Research Area: Human Disease

Study reveals how glial cells may play key epilepsy role

Mutation in disease model flies undermines maintenance of key ion balance.

David Orenstein | Picower Institute
May 2, 2019

A new study provides potential new targets for treating epilepsy and new fundamental insights into the relationship between neurons and their glial “helper” cells. In eLife, scientists at MIT’s Picower Institute for Learning and Memory report finding a key sequence of molecular events in which the genetic mutation in a fruit fly model of epilepsy leaves neurons vulnerable to becoming hyperactivated by stress, leading to seizures.

About 60 million people worldwide have epilepsy, a neurological condition characterized by seizures resulting from excessive neural activity. The “zydeco” model flies in the study experience seizures in a similar fashion. Since discovering zydeco, the lab of MIT neurobiologist Troy Littleton, the Menicon Professor in Neuroscience, has been investigating why the flies’ zydeco mutation makes it a powerful model of epilepsy.

Heading into the study, the team led by postdoc Shirley Weiss knew that the zydeco mutation was specifically expressed by cortex glial cells and that the protein it makes helps to pump calcium ions out of the cells. But that didn’t explain much about why a glial cell’s difficulty maintaining a natural ebb and flow of calcium ions would lead adjacent neurons to become too active under seizure-inducing stresses, such as fever-grade temperatures or the fly being jostled around.

The activity of neurons rises and falls based on the flow of ions — for a neuron to “fire,” for instance, it takes in sodium ions, and then to calm back down it releases potassium ions. But the ability of neurons to do that depends on there being a conducive balance of ions outside the cell. For instance, too much potassium outside makes it harder to get rid of potassium and calm down.

The need for an ion balance — and the way it is upset by the zydeco mutation — turned out to be the key to the new study. In a four-year series of experiments, Weiss, Littleton, and their co-authors found that excess calcium in cortex glia cells causes them to hyper-activate a molecular pathway that leads them to withdraw many of the potassium channels that they typically deploy to remove potassium from around neurons. With too much potassium left around, neurons can’t calm down when they are excited, and seizures ensue.

“No one has really shown how calcium signaling in glia could directly communicate with this more classical role of glial cells in potassium buffering,” Littleton says. “So this is a really important discovery linking an observation that’s been found in glia for a long time — these calcium oscillations that no one really understood — to a real biological function in glial cells, where it’s contributing to their ability to regulate ionic balance around neurons.”

Weiss’s work lays out a detailed sequence of events, implicating several specific molecular players and processes. That richly built knowledge meant that along the way, she and the team found multiple steps in which they could intervene to prevent seizures.

She started working the problem from the calcium end. With too much calcium afoot, she asked, what genes might be in a related pathway such that, if their expression was prevented, seizures would not occur? She interfered with expression in 847 potentially related genes and found that about 50 affected seizures. Among those, one stood out both for being closely linked to calcium regulation and also for being expressed in the key cortex glia cells of interest: calcineurin. Inhibiting calcineurin activity, for instance with the immunosuppressant medications cyclosprorine A or FK506, blocked seizures in zydeco mutant flies.

Weiss then looked at the genes affected by the calcineurin pathway and found several. One day at a conference where she was presenting a poster of her work, an onlooker mentioned that glial potassium channels could be involved. Sure enough, she found a particular one called “sandman” that, when knocked down, led to seizures in the flies. Further research showed that hyperactivation of calcineurin in zydeco glia led to an increase in a cellular process called endocytosis, in which the cell was bringing too much sandman back into the cell body. Without sandman staying on the cell membrane, the glia couldn’t effectively remove potassium from the outside.

When Weiss and her co-authors interfered to suppress endocytosis in zydeco flies, they also were able to reduce seizures, because that allowed more sandman to persist where it could reduce potassium. Sandman, notably, is equivalent to a protein in mammals called TRESK.

“Pharmacologically targeting glial pathways might be a promising avenue for future drug development in the field,” the authors wrote in eLife.

In addition to that clinical lead, the study also offers some new insights for more fundamental neuroscience, Littleton and Weiss said. While zydeco flies are good models of epilepsy, Drosophila’s cortex glia do have a property not found in mammals: They contact only the cell body of neurons, not the synaptic connections on their axon and dendrite branches. That makes them an unusually useful test bed to learn how glia interact with neurons via their cell body versus their synapses. The new study, for instance, shows a key mechanism for maintaining ionic balance for the neurons.

In addition to Weiss and Littleton, the paper’s other authors are Jan Melom, who helped lead the discovery of zydeco, postdoc Kiel Ormerod, and former postdoc Yao Zhang.

The National Institutes of Health and the JPB Foundation funded the research.

A Troubling Inheritance
Greta Friar | Whitehead Institute
April 9, 2019

CAMBRIDGE, MA — Cancers have a habit of running in the family. This is due in large part to the inheritance of versions of genes that are linked with cancer, but some researchers are investigating another heritable risk factor: epigenetic modifications. These are not changes in the DNA sequence of a gene itself but rather are processes that change a DNA sequence’s accessibility or ability to be expressed. These changes can regulate gene expression, and in certain circumstances, be passed down from parent to child alongside the genes they regulate. New research published in eLife on April 9 from the lab of Whitehead Member and Institute Director David Page, also a professor of biology at the Massachusetts Institute of Technology and a Howard Hughes Medical Institute investigator, and colleagues has found evidence that when atypical epigenetic modifications, or marks, caused by a gene deletion in the parent’s cells, are inherited it can lead to increased cancer incidence and shorter lifespans in mice.

Studying epigenetic inheritance in mammals can be difficult because mammalian embryos undergo strong epigenetic reprogramming, a kind of “erasing and starting over” for the next generation. Some of the parents’ epigenetic marks resist this reprogramming, but the vast majority are erased, and often what may appear to be epigenetic inheritance can be explained by other factors like environmental exposures during fetal development leading to similar epigenetic profiles.

“We had to design an experiment with a specific, well-defined initiating event, so the epigenetic patterns and health effects would be easy to track,” says first author Bluma Lesch, then a postdoctoral researcher in the Page lab at Whitehead Institute and now an assistant professor of Genetics at Yale School of Medicine and a member of the Genomics, Genetics and Epigenetics Program at Yale Cancer Center.

In order to do this, the researchers first deleted Kdm6a (also called Utx), a gene on the X chromosome that encodes a protein involved in epigenetic regulation, in the male mouse germline—the repository of cells that become sperm. Kdm6a removes epigenetic modifications from histones, the spool-like proteins that house strands of DNA. Deleting Kdm6a led to higher than usual levels of specific types of histone modifications in the genome of the mice’s sperm, which in turn prompted a secondary epigenetic shift, an increase in DNA methylation—the addition of a methyl group to DNA that can alter gene expression.

The researchers used the hypermethylated sperm to create a generation of offspring. A crucial aspect of the experiment was creating offspring that inherited the atypical epigenetic marks but not the gene deletion that caused them in order to uncouple the effects of the two changes. Offspring were bred from a modified male germline and an unmodified female germline, so male offspring inherited a healthy X chromosome from their mothers, and an unaffected Y chromosome from their fathers. Genetically, the mice were normal, but they were formed from sperm that had been exposed to the Kdm6a deletion’s epigenetic effects.

When the researchers studied the epigenome of these offspring, they found that while many of the modifications had been erased due to reprogramming, more than 200 of the sections of DNA that had been hypermethylated in the father’s germline following Kdm6a deletion were likewise hypermethylated in the offspring. That persistence is much higher than would be expected by chance or observed in normal mice. The researchers found matching instances of hypermethylation in the offspring’s bone marrow, liver tumors, and spleen, indicating that the inherited epigenetic changes stuck with the offspring though embryonic development into adulthood. The researchers did not pinpoint the mechanism that allowed these epigenetic marks to resist reprogramming; Lesch hopes to pursue that question in the future.

Then the researchers watched the mice grow, waiting to see how the unusual DNA methylation would affect the mice’s health. For a while, the mice appeared perfectly healthy — until they hit middle age. The mice then began developing tumors, experiencing an increase in cancer incidence and a decrease in lifespan.

To get a better understanding of the effects they were seeing, Page and Lesch sought help from cancer experts Benjamin Ebert, chair of medical oncology at the Dana Farber Cancer Institute (DFCI) and member of the Broad Institute; Zuzana Tothova, DFCI investigator and associate member of the Broad Institute; and Roderick Bronson, veterinary pathologist at Harvard Medical School. The experts helped characterize the mice’s diseases. Instead of becoming more susceptible to one specific type of cancer, the mice had a diverse set of diagnoses, similar to what would be expected of normal mice at a much older age. The researchers believe this is due to hypermethylation that they observed in enhancers, regions of DNA that help increase transcription of many genes but are also commonly implicated in cancer.

Although the researchers cannot say whether the same sort of epigenetic inheritance is occurring in humans, they believe that this is a valuable question for future research. Inherited epigenetic marks would not appear in a typical genetic screen for cancer risk, and as such could be overlooked to the detriment of preventative care. Likewise, the researchers note, cancer drugs that target epigenetic mechanisms are on the rise, and there has been no research into the effects that this might have on children conceived by people taking the drugs. If human embryos are inheriting aberrant epigenetic marks in the manner observed in mice in this investigation, then people taking drugs with epigenetic targets should be warned against conceiving children until after they are clear of the effects of their medication.

“We hope that this research demonstrating the cancer risk of inherited epigenetic marks in mice adds to the burgeoning field of mammalian epigenetic inheritance research,” Page says, “and that we have drawn attention to the possible implications for human health.”

 

Written by Greta Friar

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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.

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Full citation:

“Intergenerational epigenetic inheritance of cancer susceptibility in mammals”

eLife, April 9, 2019, DOI: https://doi.org/10.7554/eLife.39380

Bluma J. Lesch, Zuzana Tothova, Elizabeth A. Morgan, Zhicong Liao, Roderick T. Bronson, Benjamin L. Ebert, and David C. Page.

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.

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.”

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 up 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

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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.

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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

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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.

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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

Bacteria promote lung tumor development, study suggests

Antibiotics or anti-inflammatory drugs may help combat lung cancer.

Anne Trafton | MIT News Office
January 31, 2019

MIT cancer biologists have discovered a new mechanism that lung tumors exploit to promote their own survival: These tumors alter bacterial populations within the lung, provoking the immune system to create an inflammatory environment that in turn helps the tumor cells to thrive.

In mice that were genetically programmed to develop lung cancer, those raised in a bacteria-free environment developed much smaller tumors than mice raised under normal conditions, the researchers found. Furthermore, the researchers were able to greatly reduce the number and size of the lung tumors by treating the mice with antibiotics or blocking the immune cells stimulated by the bacteria.

The findings suggest several possible strategies for developing new lung cancer treatments, the researchers say.

“This research directly links bacterial burden in the lung to lung cancer development and opens up multiple potential avenues toward lung cancer interception and treatment,” says Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and the senior author of the paper.

Chengcheng Jin, a Koch Institute postdoc, is the lead author of the study, which appears in the Jan. 31 online edition of Cell.

Linking bacteria and cancer

Lung cancer, the leading cause of cancer-related deaths, kills more than 1 million people worldwide per year. Up to 70 percent of lung cancer patients also suffer complications from bacterial infections of the lung. In this study, the MIT team wanted to see whether there was any link between the bacterial populations found in the lungs and the development of lung tumors.

To explore this potential link, the researchers studied genetically engineered mice that express the oncogene Kras and lack the tumor suppressor gene p53. These mice usually develop a type of lung cancer called adenocarcinoma within several weeks.

Mice (and humans) typically have many harmless bacteria growing in their lungs. However, the MIT team found that in the mice engineered to develop lung tumors, the bacterial populations in their lungs changed dramatically. The overall population grew significantly, but the number of different bacterial species went down. The researchers are not sure exactly how the lung cancers bring about these changes, but they suspect one possibility is that tumors may obstruct the airway and prevent bacteria from being cleared from the lungs.

This bacterial population expansion induced immune cells called gamma delta T cells to proliferate and begin secreting inflammatory molecules called cytokines. These molecules, especially IL-17 and IL-22, create a progrowth, prosurvival environment for the tumor cells. They also stimulate activation of neutrophils, another kind of immune cell that releases proinflammatory chemicals, further enhancing the favorable environment for the tumors.

“You can think of it as a feed-forward loop that forms a vicious cycle to further promote tumor growth,” Jin says. “The developing tumors hijack existing immune cells in the lungs, using them to their own advantage through a mechanism that’s dependent on local bacteria.”

However, in mice that were born and raised in a germ-free environment, this immune reaction did not occur and the tumors the mice developed were much smaller.

Blocking tumor growth

The researchers found that when they treated the mice with antibiotics either two or seven weeks after the tumors began to grow, the tumors shrank by about 50 percent. The tumors also shrank if the researchers gave the mice drugs that block gamma delta T cells or that block IL-17.

The researchers believe that such drugs may be worth testing in humans, because when they analyzed human lung tumors, they found altered bacterial signals similar to those seen in the mice that developed cancer. The human lung tumor samples also had unusually high numbers of gamma delta T cells.

“If we can come up with ways to selectively block the bacteria that are causing all of these effects, or if we can block the cytokines that activate the gamma delta T cells or neutralize their downstream pathogenic factors, these could all be potential new ways to treat lung cancer,” Jin says.

Many such drugs already exist, and the researchers are testing some of them in their mouse model in hopes of eventually testing them in humans. The researchers are also working on determining which strains of bacteria are elevated in lung tumors, so they can try to find antibiotics that would selectively kill those bacteria.

The research was funded, in part, by a Lung Cancer Concept Award from the Department of Defense, a Cancer Center Support (core) grant from the National Cancer Institute, the Howard Hughes Medical Institute, and a Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship Award.