Duke Research Blog

Following the people and events that make up the research community at Duke.

Category: Cancer (Page 2 of 7)

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

3-D Movies of Life at Nanoscale Named Best Science Paper of the Year

If you’ve ever wanted to watch a killer T cell in action, or see human cancer make new cells up-close, now is your chance.

A collection of 3-D movies captured by Duke biology professor Dan Kiehart and colleagues has won the 2015 Newcomb Cleveland Prize for most outstanding paper in the journal Science.

The paper uses a new imaging technique called lattice light-sheet microscopy to make super high-resolution three-dimensional movies of living things ranging from single cells to developing worm and fly embryos.

Cutting-edge microscopes available on many campuses today allow researchers to take one or two images a second. But the lattice light-sheet microscope, co-developed by 2014 Nobel Prize winner Eric Betzig, lets researchers take more than 50 images a second, and in the specimen’s natural state, without smooshing it under a cover slip.

You can watch slender antennae called filopodia extend from the surface of a human cancer cell, or tiny rods called microtubules, several thousand times finer than a human hair, growing and shrinking inside a slide mold.

Daniel Kiehart and former Duke postdoctoral fellow Serdar Tulu made a video of the back side of a fruit fly embryo during a crucial step in its development into a larva.

Chosen from among nominations submitted by readers of Science, the paper has been viewed more than 20,000 times since it was first published on October 24, 2014.

The award was announced on February 12, 2016, at an award ceremony held during the annual meeting of the American Association for the Advancement of Science (AAAS) in Washington, D.C.

Winners received a commemorative plaque and $25,000, to be shared among the paper’s lead authors Eric Betzig, Bi-Chang Chen, Wesley Legant and Kai Wang of Janelia Farm Research Campus.

Read more: “Lattice light-sheet microscopy: Imaging molecules to embryos at high spatiotemporal resolution,” Chen, B.-C., et al. Science, October 2014. DOI:10.1126/science.1257998

 

Post by Robin A. Smith Robin Smith

 

Measuring the Mechanical Forces of Disease

“All these complicated diseases that we don’t have a good handle on — they all have this mechanical component. Well why is that?”

Brent Hoffman is an assistant professor of biomedical engineering

Brent Hoffman is an assistant professor of biomedical engineering

This is exactly the question Brent Hoffman, Duke biomedical engineering assistant professor, is helping answer. Many of the common diseases that we fear have a mechanical component. In asthma attacks, a chemical or physical stimulus causes the air channels in the lung to shut as the muscles that control the width of the channel contract– the mechanical component.

Another example is atherosclerosis, commonly known as the hardening of the arteries, the leading killer in developed countries. Instead of air flow, blood flow is affected as the walls of the blood vessels get thicker. Factors such as smoking, being overweight, and having high cholesterol increase the chance of getting this disease. However, examining the mechanical portion, the plaques associated with atherosclerosis tend to occur at certain parts of the blood vessels, where they branch or curve. You can think of it like a hose. When you kink a hose or put your thumb over the nozzle, the fluid flows in a different way. Hoffman said there are similar stories concerning mechanical portions of major diseases, such as muscular dystrophy and breast cancer.

Hoffman's lab is building tension sensors to measure forces during collective cell migration.

Hoffman’s lab is building tension sensors to measure forces during collective cell migration.

This all sounds very biological, so why is he in the engineering department? As mechanobiology is a new field, there are few tools available for reporting a protein’s shape or its forces inside living cells. Hoffman makes the tools enabling the study of mechanobiology. During Hoffman’s postdoctoral research, he worked on recording forces across proteins in living cells, their natural environment. Now, he’s expanding that technology and using it to do basic science studies to understand mechanobiology.

Hoffman said he hadn’t planned this. From high school, he knew he wanted to be an engineer. As an undergraduate, Hoffman interned at IBM, where he worked on the production of chip carriers using copper-plating. Hoffman was able to apply knowledge, such as changing pH to get various amounts of copper, and make everything perform at optimal performance, but he wanted to know more about the processes.

So he set out to get his Ph.D in process control, which involves deciding how to set all the numbers and dials on the equipment, how large the tank should be, what pressure and temperature should be used, etc. in chemical plants. Hoffman was set on the path to become a chemical engineer. However, during the first week of graduate school, he attended a biophysics talk, in which he understood very little. Biophysics interested Hoffman, so he went from intending to do research on one of the most applied engineering projects on campus to arguably one of the least applied in a week. This was the beginning of his biophysics journey. However, as his Ph. D was much more heavily interested in the physics aspect, Hoffman chose to do his postdoc in cell biology to balance his training. Mixing everything together, he got biomedical engineering.

Hoffman reflects that his decisions were logical, but he had not planned to take the route he did. Hoffman cautions that it is better to have a plan than not because if you do not plan, you won’t know where you are going. However, he advises that since a person learns more about likes and dislikes as one proceeds on their route, students should not be afraid to incorporate what they learn into their plans.

Hoffman’s journey is characterized by finding and doing what he enjoyed. Trained in both the worlds of physics and biology, but never intending to pursue a future in either, Hoffman is uniquely suited for his current position in the revolutionary emerging field of mechanobiology. He is able to put his biology hat on and his physicist hat on for a bit, while the engineer in him is thinking, “is any of this practical?”
“If you had to pick out the key to my success, it would be doing that,” Hoffman said.

AmandaLi_100Guest Post by Amanda Li, a senior at the North Carolina School of Science and Math

 

Mapping the Pathways of Least Resistance

Cancer is a notoriously slippery target. It can assume multiple genetic identities, taking a different pathway whenever it needs to dodge the latest treatment. A recent study found that just a single, tiny tumor can contain more than a million distinct mutations, priming it for resistance.

A series of brain-scans on one patient whose brain tumor bounced back repeatedly despite surgery, chemotherapy and radiation. (Fujimaki T et al. “Effectiveness of interferon-beta and temozolomide combination therapy against temozolomide-refractory recurrent anaplastic astrocytoma.” doi:10.1186/1477-7819-5-89)

A series of brain-scans on one patient whose tumor (white) bounced back repeatedly despite surgery, chemotherapy and radiation. (Fujimaki T et al. “Effectiveness of interferon-beta and temozolomide combination therapy against temozolomide-refractory recurrent anaplastic astrocytoma.” doi:10.1186/1477-7819-5-89)

So, while one treatment might be able to wipe out most of the cancer cells, the few that remain with the right genetic makeup will go on to forge a resistance.

Such resistance is a huge problem and one of the reasons that cancer is on its way to becoming the number one killer disease in the United States. By the end of this year, cancer will kill nearly 600,000 Americans and millions more around the world.

Kris Wood, Ph.D., spoke about the challenges of combating cancer drug resistance at the Basic Science Day on Nov. 16. The annual event brought together faculty, staff, trainees, and students to celebrate basic science research and to encourage collaborations. During the day, attendees heard TED-length talks from faculty members studying a wide range of topics, from vocal learning to asexual reproduction.

“My lab is most interested in the basic question of what are the things that cancer cells can do that allow them to survive in what should be toxic environments created by drug treatments,” said Wood, an assistant professor of pharmacology and cancer biology. “By understanding how cancer cells survive in drug environments, we might be able to both predict those patients who will respond well and respond poorly to treatments, and also design combination therapies that could work more effectively.”

Kris Wood is an assistant professor of pharmacology and cancer biology.

Kris Wood is an assistant professor of pharmacology and cancer biology.

Wood said that knowing that so many different genetic alterations can lead to resistance might make researchers wonder what chances they have of ever stopping a tumor.

But he thinks there is reason to be optimistic, because these myriad mutations seem to function by altering a discrete set of pathways. In turn, many of these pathways seem to create the same kinds of effects in cells – chiefly, fueling growth and shirking death. Targeting the effects that enable resistance could bring about better ways to treat cancers.

For example, half of melanomas are driven by mutations in a gene called BRAF. Wood began to map out the different drug resistance pathways that are controlled by the BRAF signaling molecule. He found that many of these pathways converge on another signaling molecule called MYC, which is known to promote cell proliferation.

When Wood blocked MYC in drug-resistant melanoma cells, he found that it could make them sensitive to further rounds of chemotherapy. He also found that suppressing MYC in melanoma cells before treatment could dramatically delay the time that it takes for resistance to emerge.

Mutant tumor cells (brown) in a brain metastisis of malignant melanoma. BRAF is stained. (Image by Jensflorian via Wikimedia Commons.)

Mutant tumor cells (brown) in a brain metastisis of malignant melanoma. BRAF is stained. (Image by Jensflorian via Wikimedia Commons.)

“MYC is a complicated beast, and there are lots of things it can do,” said Wood. “I think there are some promising strategies for inhibiting MYC, which could lead to intelligent therapies that target resistance.”

Broadfoot_100Guest post by Marla Vacek Broadfoot Ph.D.

E-cigarettes might help smoking cessation

Research has shown that nicotine replacement therapies such as the patch, gum lozenges and nasal spray are only 25 percent effective in smoking cessation within the first year of use.

Jed Rose, Ph.D.

Jed Rose, Ph.D.

Jed Rose, Director of the Duke Center for Smoking Cessation, thinks the use of e-cigarettes, or electronic nicotine delivery systems (ENDS) could be a better way to quit smoking.

Rose spoke Tuesday in a session sponsored by the Center on Addiction and Behavior Change.

He said nicotine replacement is delivered at a slower rate and a lower dose than in actual cigarettes, so it fails to curb craving among smokers. Replacements also don’t replicate one of the main sensory behaviors of smoking: inhalation.

Rose discussed a study in which he and his colleagues anesthetized participants’ airways to see if they could detect the smoke, while keeping the same dose of nicotine to the brain. When participants couldn’t feel the smoke as much, there were more cravings for cigarettes and less satisfaction.

An e-cigarette vaporizes nicotine with battery power, avoiding the combustion byproducts of burning tobacco. (TBEC Review, via Wikimedia Commons

An e-cigarette vaporizes nicotine with battery power, avoiding the combustion byproducts of burning tobacco. (Vaping360, via Wikimedia Commons

They’ve also found that replacement treatments, when given on a temporary basis of just one year, often resulted in relapse.

So what does an e-cigarette actually do? The battery of this electronic cigarette heats an oil that vaporizes the nicotine with a substance called propylene glycol. The gas is released and condenses immediately into a cloud of smoke.

Why is the e-cigarette safer? It’s the combustion products in smoke, rather than the nicotine, that are responsible for most smoking-related disease. Rose cited the 2010 Surgeon General’s Report that backs up this claim that nicotine itself is not responsible for cardiovascular problems or cancers.

GUIDE-Inside-a-eCig

Rose thinks that e-cigarettes could be the best of both worlds, allowing smokers the same sensory effects they enjoy, while possibly avoiding other health hazards of regular cigarette smoking.

Rose also addressed concerns about formaldehyde being present in e-cigarettes. He says this is rare, and only occurs with e-cigarettes that have higher voltages which causes overheating to occur. While there is evidence from two trials that the new devices help smokers to stop smoking long-term compared with placebo, unfortunately, very few studies have looked at this issue. Rose also shares concerns that the new product could be picked up by youth who wouldn’t normally smoke cigarettes, or serve as a gateway between e-cigarettes and real ones.

In the end, however, he thinks this product has the potential to be highly effective in treating addiction, and hopes it will be evaluated further.

“The agency that has to sort through this is the FDA,” he said. “They have to prove that it will help society as a whole. It has to benefit the health of the population.”

 

madeline_halpert_100By Madeline Halpert

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