March 26, 2013,
Volume 59, No. 26
Fels Institute of Government Offers Solutions for Economic Development
Penn’s Fels Institute of Government lays out six proven strategies to help governments, businesses and workers successfully address the problem of creating and retaining a quality workforce in a new report, “Solving the Skills Crisis: Promising Practices for Talent Pipeline Development.”
Funded with support from the Annie E. Casey Foundation, the report highlights strategies to build a talent-development pipeline:
- Onboarding—teaching new employees about the organization and how their position fits into the overall scheme of the company.
- Learn and earn—combining paid work with education that leads to a credential.
- Mentorship—providing readily accessible veteran employees to guide newer workers.
- Public/private intermediaries—leveraging the resources of other businesses, non-profits and government organizations to provide services and resources.
- Work/life support—addressing employees’ personal issues to decrease turnover.
- Career coaches—designating an individual to guide employees through the various stages and opportunities of the talent-development pipeline.
In addition to the site visits and interviews, the report features a scalability index that business can use as a checklist to decide which strategies can be successfully implemented. Numerous case studies for each strategy illustrate the real-world value for decision makers of adopting the tactics in the public and private sector. The full report is available at www.fels.upenn.edu/job-centered-economic-development
Nanoparticles Engineered to Shuttle Cancer Drug Past Immune System
The body’s first line of defense, known as the innate immune system, protects against foreign invaders, including tiny microbes, bacteria or viruses. Yet it also poses a major challenge for therapeutic applications that rely on microscopic drug-delivering vehicles, or nanoparticles. These nanoparticles are in the same size range as many pathogens and are quickly detected and destroyed by macrophages, the innate immune system’s sentinel cells.
Macrophages rely on proteins in blood serum that stick to foreign objects in the bloodstream; these biological ‘red flags’ attract macrophages to engulf the intruders. In the past, scientists working on nanoparticles have attempted to circumvent this process by, for example, masking the engineered particles with a compound called polyethylene glycol, or PEG, to create a “stealth” coat that blocks these blood proteins from sticking to the nanoparticle surface.
A new approach exploits an Achilles’ heel of the innate immune system. Despite their voracious appetite, macrophages are discriminate consumers because they recognize a specific “don’t eat me” signal on the surface of our own cells, represented by a protein called ‘cluster of differentiation 47’, or CD47. On the basis of this insight, Dr. Dennis Discher, a biochemist at Penn’s School of Engineering & Applied Science and his team devised a new way to get these nanoparticles past the body’s immune defenses. The scientists designed a short peptide sequence derived from CD47 and attached it to nanoparticles to fool macrophages into accepting them as ‘self’ rather than foreign. The details of the technique appeared in the February 22 issue of Science.
Using this knowledge and computational modeling, Dr. Discher and his colleagues chemically synthesized a minimal self peptide sequence of 21 amino acids designed to resemble a portion of CD47 protein that is highly conserved in the human genome. The group attached this peptide to conventional nanoparticles that could be used in a variety of therapies. After mixing equal amounts of particles with or without the peptide and injecting this mixture into mice, the scientists measured the amount of particles remaining in the bloodstream 30 minutes later and saw that there were four times as many particles left with the peptide mixture.
The relative ease of synthesizing the CD47 peptide fragment and attaching it to nanoparticles means it could be applied to deliver a wide range of drugs, including gene therapy delivery vehicles. “The next step is to be more exotic and tailor particles of different shapes and flexibility to load more drugs for more realistic approaches with various disease models,” Dr. Discher said.
Reprogramming Cells to Fight Diabetes
For years researchers have been searching for a way to treat diabetics by reactivating their insulin-producing beta cells, with limited success. Type 2 diabetics not only lack insulin, but they also produce too much glucagon. Both type 1 and type 2 diabetes are caused by insufficient numbers of insulin-producing beta cells. In theory, transplantation of healthy beta cells—for type 1 diabetics in combination with immunosuppression to control autoimmunity—should halt the disease, yet researchers have not yet been able to generate these cells in the lab at high efficiency, whether from embryonic stem cells or by reprogramming mature cell types.
The “reprogramming” of related alpha cells into beta cells may one day offer a novel and complementary approach for treating type 2 diabetes. Treating human and mouse cells with compounds that modify cell nuclear material called chromatin induced the expression of beta cell genes in alpha cells, according to a new study that appears online in the Journal of Clinical Investigation.
“This would be a win-win situation for diabetics—they would have more insulin-producing beta cells and there would be fewer glucagon-producing alpha cells,” said lead author Dr. Klaus H. Kaestner, professor of genetics at Penn’s Perelman School of Medicine and member of Penn’s Institute of Diabetes, Obesity and Metabolism. Alpha cells are another type of endocrine cell in the pancreas. They are responsible for synthesizing and secreting the peptide hormone glucagon, which elevates glucose levels in the blood.
The team discovered that many genes in alpha cells are marked by both activating- and repressing-histone modifications. This included many genes important in beta-cell function. In one state, when a certain gene is turned off, the gene can be readily activated by removing a modification that represses the histone.
Co-authors are Nuria C. Bramswig, postdoctoral fellow, Logan Everett, postdoctoral fellow, Jonathan Schug, FGC technical director, Chengyang Liu, adjunct assistant professor of surgery, Yanping Luo, researcher and Dr. Ali Naji, the J. William White Professor of Surgical Research, all from Penn, and Markus Grompe, Craig Dorrell, and Philip R. Streeter from the Oregon Health & Science University. The Oregon group developed a panel of human endocrine cell type-specific antibodies for cell sorting.
Penn Vet Team Uncovers a Pathway That Stimulates Bone Growth
Researchers from Penn’s School of Veterinary Medicine have discovered that a protein called Jagged-1 stimulates human stem cells to differentiate into bone-producing cells. This protein could help both human and animal patients heal from bone fractures faster and may form the basis of treatments for a rare metabolic condition called Alagille syndrome.
The study, published in the journal Stem Cells, was authored by three members of Penn Vet’s departments of Clinical Studies-New Bolton Center and Animal Biology: postdoctoral researchers Fengchang Zhu and Mariya T. Sweetwyne and associate professor Dr. Kurt Hankenson, who also holds the Dean W. Richardson Chair in Equine Disease Research.
Last November, on the promise of these and other findings, Dr. Hankenson and his former doctoral student Mike Dishowitz launched a company, Skelegen, through Penn’s Center for Technology Transfer UPstart program. Skelegen’s focus is to continue to develop and improve a system for delivering Jagged-1 to sites that require new bone growth, in the hope of eventually treating bone fractures and other skeletal problems.
Although human bones seem static and permanent, bone tissue actually forms and reforms throughout our lives. Cells called osteoblasts form bone and are derived from precursor cells known as mesenchymal stem cells, which are stored in bone marrow. These stem cells must receive specific signals from the body in order to become osteoblasts.
Prior research had identified a molecule called bone morphogenic protein, or BMP, as one of these proteins that drives stem cells to become bone-forming cells. As a result, BMP has been used clinically to help patients healing from broken bones or to perform spinal fusions without relying on patients’ own bone tissue.
This molecular signaling pathway is found in most animal species and is known to play a role in stem cell differentiation. The researchers chose to investigate one of the proteins that acts in this pathway by binding to the Notch receptor, Jagged-1. The Penn Vet team has previously shown that Jagged-1 is highly expressed in bone-forming cells during fracture healing and that introducing Jagged-1 to mouse stem cells blocked the progression of stem cells to osteoblasts.
Next the researchers decided to see what happened when Jagged-1 was introduced to human stem cells. There they came upon a very different result.
“It was remarkable to find that just putting the cells onto the Jagged-1 ligand seemed sufficient for driving the formation of bone-producing cells,” Dr. Hankenson said.
This finding aligns with other evidence linking Jagged-1 to bone formation. Patients with a rare disease known as Alagille syndrome frequently have mutations in the gene that codes for Jagged-1. Individuals with this condition have problems with their metabolism that severely affect their livers but also tend to have challenges with their skeletal system and break bones easily.
Genome-wide association studies, which search large populations for mutations that may be linked with particular characteristics, have found a connection between mutations near the Jagged-1 gene and low bone mass.
Dr. Hankenson has multiple collaborations with other researchers at Penn to further investigate how manipulating the Jagged-1 protein may one day help patients. He is working with Dr. Kathleen Loomes, associate professor of pediatrics at CHOP, to study pediatric patients with Alagille syndrome to find out whether their bone abnormalities are indeed connected to Jagged-1 malfunctions.
In addition to partnering with Mr. Dishowitz to develop the technology to deliver Jagged-1 to bone repair sites, Dr. Hankenson is also collaborating with Dr. Jason Burdick, associate professor of bioengineering in SEAS, Dr. Jaimo Ahn and Dr. Samir Mehta, both assistant professors of orthopaedic surgery of the Perelman School of Medicine, to improve and implement this system.
Psych Professor Puts New Wrinkle in Marshmallow Test
For decades, a psychological experiment known as the marshmallow test has captured the public’s imagination as a marker of self-control and a predicator of future success. In the test, a researcher presents a child with a marshmallow and leaves him or her alone for a few minutes. If the child can resist eating the marshmallow until the researcher returns, he or she can have two marshmallows instead of one.
Hidden cameras show that some kids wait patiently for the second treat, while others twist themselves into knots resisting temptation, only to eventually cave in and gobble up the sole marshmallow.
This test of delayed gratification has been found to be better correlated with scholastic performance than traditional IQ tests, but a new study shows that waiting for a bit and then giving up can actually be a rational decision.
Dr. Joseph Kable, assistant professor in psychology in SAS, studies how people make value-based decisions, especially when they require valuing something in the present with something else in the future. When trying to replicate the marshmallow test in his own research, he found that a key fact had been glossed over in both popular and academic discussions: The participants don’t know how long it will be before the researcher returns.
“The kids’ responses seem illogical—if you decided to wait in the first place, why wouldn’t you wait the whole way through?” Dr. Kable said. “Stopping in the middle seems self-defeating, but when you exert self-control in the real world, you don’t know when it’s going to pay off.”
In addition to analyzing data from earlier marshmallow test studies, Dr. Kable and post-doc Joseph McGuire conducted their own survey-based research to see how people estimate the lengths of waiting times in different situations. The researchers asked participants to imagine themselves in a variety of scenarios, such as watching a movie, practicing the piano, or trying to lose weight. Participants were told the amount of time they had been at the activity, and were asked to respond how long they thought it would be until they reached their goal or the end.
“Our intuition is that when we are waiting for something, the longer we wait, the closer and closer we get to that thing, which is what we see when we ask people about familiar things, like how long a movie will last,” Dr. Kable said. “But what we’ve found is that if you don’t know anything about when the outcome will occur, the longer you wait the more you think you’re getting farther and farther away from that outcome.”
While the marshmallow test remains a good predictor of who is better or worse at delaying gratification, Dr. Kable’s research suggests that the mechanism behind that ability needs to be reinterpreted. It may give some hope to the impatient.
“This is exciting to us because it suggests a way to get people to persist to the end,” Dr. Kable said. “You need to give them experiences that provide them with the right kinds of expectations.”
Two-pronged Immune Cell Approach Could Lead to a Universal Shot Against the Flu
Seasonal epidemics of influenza result in nearly 36,000 deaths annually in the United States, according to the Centers for Disease Control. Current vaccines against the influenza virus elicit an antibody response specific for proteins on the outside of the virus, specifically the hemagglutinin (HA) protein.
Yearly vaccines are made by growing the flu virus in chicken eggs. The viral-enveloped proteins, including HA, are cleaved off and used as the vaccine, but vary from year to year, depending on what flu strains are prevalent. However, high mutation rates in envelope HA proteins result in the emergence of new viral types each year, which elude neutralization by preexisting antibodies in the body (specifically the HA proteins’ specific receptor binding sites that are the targets of neutralizing antibodies). On the other hand, other immune cell types are capable of mediating protection through recognition of other, more conserved parts of HAs or highly conserved internal proteins in the influenza virus.
Dr. E. John Wherry, associate professor of microbiology and director of the Institute for Immunology at the Perelman School of Medicine, and colleagues, report in PLOS Pathogens that influenza virus-specific CD8+ T cells or virus-specific non-neutralizing antibodies are each relatively ineffective at conferring protective immunity alone. But, when combined, the virus-specific CD8+ T cells and non-neutralizing antibodies cooperatively elicit robust protective immunity.
This synergistic improvement in protective immunity is dependent, at least in part, on other immune cells—lung macrophages and phagocytes. An implication of this work is that immune responses targeting parts of the virus that are not highly variable can be combined for effective protection.
“The two-pronged approach is synergistic, so by enlisting two suboptimal vaccine approaches, we achieved a better effect than each alone in an experimental model,” said Dr. Wherry. “Now, we are rethinking past approaches and looking for ways to combine T-cell vaccines and antibody vaccines to make a more effective combined vaccine.”
“Overall, our studies suggest that an influenza vaccine capable of eliciting both CD8+ T cells and antibodies specific for highly conserved influenza proteins may be able to provide protection in humans, and act as the basis for a potential ‘universal’ vaccine,” said Dr. Wherry.
These results suggest a novel strategy that could potentially form a primary component of a universal influenza vaccine capable of providing long-lasting protection.
Co-authors include Brian J. Laidlaw, Vilma Decman, Mohammed-Alkhatim A. Ali, Michael C. Abt, Amaya I. Wolf, Laurel A. Monticelli, Krystyna Mozdzanowska, Jill M. Angelosanto, David Artis, and Jan Erikson.
Tweaking Gene Expression to Repair Lungs
Lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are on the rise, according to the American Lung Association and the National Institutes of Health.
These ailments are chronic, affect the small airways of the lung, and are thought to involve an injury-repair cycle that leads to the breakdown of normal airway structure and function. For now, drugs for COPD treat only the symptoms.
“A healthy lung has some capacity to regenerate itself like the liver,” noted Dr. Ed Morrisey, professor of medicine and cell and developmental biology and the scientific director of the Penn Institute for Regenerative Medicine at Penn’s Perelman School of Medicine. “In COPD, these reparative mechanisms fail.”
Dr. Morrisey is looking at how epigenetics controls lung repair and regeneration. Epigenetics involves chemical modifications to DNA and its supporting proteins that affect gene expression. Previous studies found that smokers with COPD had the most significant decrease in one of the enzymes controlling these modifications, called HDAC2.
Using genetic and pharmacological approaches, Dr. Morrisey’s team showed that development of progenitor cells in the lung is specifically regulated by the combined function of two highly related HDACs, HDAC/1 and /2. Dr. Morrisey and colleagues published their findings in the February 25 issue of Developmental Cell.
By studying how HDAC activity, as well as other epigenetic regulators, controls lung development and regeneration, they hope to develop new therapies to alleviate the unmet needs of patients with asthma and COPD.
HDAC1/2 deficiency leads to a loss of expression of the key transcription factor, a protein called Sox2, which in turn leads to a block in airway epithelial cell development. This is affected in part by deactivating a repressor of expression (derepressing) of two other proteins, Bmp4 and the tumor suppressor Rb1 targets of HDAC1/2.
In the adult lung, loss of HDAC1/2 leads primarily to increased expression of inhibitors of cell proliferation including the proteins Rb1, p16, and p21. This results in decreased epithelial proliferation in lung injury and inhibition of regeneration.
Together, these data support a critical role for HDAC-mediated mechanisms in regulating both development and regeneration of lung tissue. Since HDAC inhibitors and activators are currently in clinical trials for other diseases, including cancer, such compounds could be tested in the future for efficacy in COPD, acute lung injury, and other lung diseases that involve defective repair and regeneration, said Dr. Morrisey.
March 26, 2013, Volume 59, No. 26