process is arduous and the success rate is low.

dTERMen, by contrast, necessitates neither physics nor experimental screening, and leverages common units of known protein structures, like alpha helices and beta strands — called tertiary structural motifs or “TERMs” — which are compiled in collections like the Protein Data Bank. dTERMen extracts these structural elements from the data bank and uses them to calculate which amino acid sequences can adopt a structure capable of binding to and interrupting specific protein-protein interactions. It takes a single day to build the model, and mere seconds to evaluate a thousand sequences or design a new peptide.

“dTERMen allows us to find sequences that are likely to have the binding properties we’re looking for, in a robust, efficient, and general manner with a high rate of success,” Jenson says. “Past approaches have taken years. But using dTERMen, we went from structures to validated designs in a matter of weeks.”

Of the 17 peptides they built using the designed sequences, 15 bound with native-like affinity, disrupting Bcl-2 protein-protein interactions that are notoriously difficult to target. In some cases, their designs were surprisingly selective and bound to a single Bcl-2 family member over the others. The designed sequences deviated from known sequences found in nature, which greatly increases the number of possible peptides.

“This method permits a certain level of flexibility,” Frappier says. “dTERMen is more robust to structural change, which allows us to explore new types of structures and diversify our portfolio of potential binding candidates.”

Probing the sequence universe

Given the therapeutic benefits of inhibiting Bcl-2 function and slowing tumor growth, the Keating lab has already begun extending their design calculations to other members of the Bcl-2 family. They intend to eventually develop new proteins that adopt structures that have never been seen before.

“We have now seen enough examples of various local protein structures that computational models of sequence-structure relationships can be inferred directly from structural data, rather than having to be rediscovered each time from atomistic interaction principles,” says Grigoryan, dTERMen’s creator. “It’s immensely exciting that such structure-based inference works and is accurate enough to enable robust protein design. It provides a fundamentally different tool to help tackle the key problems of structural biology — from protein design to structure prediction.”

Frappier hopes one day to be able to screen the entire human proteome computationally, using methods like dTERMen to generate candidate binding peptides. Jenson suggests that using dTERMen in combination with more traditional approaches to sequence redesign could amplify an already powerful tool, empowering researchers to produce these targeted peptides. Ideally, he says, one day developing peptides that bind and inhibit your favorite protein could be as easy as running a computer program, or as routine as designing a DNA primer.

According to Keating, although that time is still in the future, “our study is the first step towards demonstrating this capacity on a problem of modest scope.”

This research was funded the National Institute of General Medical Sciences, National Science Foundation, Koch Institute for Integrative Cancer Research, Natural Sciences and Engineering Research Council of Canada, and Fonds de Recherche du Québec.

Why too much DNA repair can injure tissue

Overactive repair system promotes cell death following DNA damage by certain toxins, study shows.

Anne Trafton | MIT News Office
February 14, 2019

DNA-repair enzymes help cells survive damage to their genomes, which arises as a normal byproduct of cell activity and can also be caused by environmental toxins. However, in certain situations, DNA repair can become harmful to cells, provoking an inflammatory response that produces severe tissue damage.

MIT Professor Leona Samson has now determined that inflammation is a key component of the way this damage occurs in photoreceptor cells in the retinas of mice. About 10 years ago, she and her colleagues discovered that overactive initiation of DNA-repair systems can lead to retinal damage and blindness in mice. The key enzyme in this process, known as Aag glycosylase, can also cause harm in other tissues when it becomes hyperactive.

“It’s another case where despite the fact that inflammation is there to protect you, in some circumstances it can actually be harmful, when it’s overactive,” says Samson, a professor emerita of biology and biological engineering and the senior author of the study.

Aag glycosylase helps to repair DNA damage caused by a class of drugs known as alkylating agents, which are commonly used as chemotherapy drugs and are also found in pollutants such as tobacco smoke and fuel exhaust. Retinal damage from these drugs has not been seen in human patients, but alkylating agents may produce similar damage in other human tissues, Samson says. The new study, which reveals how Aag overactivity leads to cell death, suggest possible targets for drugs that could prevent such damage.

Mariacarmela Allocca, a former MIT postdoc, is the lead author of the study, which appears in the Feb. 12 issue of Science Signaling. MIT technical assistant Joshua Corrigan, former postdoc Aprotim Mazumder, and former technical assistant Kimberly Fake are also authors of the paper.

A vicious cycle

In a 2009 study, Samson and her colleagues found that a relatively low level of exposure to an alkylating agent led to very high rates of retinal damage in mice. Alkylating agents produce specific types of DNA damage, and Aag glycosylase normally initiates repair of such damage. However, in certain types of cells that have higher levels of Aag, such as mouse photoreceptors, the enzyme’s overactivity sets off a chain of events that eventually leads to cell death.

In the new study, the researchers wanted to find exactly out how this happens. They knew that Aag was overactive in the affected cells, but they didn’t know exactly how it was leading to cell death or what type of cell death was occurring. The researchers initially suspected it was apoptosis, a type of programmed cell death in which a dying cell is gradually broken down and absorbed by other cells.

However, they soon found evidence that another type of cell death called necrosis accounts for most of the damage. When Aag begins trying to repair the DNA damage caused by the alkylating agent, it cuts out so many damaged DNA bases that it hyperactivates an enzyme called PARP, which induces necrosis. During this type of cell death, cells break apart and spill out their contents, which alerts the immune system that something is wrong.

One of the proteins secreted by the dying cells, known as HMGB1, stimulates production of chemicals that attract immune cells called macrophages, which specifically penetrate the photoreceptor layer of the retina. These macrophages produce highly reactive oxygen species — molecules that create more damage and make the environment even more inflammatory. This in turn causes more DNA damage, which is  recognized by Aag.

“That makes the situation worse, because the Aag glycosylase will act on the lesions produced from the inflammation, so you get a vicious cycle, and the DNA repair drives more and more degeneration and necrosis in the photoreceptor layer,” Samson says.

None of this happens in mice that lack Aag or PARP, and it does not occur in other cells of the eye or in most other body tissues.

“It amazes me how segmented this is. The other cells in the retina are not affected at all, and they must experience the same amount of DNA damage. So, one possibility is maybe they don’t express Aag, while the  photoreceptor cells do,” Samson says.

“These molecular studies are exciting, as they have helped define the underlying pathophysiology associated with retinal damage,” says Ben Van Houten, a professor of pharmacology and chemical biology at the University of Pittsburgh, who was not involved in the study. “DNA repair is essential for the faithful inheritance of a cell’s genetic material. However, the very action netbet online sports bettingof some DNA repair enzymes can result in the production of toxic intermediates that exacerbate exposures to genotoxic agents.”

Varying effects

The researchers also found that retinal inflammation and necrosis were more severe in male mice than in female mice. They suspect that estrogen, which can interfere with PARP activity, may help to suppress the pathway that leads to inflammation and cell death.

Samson’s lab has previously found that Aag activity can also exacerbate damage to the brain during a stroke, in mice. The same study revealed that Aag activity also worsens inflammation and tissue damage in the liver and kidney following oxygen deprivation. Aag-driven cell death has also been seen in the mouse cerebellum and some pancreatic and bone marrow cells.

The effects of Aag overactivity have been little studied in humans, but there is evidence that healthy individuals have widely varying levels of the enzyme, suggesting that it could have different effects in different people.

“Presumably there are some cell types in the human body that would respond the same way as the mouse photoreceptors,” Samson says. “They may just not be the same set of cells.”

The research was funded by the National Institutes of Health.

Nedivi named to new professorship
Picower Institute
February 8, 2019

Elly Nedivi, a professor in the Picower Institute and the Departments of Brain and Cognitive Sciences and Biology, has been named the inaugural William R. (1964) & Linda R. Young Professor of Neuroscience, the MIT School of Science announced.

Nedivi, an MIT faculty member since 1998, studies the cellular mechanisms that underlie activity-dependent plasticity in the developing and adult brain through studies of neuronal structural dynamics, identification of the participating genes, and characterization of the proteins they encode.

Her work to identify “candidate plasticity genes” has yielded many insights, including elucidating the neuronal and synaptic function of two previously unknown CPGs: CPG2 and CPG15. In a study published earlier this year, her lab showed that the protein CPG2 is significantly less abundant in the brains of people with bipolar disorder and showed how specific mutations in the SYNE1 gene that encodes CPG2 undermine the protein’s expression and its function in neurons, potentially contributing to disease.

Motivated by the large number of CPGs that affect neuronal structure, her lab has also been collaborating with that of Peter So’s in MIT’s Department of Mechanical Engineering to develop multi-color two photon microscopy for large volume, high resolution imaging of dendritic arbor and synaptic structural dynamics in vivo. Nedivi’s lab was the first to show unambiguous evidence of dendritic arbor remodeling in the adult brain, and identify inhibitory connections as the most plastic component of experience-dependent circuit rearrangements.

Nedivi thanked the Youngs for their support of neuroscience research at MIT.

“I recently met the Youngs, and share their view that study of the brain and mind is an area of science with tremendous potential to improve people’s lives,” she said. “I respect their wish to give back to MIT, and am deeply honored to be named the inaugural William R. (1964) & Linda R. Young Professor of Neuroscience.”