Cells Need Their Personal Space

One of the body’s first lines of defense against harmful pathogens is the skin. The constant maintenance of this epithelial cell layer which serves as a barrier to infection  is essential to fighting off disease.

Jody Rosenblatt, an Associate Professor in the Department of Oncological Sciences at the University of Utah School of Medicine, has made it her lab’s mission to study the function of epithelia as a barrier, how this barrier is maintained, and what happens when it goes awry.

Jody Rosenblatt, PhD is an investigator for the Huntsman Cancer Institute at the University of Utah School of Medicine and a Howard Hughes Medical Institute Faculty Scholar

Rosenblatt recently spoke at Duke’s Developmental & Stem Cell Biology Colloquium where she presented some extraordinary findings about how epithelia can squeeze out  both healthy and dying cells  to preserve the protective barrier.

Some c cells commit suicide via programed cell death and are forced out of the cell layer because they are no longer functional. But in the case of forcing out living cells, “cell extrusion is more like a homicide” said Rosenblatt. The fact that perfectly functional living cells are pushed out of a cell layer perplexed her group until they discovered it was happening as a response to cell overcrowding.

Rosenblatt explained that like people, cells tend to like their personal space, so when this is compromised, live cells are actively pushed out of the cell layer, restoring balanced cell numbers.

Rosenblatt’s lab took this discovery a step farther and pinpointed the pathway that likely induces the extrusion of live cells.

Piezo1, a stretch-activated calcium ion channel present in epithelial cells, senses crowding and activates sphingosine-1-phosphate (S1P), the driver of epithelial cell extrusion. When Piezo1 channels are inhibited and don’t sense stretching, cells cannot extrude.

Using zebrafish, Rosenblatt showed that when extrusion was blocked by compromising the S1P2 pathway, epidermal cells form masses that are resistant to chemotherapy drugs and signals for programmed cell death.

Rosenblatt explains the importance of regulating cell extrusion in the epithelium to maintain the tissue’s function as a protective barrier for our organs. Misregulation of this function can result in diseases such as metastatic cancers.

This finding lead them to examine samples of human pancreatic, lung, colon, and breast tumors. They found that in all of these cancers, S1P2 is significantly reduced. But if they restored S1P2 activity in cell lines of these cancers, the extrusion pathway was rescued and tumor size and metastases were greatly decreased!

Rosenblatt and her colleagues have shown that the importance of cell extrusion cannot be overstated. If extrusion is compromised, cells can begin to pile up and move beneath the cell layer, which can lead to invasion of the tissues beneath the epithelium and metastasis to other sites in the body.

Now that we are uncovering more of the pathways involved in tumor formation and metastasis, we can develop new drugs that may be the key to fighting these devastating diseases.

Guest Post by Amanda Cox, PhD candidate in biology

 

José Jerónimo – Innovations in Cervical Cancer Screening

José Jerónimo and his team are transforming the face of cervical cancer screening. Jerónimo is a physician and senior advisor for the women’s cancers branch of PATH, an international nonprofit organization that uses innovative technologies to improve health outcomes in developing countries. Jerónimo, who’s work at PATH has facilitated the prevention and treatment of cervical cancer for thousands in the developing world, spoke at the Duke Institute for Global Health on Dec. 2.

Cervical cancer testing has been a point of conflict in the medical community for quite some time now, for the pap smear — for many years, the only test available to detect cervical cancer — is not very sensitive to abnormal tissue. Since skepticism with the pap smear arose a few decades ago, doctors like Jerónimo have been working tirelessly to find more effective screening strategies.

José Gerónimo, Peruvian physician and public health advocate, received his specialty training in gynecologic oncology at the National Cancer Institute in Peru.

José Jerónimo, Peruvian physician and public health advocate, received his specialty training in gynecologic oncology at the National Cancer Institute in Peru.

Cervical cancer can be acquired through the presence of HPV (human papilloma virus). Chronic infections of HPV have been proven to increase the likelihood of contracting cervical cancer, so developing primary prevention initiatives to avoid developing HPV to begin with are essential to decrease the prevalence of cervical cancer. HPV testing, unlike the pap smear, can be self-collected and does not require the complex, expensive machinery that the pap smear does. Initial self-sampling studies in India, Uganda, and Nicaragua indicated a willingness by the female community to self-test, so long as sanitary and private conditions were provided.

Studies in the Jujuy province of Argentina indicated that community health workers played a key role in facilitating the self-sampling process. When the health workers differed locals to clinics or sent them to facilities for testing, only 20 percent actually went. But, when they brought the self-sampling tests to locals’ homes directly, testing was above 80 percent. The easy accessibility of self-sampling, along with encouragement by local health volunteers, clearly showed that self-sampling was much more effective.

A group of female community health workers in Lima, Peru, educating the community about HPV testing.

Jerónimo’s current work focuses on strengthening government screening systems for HPV that are already in place. By helping ministries introduce and scale up the testing, he and others at PATH hope to decrease HPV and cervical cancer rates.

But, it goes beyond testing. Jerónimo emphasizes the need for evaluation and follow-up mechanisms after testing positive. Although testing efforts have improved significantly, the treatment provided after for those who have tested positive is still lagging. Jerónimo claims that much of this is due to minimal efforts by the local governments to really follow through beyond the testing phase.

PATH is looking for innovative ways to treat HPV that are inexpensive and effective. They recently developed their own version of the thermal coagulator, a probe that treats infected tissue using heat. Their design runs on a battery, rather than needing constant electricity, and uses a progressive heating mechanism that is only activated upon touching the cervix. There is still progress to be made, in both testing and treatment of HPV and cervical cancer, but through efforts by both local and international communities, Jerónimo shows us that is possible.

lola_sanchez_carrion_100hedPost by Lola Sanchez-Carrion

Fostering a Collaborative Research Environment in Peru

We are told time and time again that Duke is a global university, one that transcends borders and takes interdisciplinary education to the next level.

On Monday, I was able to experience this international mindset firsthand at the Peru Health Symposium, a conference that celebrated a decade of culminating research efforts by Duke in Peru.

The symposium was organized by Dr. William Pan, a professor of Global Environmental Health at Duke who has worked on many research projects in Peru ranging from reproductive health to tuberculosis. In his opening remarks, Pan said the trademark interdisciplinary nature of Duke has allowed it to succeed as a research institution in Peru, along with its affiliation to pioneers in Peruvian health/environmental research, like John Terborgh.

“We are standing on the shoulders of giants,” said Pan. During the first panel, several research projects were presented.

Field Work in Peru

Helena Frischtak conducting research with Peruvian children in the field.

Helena Frischtak, a 4th year medical student at UVA and former Doris Duke Fellow spent a year studying the neurological effects of mercury exposure on children. She performed basic neurological exams, along with cognitive tests amongst 5-11 year-old children, and preliminary data suggests potential impacts of mercury exposure on cognitive development.

Marlee Krieger of the Center for Global Women’s Health Technologies presented a cervical cancer treatment that brings colposcopy into the primary care setting. When one is screened for cervical cancer, a pap smear is first conducted and if abnormalities are detected, a colposcopy is performed and tissue is biopsied from the cervix. This multiple-step process is tedious, and the number of patients that return for the colposcopy often declines. By combining the steps into one visit and performing it with a simpler and cheaper device, testing efficiency has increased.

Maria Lazo Porras of Cayetano Heredia University (Lima’s prominent medical university) presented findings on the effects of migration from rural to urban regions on chronic disease. Her findings suggest a correlation between urbanization and obesity, but provided surprising results that indicate higher rates of hypertension and diabetes in rural communities.

Peru amazon

Illegal mining scars the Amazon’s lush forests and flushes mercury runoff into streams.

Students doing research in the Amazon presented posters of their findings to faculty members of the Nicolas School and DGHI.

The main theme resonating throughout the conference was the need for collaboration not only to address public/environmental health concerns, but to organize symposiums like this one. The culmination of efforts by the Center for Latin American and Caribbean Studies (CLACS), DGHI, and the Nicholas School have fueled the Peru project’s palpable success.

Below is the link to the documentary shown at the symposium:

http://www.daughterofthelake.pe/ – “Hija de la Laguna” (Daughter of the Lake), 2015. The documentary tells the story of how a Peruvian woman used her powers to stop illegal mining from destroying the lake in her community; a lake that to her, represents her mother’s spirit.

lola_sanchez_carrion_100hedPost by Lola Sanchez-Carrion

In Sync

DiTalia2The dividing red spots in this time-lapse video belong to a busily developing fruit fly embryo. A fruit fly egg can divide into some 6,000 cells in just two hours —  faster division than cancer tumors. To watch them action, graduate student Victoria Deneke and assistant professor Stefano Di Talia tagged the nuclei with a protein that glows red. In a recent study, they show that the cells coordinate their rapid divisions via waves of protein activity that spread across the embryo. The waves help ensure that all the cells enter the next stage of development at the same time.

Duke graduate student Victoria Deneke has been awarded an international student research fellowship from the Howard Hughes Medical Institute.

Duke graduate student Victoria Deneke has been awarded an international student research fellowship from the Howard Hughes Medical Institute.

Starting September 2016, Deneke became one of 20 graduate students from 14 countries selected for an international student research fellowship from the Howard Hughes Medical Institute.

Three-year fellowship is designed to support outstanding international graduate students studying in the United States who are ineligible for fellowships or training grants through U.S. federal agencies.

Born in El Salvador, Deneke earned her undergraduate degree in chemical engineering from the University of Notre Dame before joining Stefano Di Talia’s at Duke in 2013.

Fellows must be nominated by their institution; participation is by invitation only. Deneke is only the second student at Duke to receive an HHMI International Student Research Fellowship since the program was established in 2011.

CITATION:  “Waves of Cdk1 Activity in S Phase Synchronize the Cell Cycle in Drosophila Embryos,” Victoria Deneke, Anna Melbinger, Massimo Vergassola and Stefano Di Talia. Developmental Cell, August 2016. http://dx.doi.org/10.1016/j.devcel.2016.07.023

Turning Duke Experiences into Science Fair Gold

Do we each have our own story about science fair? Mine is about that time my grandpa and I set fire to my parents’ garage while testing out the new corn stove we had built together. We were looking into cleaner fuels. It was a small fire, easily squelched, fortunately.

Katherine Yang presenting her poster

Katherine Yang presenting her poster

But in the rite of passage that is the science fair, two Duke-mentored high schoolers are not embarking on half-baked projects with non-scientific relatives like mine, but are instead blazing new trails in science with all of the high-end equipment and faculty mentoring that Duke has to offer.

Katherine Yang and Alisa Cui, of the North Carolina School of Science and Mathematics in Durham, are presenting their results in Phoenix this week in Intel’s International Science and Engineering Fair (ISEF), a prestigious annual science fair that convenes 1,700 of the best and brightest STEM students from around the world

Working in Qiu Wang’s group, Yang has discovered a potential new drug to treat cancer, focusing on a protein targeted called CARM1, which is known to cause breast and prostate cancers to grow uncontrollably.

Yang’s new molecule blocks CARM1. What’s more, in the process of narrowing her list of five candidates, she developed a new cell-based test that can inform the development of future screening tools for other CARM1 inhibitors.

Cui has worked in Jorg Grandl’s lab on the mechanism by which a family of proteins called Piezo ion channels allow cells to detect mechanical touch and eventually become desensitized to repeated stimulation and shut off. By recording the electrical activity of cells that express one type of Piezo, Cui determined that the channels do not use a particular type of shutdown mechanism that researchers had previously thought. Now, the group will move on to test another major mechanism.

NCSSM_Alisa Cui

Alisa Cui and her award-winning project.

On Friday, it was announced that Alisa had won a fourth place grand award in Cellular and Molecular Biology, which includes a $500 prize.

“I am very impressed by the impact Alisa made,” said Grandl, who is a member of the Duke Institute for Brain Sciences. “The data she collected helped starting a completely new line of research,” in understanding how these channels deal with repeated stimulations, such as vibrations.

Growing up, I was oblivious to the existence of international science fairs but my own experiences ignited a lifelong love for science. I can only hope that these young ladies felt something similar.

KellyRae_Chi_100Guest Post by Kelly Rae Chi

A Link Between Stress and Aging in African-Americans

A recent study finds that lifetime stress in a population of African Americans causes chemical changes to their DNA that may be associated with an increased risk of aging related diseases.

(Image: Rhonda Baer, National Cancer Institute)

(Image: Rhonda Baer, National Cancer Institute)

Using a previously established DNA-based predictor of age known as the “epigenetic clock,” researchers found that a cohort of highly-traumatized African Americans were more likely to show aging-associated biochemical signatures in their DNA’s epigenetic clock regions at an earlier age than what would otherwise be predicted by their chronological age.

These chemical alterations to DNA’s epigenetic clock were found to be a result of hormonal changes that occur during the body’s stress response and corresponded to genetic profiles associated with aging-related diseases.

The study was performed by researchers at the Max Planck Institute of Psychiatry in Germany, including Duke University adjunct faculty and psychiatrist Dr. Anthony S. Zannas. The findings were published in a recent issue of Genome Biology.

“Our genomes have likely not evolved to tolerate the constant pressure that comes with today’s fast-paced society,” says lead author Zannas.

Though it may come as no surprise that chronic stress is detrimental to human health, these findings provide a novel biological mechanism for the negative effects of cumulative lifetime stressors, such as those that can come with being a discriminated minority.

Epigenetics is the study of how environmental factors switch our genes on or off. The epigenetic clock is comprised of over 300 sites in our DNA that are subject to a certain chemical modification known as methylation, which physically prevents those sites from being expressed (i.e., turns them off). Conversely, areas within the epigenetic clock can also be de-methylated to turn genes on. Each methylation event can be thought of as a tick of the epigenetic clock’s metaphorical second-hand, corresponding to the passing of physiological time.

During times of stress, a family of hormones known as glucocorticoids becomes elevated throughout the body. These glucocorticoids cause the chemical addition or removal of methyl groups to areas of DNA that the authors found to be located in the same regions that comprise the epigenetic clock. What’s more, the specific changes in methylation were found to correspond with gene expression profiles associated with coronary artery disease, arteriosclerosis, and leukemias.

This link between stress, glucocorticoids, and the epigenetic clock provides evidence that lifetime stress experienced by highly traumatized African Americans promotes physiological changes that affect their overall health and longevity.

The authors make an important distinction between cumulative lifetime stress and current stress. A small number of instances of acute stress may result in a correspondingly small number of methylation changes in the epigenetic clock, but it is the cumulative methylation events from chronic stress that give rise to lasting physiological detriments.

Though the authors make no direct claims regarding the physiological effects of racial inequities prevalent in today’s society, the findings perhaps shed light on the health disparities observed between disadvantaged African American populations and more privileged demographics, including increased mortality rates for cancer, heart disease, and stroke.

KatyRiccione

Glucocorticoids become elevated during the body’s stress response and lead to changes in DNA methylation that promote the expression of genes associated with aging.
Illustration by Katy Riccione

Interestingly, the epigenetic effects of lifetime stress were blunted in individuals who underwent significant childhood trauma, suggesting that early trauma may trigger mechanisms of physiological resilience to chronic stress later in life. In other words, if racial minorities are more likely to face hardships during their upbringing, perhaps they are also better prepared to cope with the chronic stress that comes with, for instance, losing a job or ending a marriage.

Though the study relies on data from an African American cohort, Dr. Zannas believes that the same conclusions are likely applicable to other highly stressed populations: chronic stress leads to lasting changes in our epigenome that may increase our likelihood of aging-related diseases, while acute stress was not found to have any long-term epigenetic effects.

So a single tough calculus exam won’t shave years off of your life, but consistent 80-hour work weeks just may.

In a world where everyday stress is unavoidable, whether it be from the hardships faced as a minority or the demands of being a full-time student, what lifestyle choices can we make to limit the detriments to our health? Dr. Zannas emphasizes that the “solution is not to avoid all stressors, but to prevent excessive stressors when possible and to learn to live with unavoidable stress constructively.”

The study underscores the importance of stress management on our general well-being. Future research may highlight the direct chemical benefits to our epigenome that are afforded by mindfulness, psychotherapy, diet/exercise, and other modes of stress relief. “Learning to better cope with stress is the best way to reduce our physiological response to it and the resultant harmful effects.”

Katy_Riccione_100Guest Post by Katy Riccione, Ph.D. Candidate in Biomedical Engineering