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June 23, 2011

Research Notes

Leaky genes speed evolution

Small genetic mutations that add up over time could create an evolutionary express lane that leads to the rapid development of new traits, say researchers from Pitt and the University of Wisconsin-Madison.

The team reports in the Proceedings of the National Academy of Sciences (PNAS) that slight changes in segments of DNA known as transcriptional enhancers — which determine the when, where and how much in gene production — can activate dormant genetic imperfections. These alterations awaken specific genes to low-level activity, or “leakiness,” in developing tissue different from the genes’ typical location. Just a few subsequent mutations built on that stirring can result in a new function for an old gene — and possibly a novel trait.

Co-author Mark Rebeiz, a faculty member in biological sciences, and his colleagues traced how a certain unwitting gene found itself in the unique optical neurons of a species of fruit fly.

They found that tiny alterations in the transcriptional enhancers of the species’ ancestor caused the gene to take root in these neurons for the first time. A couple of mutations later and the gene became a permanent fixture in the fly’s brain cells.

The work expands on research during the past 30 years that demonstrates that new genes made from scratch are rare in animals, Rebeiz said. Instead, the diversity of living things is thought to stem from existing genes showing up in new locations. In a famous example, researchers at the University of Basel in Switzerland reported in Science in 1995 that a gene known as PAX6, a “master control” gene for the formation of eyes and other features in flies, mice and humans, could cause the growth of additional eyes on the legs and antennae of fruit flies.

With their report in PNAS, Rebeiz and his co-authors offer the first explanation of what makes these genes go astray in the first place — and they identified the deviant DNA as the culprit. The researchers found that the gene Neprilysin-1 present in the optical neurons of the fruit fly species Drosophilia santomea emerged in that location about 400,000 years ago — a blip in evolutionary terms — in the last common ancestor the fly shared with its relative D. yakuba. The mutation began with a transcriptional enhancer for the gene, which caused Neprilysin-1 to show up in different neurons than usual. From there, Rebeiz said, the development of D. santomea’s distinguishing neurons plays out with the clarity of a film as four mutations in subsequent generations intensify the errant enhancer’s impact until Neprilysin-1’s presence in optical neurons become an exclusive feature of D. santomea. On the other hand, ensuing genetic alterations in D. yakuba actually extinguished this new expression and restored that fly’s Neprilysin-1 to its original location.

“It has been long appreciated that nature doesn’t make anything from scratch, but the mystery has remained of how genes that have been performing the same job for hundreds of millions of years are suddenly expressed in new places,” Rebeiz said. “Our work shows that even slight mutations in a transcriptional enhancer can cause leaky gene activity, which can initiate a short route to the development of new traits.”

RFID system reads implants

Radio-frequency technology developed at Pitt is being used as the basis of a new electronic “tag” system designed to track and monitor orthopaedic implants. The noninvasive system, known as Ortho-Tag, features a wireless chip attached to the implant and a handheld receiver that together would let physicians view the critical information about artificial knees, hips and other internal prosthetics — as well as the condition of the surrounding tissue — that currently can be difficult to track down.

The chip, or tag, would have information about the patient, the implant and the procedure uploaded to it prior to an operation and sensors within the chip would gauge the pressure on the implant, the chemical balance and temperature of the tissue and the presence of harmful organisms.

The information would be read by a handheld probe developed in the laboratory of Pitt electrical and computer engineering faculty member Marlin Mickle.

When placed against the patient’s skin, the probe communicates with a radio-frequency identification (RFID) tag, devised by graduate researcher Xiaoyu Liu, that emits a unique wavelength designed to travel through human tissue. Special software would display information from the tag on a computer.

New Jersey-based orthopaedic surgeon Lee Berger, CEO of Ortho-Tag and inventor of the tagged implant, recently patented the Ortho-Tag system and his company has optioned the rights to Mickle’s work.

Berger, who envisions Ortho-Tag being attached to implants by the manufacturer, currently is building partnerships with manufacturers. Ortho-Tag would distribute the software and probe to physicians.

For people with existing orthopaedic devices, the company is considering producing wallet-sized cards with an affixed RFID tag uploaded with information about the patient and the implant, Mickle said.

Berger said he developed the Ortho-Tag concept because patients who had received orthopaedic implants often knew little about the type of device they had received, the company that manufactured it or even the surgeon who had performed the procedure.

“Other than written records, the only way to learn about a device once it’s implanted is through an X-ray. But even that does not provide such details as size, model number or manufacturer, or health information about the patient that is directly related to the implant’s performance,” Berger said.

“For a physician to provide follow-up care, it’s important to know the exact device a patient has, and there are several different models, shapes and sizes of devices for use in knees, hips, feet, the spine and other parts of the skeleton. With Ortho-Tag, a doctor only has to scan a chip to see all that information.”

In addition, said Mickle, defective implants typically are recalled by serial number, crucial information that usually is kept on written records where the original surgery took place. Ortho-Tag could be used to identify a suspect implant quickly and easily.

“There are a lot of different devices manufactured by a lot of different companies and implanted at a lot of different hospitals by a lot of different surgeons,” Mickle said. “There has to be accountability for objects implanted in the body, and we hope that this technology will finally make orthopaedic devices much easier to monitor and, thus, safer for patients.”

Vaccine access affects flu spread

Pitt researchers say that giving wealthier counties greater access to influenza vaccine than poorer counties could worsen a flu epidemic because poor areas have fairly high population densities with higher levels of interaction among households and communities, enabling the infection to spread faster.

The study, published in the June issue of Health Affairs, used a detailed computer simulation of the Washington, D.C., metropolitan area and found that limiting or delaying the vaccination of residents in poorer counties could raise the total number of influenza infections.

Moreover, inequitable access to vaccinations increased the number of new infections during the peak of an epidemic in both poor and wealthier counties — even though the wealthier counties had received more timely and abundant vaccine access.

The study’s lead author, Bruce Y. Lee, a faculty member in medicine, epidemiology and biomedical informatics, said, “When vaccines are in short supply, distributing them quickly and equitably among populations and localities can be a difficult challenge. However, policymakers across the country, in poor and wealthy areas alike, have an incentive to ensure that poorer residents have equal access to vaccines.”

Lee is the applied modeling project principal investigator for the Models of Infectious Disease Agent Study (MIDAS) National Center of Excellence.

He and his co-authors developed the flu vaccination model while working with the Department of Health and Human Services during the 2009 H1N1 pandemic. The team studied how the course of the pandemic might have been affected by vaccinating residents of various counties at different rates and times.

Computer simulation modeling suggested that equitable vaccination could reduce an epidemic’s severity because poorer counties tend to have high-density populations and more people considered higher risk — such as children — per household, resulting in more interactions. This leads to increased transmission of influenza and greater risk for poorer influenza outcomes, the study found.

Even with the best intentions, inadequate infrastructure, geographical or socioeconomic barriers or cultural differences can lead to inequitable access to vaccines, Lee said.

Research has shown that poorer people may have less access to medical care, including vaccination, than wealthier people.

The study was supported by the National Institute of General Medical Sciences and the Vaccine Modeling Initiative, funded by the Bill & Melinda Gates Foundation.

Pitt co-authors included Shawn T. Brown and John J. Grefenstette of biostatistics; Rachel R. Bailey, Sarah M. McGlone and Shanta M. Zimmer of medicine; Richard K. Zimmerman of family medicine; Margaret Ann Potter of health policy and management, and MIDAS center head Donald S. Burke, dean of the Graduate School of Public Health.

MIDAS was initiated by the National Institute of General Medical Sciences to investigate novel computational and mathematical models of existing and emerging infectious diseases. In 2009, the University was designated a MIDAS National Center of Excellence, leading a collaborative network of scientists in the development and use of computational models that will prepare the nation to respond to outbreaks of infectious diseases, such as the H1N1 swine flu. The MIDAS research agenda includes the development of computational tools for the analysis of the dynamics of emergent diseases and for the predictive evaluation of the effectiveness of proposed intervention strategies.

Prof receives DoE early career funding

Gurudev Dutt, a faculty member in physics and astronomy, recently received a five-year, $750,000 grant from the Department of Energy’s early career research program. Dutt was chosen among 65 promising researchers nationwide from a field of 1,150 applicants. Selection was based on peer review by outside scientific experts.

Dutt is working to develop a magnetic field imaging technique with nanoscale resolution that would allow for non-invasive, non-destructive probing of a variety of important physical phenomena such as quantum tunneling in single-molecule magnets and quantum bits encoded into spins in quantum dots.

Diamond single spin magnetic sensors are a highly promising material platform featuring high magnetic field sensitivity, nanometer spatial resolution and the important ability to operate under ambient or harsh environmental conditions required to study many material systems.

Dutt’s proposed work will take a multifaceted approach toward improving the accuracy, sensitivity and robustness of this platform through investigations into quantum control and precision quantum metrology coupled with innovative design, sophisticated nanofabrication and advanced measurement techniques.

Neurons slow to mature

New neurons take more than six months to mature in adult monkeys and that time is likely even longer in humans, according to researchers from the School of Medicine, Penn State and the University of Illinois.

Their findings, reported online in the Proceedings of the National Academy of Sciences, challenge the notion that the time it takes for neurogenesis is the reason antidepressant medications are not fully effective until three-five weeks after treatment begins.

Pitt psychiatry faculty member Judy Cameron, who also is a senior scientist at the Oregon National Primate Research Center, Oregon Health and Science University, said: “Expanding our knowledge beyond rodent models to understand how neurons mature in non-human primates will give us more insight into what happens in the human brain. In rodents, neuronal maturation happens in four weeks, which is considerably different than what we have found in our monkey studies.”

Cameron’s research team gave adult monkeys injections of an agent called BrdU, which can be used as an indicator of new neuron formation, then examined brain tissue at different times to look for markers of stages of maturation in tiny neurons called granule cells.

Six weeks after an injection, 84 percent of the new cells still bore markers of immaturity and were immature in shape; in a rodent, all of the cells would have matured by this time. Only one-third of the monkey granule cells had markers of maturity up to 28 weeks after BrdU injections. That means the majority of new granule cells will not reach maturity until more than six months have passed, the researchers said. Also, because the human brain is larger than the monkey brain and takes longer to develop, maturation of adult human neurons likely would take even longer.

The study was funded by the National Institutes of Health, the Spastic Paralysis and Allied Diseases of the Central Nervous System Foundation and the Retirement Research Foundation.

Public health research grant announced

The Public Health Adaptive Systems Studies (PHASYS) at the Graduate School of Public Health (GSPH) recently announced that Shawn T. Brown, a faculty member in the Department of Biostatistics and a research fellow at the Pittsburgh Supercomputing Center, is the 2011 PHASYS pilot study grant recipient.

Brown’s study is “The Geospatial Area and Information Analyzer (GAIA), a Visualization Tool for Understanding Emergency Preparedness Through Geospatial Analysis.” Brown’s group has been developing a Geospatial Area and Information Analyzer to create information-based visualization for public health. In Brown’s pilot study, an interactive, web-based application of a preparedness dataset will be created for public health officials to explore.

Under a five-year grant from the Centers for Disease Control and Prevention, PHASYS, located in the Center for Public Health Practice at GSPH, conducts research to develop, test and apply criteria and metrics for measuring the effectiveness and efficiency of preparedness and emergency response to hazards with public health consequences.

PHASYS annually seeks applications for pilot studies that expand the research capability of GSPH in the field of public health systems research, with a strong focus on preparedness.

Sociology project funded

The Department of Sociology recently announced that faculty member Waverly Duck has received funding from the Center on Race and Social Problems for his research on “Social Policy, the State, and the Poor: An Ethnographic Examination of Policy Intersections in an Impoverished Urban Neighborhood.”


The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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