Penn Medicine News Blog Posts by Karen Kreeger

Now that the school year and the focus on formal science education is slowing down, these images of Penn Medicine faculty, staff, and students sharing their love and knowledge of biomedical science with members of the public from infants to senior citizens during the 2013 Philadephia Science Festival may spark inspiration to last all year. Penn Med took part in a dozen activities all over the city, from a Carnival on the Ben Franklin Parkway that reached over 25,000 people to a TED-talk style panel discussion on innovation and funding at the historic Iron Gate Theatre. See ya' in 2014! 

Two years ago, Penn neurodegenerative researchers determined that a well-known chemical process called acetylation has a previously unrecognized association with one of the biological processes associated with Alzheimer’s disease and related disorders. The findings were published in Nature Communications by first author postdoctoral fellow Todd Cohen, PhD, and senior author Virginia M.-Y. Lee, PhD, director of Penn’s Center for Neurodegenerative Disease Research.

Tau is one of the primary disease proteins associated with neurodegenerative diseases. Tau proteins are expressed primarily in the central nervous system where they help with the assembly and stability of microtubules, protein structures that are the backbone of nerve-cell axons.  

Science comes to life in countless ways -- in hundreds of booths on the Ben Franklin Parkway and dozens of cafes during the Philadelphia Science Festival, in children's books like the "Magic Schoolbus" series, but sometimes it's the simplest tools that provoke an aha moment.  

In an online video series, Florie Charles, a doctoral student at the University of California at San Francisco, and founder of Youreka Science, simply uses a white board and colored markers (and occasionally a small cut out mouse -- animal, not computer peripheral) to explain findings from recent papers in an accessible, fresh, and engaging way. One of her newest videos happens to feature a recent publication from the lab of Garret FitzGerald, MD, FRS, director of Penn Medicine's Institute of Translational Medicine and Therapeutics.

 

More than 10 billion lab tests are performed every year by more than 300,000 medical laboratory professionals across the United States. At Penn Medicine, close to 1,200 faculty and staff in the department of Pathology and Laboratory Medicine work around the clock to perform critical patient care functions such as running blood banks and conducting tests that provide essential data to make diagnoses of all kinds and keep patients safe throughout their hospital stays.

Laboratory professionals are among the unsung heroes of patient care as the team behind the scenes who "get results" or prepare lifesaving therapeutic products, ranging from donated immune cells for infusing into cancer patients undergoing bone marrow transplants to blood for resuscitating patients who've had traumatic accidents.

Increasingly, technology allows patients a glimpse of this important work, by delivering real-time results that help physicians select and manage therapies. But much of this work still remains out of sight from hospital wards and outpatient clinics. Most patients and caregivers will never meet these lab professionals in person, although many decisions for primary and specialized care depend on the expertise and advice from clinical labs in some way.

The Philadelphia Science Festival, from April 19 – 28 this week, celebrates the region’s strengths in science and technology, bringing together more than 100 partners from academia to museums to restaurants.The Festival will include an extensive line-up of programs and exhibitions designed to inspire the next generation of scientists and spark discussion among young and old. 

This year the Center for Brain Injury and Repair (CBIR) is reaching audiences of all stripes with their message of how to mind your brain from concussions with such demos as eggs in Styrofoam to mimic a human head in a helmet.

On Saturday, April 20 CBIR was part of the “Penn village” at the Science Carnival on Ben Franklin Parkway. They and many other Penn groups of exhibitors shared their knowledge and enthusiasm of science and technology:

• Laboratory for the Research of the Structure of Matter
• Netter Center for Community Partnerships
• School of Veterinary Medicine
• Upward Bound Math and Science 
• Biomedical Graduate Studies
• GRASP Lab

Never in a million years would I have thought that I’d be writing about blues musician Blind Boy Fuller, cartoonist R. Crumb, and molecular motors in the same blog post. The Popular Science blog and sci-fi future blog io9 took notice first. The cover of last month’s Biophysical Journal likens movement of the molecular motor Myosin-V to the exaggerated, wobbly gait of R. Crumb’s “Mr. Natural” on the cover of Blind Boy Fuller's record album "Truckin' My Blues Away."

There’s even a link to a 1930s Fuller recording on the io9 post. The Pop-Sci post has a great 22 second animation of a kinesin molecule “walking” along a microtubule while dragging its large cargo and another video of Myosin-V’s tilt and wobble on an actin filament.

These all refer to papers recently published by researchers from the Pennsylvania Muscle Institute. The Biophysical Journal cover is an adaption by sci-artist Patrick Lane submitted by Penn scientists.

The labs of senior authors Yale E. Goldman, and Erika L.F. Holzbaur, both in the Physiology department, have been studying molecular motors for close to a combined five decades. Colleagues Henry Shuman, Phillip C. Nelson in Physics, Haim Bau in Mechanical Engineering, Russel J. Composto in Materials Science, and PMI director Mike Ostap round out the team.

They investigate molecular motors -- proteins that function as tiny molecular machines to move cargos within a cell – to get a better handle on what happens when the transport of cellular cargo goes off track and how that may be the start of developmental and neurodegenerative diseases.  

The Biophysical Journal paper details how Myosin-V works in the “harsh” environment of the cell on a nano scale. Myosin-V must function in a sea of water molecules that bombard it 10¹² times every second. And what’s most spectacular is that myosin uses this seemingly chaotic environment to adjust its short-lived sub-steps to search for the next binding site on its actin track to keep efficiently moving onward. Literally, myosin V uses its fluctuating environment to extend its reach to take each new step.

 

Goldman, Nelson, and company conduct their observations into this micro world with single purified molecules using custom a fluorescence microscope that Goldman and junior colleagues designed and built to see the detailed tilts and wobbles of molecular motors. He calls this the “bottom up” approach.

The researchers also use super-high resolution cell bioimaging, the “top-down approach.” A related paper recently published in the Proceedings of the National Academy of Sciences uses both approaches to understand how components of cell motility like the cytoskeleton and molecular motors work together. Using optical trapping technology in live cells, they found that different types of molecular motors work as a team to get to their target destination. In the center of cell, dynein and kinesin work on microtubule tracks and switch to myosin on actin tracks at the periphery of the cell. Using immune cells called macrophages, they asked, how the microtubule motors operate together. They found that cargoes simultaneously engage with many microtubules and generate high forces to move back and forth in the macrophages.

These papers illustrate how scientific collaborations across multiple disciplines coupled with development of new biophysical technology facilitate discriminating measurements on complex biological networks, notes Goldman. Both of the papers, he adds, show that molecular motors have also evolved sophisticated collaborative adaptations to conduct their essential transport functions. 

 

Penn’s signature event at the 3^rd annual Philadelphia Science Festival next week is a sure sign of the times. “Big Ideas: Funding and Innovation” draws on current themes and reminders of where the bright ideas really come from. Fundamental research at such government agencies as the National Institutes of Health and the National Science Foundation spur today’s most successful businesses and healthcare innovations. Federal funds from taxpayer dollars drive the development of nearly all of the top technologies that permeate our lives.

 

On Tuesday, April 23, 2013 at 6:30pm at the historic Iron Gate Theater, 3700 Chestnut Street, NSF Director and 2013 Franklin Medal awardee Subra Suresh will open a discussion on the importance of federally funded research at laboratories in research universities.

 

In TED-talk style, a group of Penn and Drexel innovators will share their real-life examples of how federal funds have contributed to their Big Ideas:

Garret FitzGerald, MD, FRS, Chair of the Department of Pharmacology, and Director, Institute for Translational Medicine & Therapeutics, Perelman School of Medicine, studies how drugs work in the body. His lab leads the way, with many firsts, to help people lead healthier lives -- discovering how low-dose aspirin is important for heart health, showing which anti-inflammatory drugs might be harmful, and finding an internal body clock important to the circulatory system and when best to take medications.

Chris Hunter, PhD, Chair of the Penn Vet Department of Pathobiology, uncovers ways in which certain proteins cause or prevent inflammatory diseases to create more accurate models of immune-system function, to combat diseases from cancer and arthritis to HIV/AIDS.

Adam Fontecchio, PhD, Professor of Electrical and Computer Engineering and the Associate Dean of Undergraduate Affairs in the College of Engineering, co-directs Drexel’s Expressive and Creative Interaction Technologies (ExCITe) Center, a hub for enabling teams of faculty, students, and entrepreneurs to pursue multi-disciplinary collaborative projects. He investigates liquid crystal interactions to develop novel devices.

Jordan Miller, post-doctoral fellow in the Tissue Microfabrication Laboratory in the School of Engineering and Applied Sciences, combines chemistry and rapid prototyping to direct cultured human cells to form complex organizations of living vessels and tissues. He is one of the founding members of the 3D maker community, using 3D printing in his regenerative medicine research.

Tickets can be purchased here and the full calendar of PSF programs is available here.

Penn Medicine will play a starring role in the Philadelphia Science Festival again this year. The Festival is a citywide collaboration showcasing science and technology every April. 

This year it runs from April 19 - 28, 10 days to celebrate the region’s strengths in science and technology, bringing together more than 100 partners from academia to museums to restaurants. The Festival will include an extensive line-up of programs and exhibitions designed to inspire the next generation of scientists and spark discussion among young and old. 

Take a look at who will be representing Penn Med at the 2013 Philadelphia Science Festival. Penn Med participants are in bold. Click on the links to each event to learn more. Watch this space for more about individual events and for coverage of the festival.

Know the traits of HIV-1 strains capable of establishing new infections could be important for AIDS vaccine development.

After developing methods for their accurate identification, George Shaw, Beatrice Hahn, and Nicholas Parrish, from the Department of Microbiology at the Perelman School of Medicine, and their colleagues, generated infectious clones of transmitted founder and chronic control HIV-1 strains and compared their traits to probe the earliest stages of HIV-1 infection.

Transmitted founder (TF) viruses from acutely infected patients have all the genetic tools to start a new infection, while chronic control (CC) viruses from long-term HIV patients have the genetic tools to sustain an infection for years.

After a transmitted founder strain of HIV-1 infects mucosal tissues, it spreads to nearby and distant tissues, including the gut-associated lymphoid tissue. There, the virus expands exponentially, triggering a systemic cytokine storm, preceding peak viral load in the blood.

The Philadelphia Science Festival is a little over a month away. So many activities to choose from in this now annual spring extravaganza of science, technology, and engineering. Penn Medicine will again participate in many events, and this year's theme is Be Curious! The new Festival video says it all. The events calendar is starting to fill out, so take a look at the new 2013 Festival site.

 

The Penn Center for Brain Injury and Repair will again participate in Science Day at the Ball Park. At the Mind Your Brain table you will be able to learn how your brain works and how to take simple preventive steps -- like wearing a helmet during any contact sport -- to "mind your brain." Families can view nerve cells under a microscope and find out how Silly Putty mimics your axons.

The Phillies are teaming up with the Festival for the third straight year, with a focus on the science of baseball. Held during the Thursday, April 25 Citizens Bank Business Persons Special game against the Pittsburgh Pirates, children can explore and take part in fun science activities throughout the concourse and complete tasks at each location to earn stamps on their own Citizens Bank Park map. If you earn five stamps or more you can receive a Science Day Water Bottle!

Classrooms are encouraged to attend the game that day and teachers can receive pre- and post-Science Day curriculum.

Tickets are on sale and at a $6 discount for tickets under $30 at the Science Day site. All purchasers just need to type in SCIENCE under the special code to apply the discount. April 25 also happens to be Take Your Child to Work Day so families are also welcome.

Watch this space for more information about other Philadelphia Science Festival events!

To celebrate February as American Heart Month, the News Blog is highlighting some of the latest heart-centric news and stories from all areas of Penn Medicine.

“I know this sounds like a cliché, but one of the main reasons I’m interested in learning about the genetic basis of heart disease is because my father’s side of the family has a terrible cardiovascular profile. If anyone understands the urgent need to identify novel targets for therapy, I certainly rank high on the list.” says Benjamin F. Voight, PhD, assistant professor of Pharmacology and Genetics at the Perelman School of Medicine, University of Pennsylvania. Voight’s father, a Major in the Air Force and a fighter pilot, passed away in his late 50s. He had his first heart attack in his late 30s, and as a result, suffered with vascular dementia, a decline in cognitive skills caused by blocked blood flow to the brain, depriving brain cells of oxygen and nutrients.

In 2004, Clifford Bailey of the Diabetes Group from Aston University in Birmingham, United Kingdom described metformin, the most widely prescribed drug for treating diabetes, as ironic: In our high-tech era of drug discovery and development this first-line treatment for type 2 diabetes is little removed from an herbal remedy of the Middle Ages. Despite its chemical simplicity and detailed investigation, metformin continues to evade a complete exposé of its cellular activity (Pract Diab Int April 2004 Vol.21 No. 3)

Now, almost a decade later, a team led by Morris Birnbaum, M.D., Ph.D. from the Institute for Diabetes, Obesity and Metabolism, is getting closer to a clear picture of how this drug works, which, in addition to its widespread use for diabetes, is being tested for treating dementia and cancer.  

The Birnbaum lab and colleagues found that metformin works in a different way than previously understood. They found that in mice it suppresses the liver hormone glucagon’s ability to generate an important signaling molecule, which points to new drug targets.

For fifty years, one of the few classes of therapeutics effective in reducing the overactive glucose production associated with diabetes has been the biguanides, which includes metformin. The inability of insulin to keep liver glucose output in check is a major factor in the high blood sugar of type 2 diabetes and other diseases of insulin resistance.

“Overall, metformin lowers blood glucose by decreasing liver production of glucose,” says Birnbaum. “But we didn’t really know how the drug accomplished that.”

Birnbaum’s Nature study describes a novel mechanism by which metformin antagonizes the action of glucagon, thus reducing fasting glucose levels. The team showed that metformin leads to the accumulation of the protein AMP in mice, which inhibits an enzyme called adenylate cyclase, thereby reducing levels of key enzymes and eventually blocking glucagon-dependent glucose output from liver cells.

Frank Oppenheimer, founder of the famed science museum in San Francisco, the Exploratorium, called artists and scientists “the official ‘noticers’ of society,” adding that “they notice things that other people either have never learned to see or have learned to ignore, and communicate those ‘noticings’ to others.”

Lili Guo, a PhD student in the lab of Xiaolu Yang, PhD, in the Department of Cancer Biology and Abramson Family Cancer Research Institute, is most definitely an official “noticier.”  

Art is in her genes. So is science.

She comes from a family of artists. Her father is a professor of lithography and her mother is a graphic designer for a major publisher, both in China. She has been doing art in many forms since she was five and has been trained in many classical forms: “It has been part of my daily life since I was very young.”

Despite this family influence, she says, “I thought I would be following a family tradition and become an artist, but I was always interested in science and did well in it. I thought art would be my career and that science would be my hobby, my side line. I realized if I pursued art, though I couldn't do science, in China. But, I could never leave science behind.”

This time of year has me pretty run down, with birthdays, holidays, concerts, you name it -- all manner of good and bad stress that weighs on one’s immune system. But I never knew my T cells could get exhausted, too. Two papers from the lab of E. John Wherry, PhD, associate professor of Microbiology and director of the Institute for Immunology at Penn, have taught me otherwise.

When you get a short-lived, acute infection, such as a flu bug, the body generally responds with a coordinated response, rapidly clearing the offending pathogen. Then, their mission done, immune cells stand down, leaving a core population of cells in case of re-infection. 

But what about long-term, chronic infections such as hepatitis C, HIV, and malaria? With these infections, the body and the pathogen essentially fight to a prolonged stalemate, neither able to gain an advantage. Over time, however, the battle-weary T cells become “exhausted,” giving the pathogen the edge.

“We showed for the first time that clotting is reversible,” says John Weisel, Ph.D., professor of Cell and Developmental Biology, in contrast to a long-standing assumption that it isn’t. Weisel and colleagues showed how these sometimes dangerous knots of protein and cells are actually a dynamic, mutable structure this month in Scientific Reports, a new Nature journal. Clotting is both a necessary function to stem blood loss, but in other dire circumstances can ultimately cause death.

In the last month since the paper has been online it has already risen to be the fifth-most-read paper in the journal in the past four weeks.

What makes this seemingly simple finding about the reversibility of clots so astounding is that researchers have tacitly assumed that clots and thrombi are stable structures until they fulfill their functions and are digested by the body. On the contrary, the Penn team found, using “fluorescence recovery after photobleaching,” that fibrin molecules come and go in clots, making them dynamic structures.

Garret FitzGerald, MD, chair of the Department of Pharmacology and Director of the Institute for Translational Medicine & Therapeutics, Perelman School of Medicine at the University of Pennsylvania, has long said the current drug-development system in the United States is in need of change, “representing an unsustainable model.” He suggests a new model for sustainability, inspired by the not-for-profit sector.

The present approach to drug development is unsustainable - roughly the same number of drugs have been approved by the Food and Drug Administration each year since 1950 while the estimated cost, mostly because of the failure to bring new medicines all the way to market - has exploded. Many groups – most recently the President’s Council of Advisors on Science and Technology (PCAST) have mulled over the problem and issued reports. The last recommendation of the one from PCAST, in which I was involved, suggests setting up a working group to re-examine incentives that might foster more efficient drug development.

This month marks three years since the late Mildred Cohn, PhD, the Benjamin Rush Professor Emerita of Physiological Chemistry at the time of her retirement from the Penn department of Biochemistry and Biophysics, passed away. Her early work using magnetic forces to study the structure of molecules led to the development of modern day magnetic resonance imaging, a mainstay of medical research and practice.

Ever since I watched the video about her life from the new Chemical Heritage Foundation’s series Women in Chemistry, I have thought each time I read a new article about gender and science, “What would Dr. Cohn think?”

Just over five years ago, Greg Sonnenberg, PhD, research associate in the Division of Gastroenterology and the Institute for Immunology, was tossing his mortarboard in the air at his now undergraduate alma mater SUNY Buffalo. This month, he will be starting his first independent research position, all before turning 30, effectively bypassing the ubiquitous postdoctoral phase of a typical career in biomedical research.  

The length of the “training period” and therefore age at which early career researchers establish independent research careers, has been steadily lengthening. According to the NIH Biomedical Research Workforce Working Group, the median age at which biomedical scientists start their first tenure-track position is 37. To address the family- and career-stymieing aspects of this trend, the NIH established the NIH Director's Early Independence Award (EIA) for exceptional early-career scientists to move directly into independent research positions by essentially omitting the traditional post-doctoral training period.

Earlier this summer, Sarah Millar, PhD, professor of Dermatology and Cell and Developmental Biology, received an unusual phone call from Carl Baker, MD PhD, Health Scientist Administrator at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). “So, Sarah, we’ve recommended that you receive a MERIT Award. Do you have any idea what that is?” asked Dr. Baker. Millar guessed that anything termed “MERIT” might possibly be good news, but admitted she had no idea what it actually meant.

It turns out that several Penn Med professors presently have these prestigious awards, in a wide range of topics, including natural reservoirs of SIV, simian immunodeficiency virus; regulation and function of thyroid hormone receptors; and genomic analysis of Alzheimer’s disease genes.

The use of DNA in forensics is powerful yet subject to uncertainties. Jennifer Wagner, JD, PhD, a Research Associate at the Center for the Integration of Genetic Healthcare Technologies at the University of Pennsylvania (Penn CIGHT), and Sara Katsanis, MS, an Associate in Research at the Duke Institute for Genome Sciences & Policy at Duke University (Duke IGSP) conducted an exhaustive search of the literature and genome databases to put forensic markers used in the Combined DNA Index System (CODIS) into a context of current understanding of the human genome. Their findings are available in an early online issue of the Journal of Forensic Sciences (“Characterization of the Standard and Recommended CODIS Markers”) and a Letter (“Out with the ‘Junk DNA’ phrase”).

CODIS is a DNA database funded by the FBI. It stores DNA profiles created by crime labs and is searchable to aid in identifying suspects in crimes. The database is comprised of DNA profiles that are indicative of a person's individual DNA, enough to infer identity but not a person’s traits and conditions. The profiles consist of sequences of variable DNA repeats, most notably ones called “short tandem repeats” or, simply, “STRs.”

Recently we have seen a tsunami of coverage of dozens of papers in major scientific journals describing a ten-year project to decipher the non-coding portions of the human genome. This well-orchestrated release of scientific reports came out the same week the Journal of Forensic Sciences paper appeared online. Wagner and Katsanis explain how their work relates to this news.

This summer, Garret FitzGerald, MD, chair of the Institute for Translational Medicine and Therapeutics (ITMAT), testified at a briefing on the Hill organized by American Association for the Advancement of Science that the current drug-development system in the United States is flawed and in need of change.

In short, it’s because of a long-term problem that many have been writing about - the number of new drugs getting to market has remained the same for decades, while costs have skyrocketed. And, to boot, the system of bringing new drugs to patients is extremely expensive and inefficient. Not to mention the regulatory and intellectual property reform that’s needed.

"This represents an unsustainable model," he said, and to change it, "we need to unlock translational opportunities afforded by science."

What could be better than a natural, compatible, long-lived cell for delivering drugs to other cells in the body? Red blood cells fit this description and could be ideal at carrying drugs to specific targets. They play well with cells of the immune system, circulate for hundreds of days in the body; and can be loaded with all manner of cargo: peptides, modified full proteins, or small organic molecules.

In the 1980s, during the early stages of development of this field, HIV-related safety issues associated with blood transfusion forced many investigators to focus on synthetic carriers instead of red blood cells (RBCs). Nevertheless, several groups in the US and Europe are now working to take advantage of the unique properties of RBCs, which are much more compatible with the body than any synthetic carrier.

A year ago this month, Penn Medicine announced the formation of the Penn Center for Orphan Disease Research and Therapy. Perelman School of Medicine researchers are currently conducting nearly 300 research projects on rare/orphan diseases, with nearly a third of those at the preclinical stage, looking at molecular intricacies at the cellular level before a full-blown clinical trial.

Case in point: A research article in a recent issue of Immunity from the lab of Mickey Marks, PhD, professor of Pathology and Laboratory Medicine, in part explains the recurrent bacterial infections in patients with a rare genetic disease called Hermansky-Pudlak Syndrome (HPS) type 2. Symptoms include albinism, prolonged bleeding, pulmonary fibrosis, and recurrent infections by both viruses and bacteria. Previous work on these patients and related mouse models had documented defects in killer T cells that attack virally infected cells and in other cell types that produce antiviral factors, but the recurrent bacterial infections had remained unexplained.

Our immune response is very effective at controlling most early and developing cancers. However, once cancer can be detected as a mass, tumor cells have very often evolved in their own version of natural selection to evade a patient’s immune system. 

Over time, tumors develop different strategies to thwart the immune system.  One way involves tumor cells becoming less visible to the immune system by altering and/or turning off biological processes that present proteins to immune cells. A second way is by establishing a potent immune-suppressive environment around the tumor. For example, pancreas tumor cells produce a molecule that attracts inflammatory cells to cloak the tumor, thereby preventing other immune cells from killing the cancer cells. 

These obstacles make for a very difficult environment in which T cells can effectively attack tumors. In this regard, immunologists such as Michael Kalos, PhD, Director of the Translational and Correlative Studies Laboratory at Penn Medicine, are building a war chest of approaches to enhance the ability of T cells to attack as many cancer types as possible.

It never ceases to amaze me how news about the rare has the potential to inform the common. Researchers from the lab of Erika Holzbaur, PhD, study molecular motors -- proteins that function as tiny molecular machines to move cargos within a cell. For the last few years, Holzbaur, a professor of Physiology at the Perelman School of Medicine, University of Pennsylvania, has been using live-cell imaging to get a better handle on what happens when the transport of cellular cargo goes off track, and how that may be the start of neurodegenerative diseases. In this case, a Parkinson’s-like disorder and a hereditary form of motor neuron disease (MND).  

In a recent study published in Neuron, Holzbaur and graduate student, Armen Moughamian, studied mutations in the molecular motor cofactor dynactin that are associated with Perry syndrome, an extremely rare, inherited neurodegenerative disease. Parkinson’s disease-like symptons and psychiatric changes are the predominant features of this syndrome. The dynactin complex is conserved from yeast to humans, and mutations in it not only cause Perry syndrome, but also cause a form of MND, called distal hereditary motor neuropathy 7B.