A team of University of Pittsburgh researchers has uncovered new details about the biology of telomeres, “caps” of DNA that protect the tips of chromosomes and play key roles in a number of health conditions, including cancer, inflammation and aging.
The new findings were published today in the journal Nature Structural and Molecular Biology.
Telomeres, composed of repeated sequences of DNA, are shortened every time a cell divides and therefore become smaller as a person ages. When they become too short, telomeres send a signal to the cell to stop dividing permanently, which impairs the ability of tissues to regenerate and contributes to many aging-related diseases, explained lead study author Patricia Opresko, Ph.D., associate professor of Environmental and Occupational Health at Pitt, and member of the University of Pittsburgh Cancer Institute Molecular and Cellular Cancer Biology program and Carnegie Mellon University Center for Nucleic Acids Science and Technology.
In contrast, in most cancer cells, levels of the enzyme telomerase, which lengthens telomeres, are elevated, allowing them to divide indefinitely.
“The new information will be useful in designing new therapies to preserve telomeres in healthy cells and ultimately help combat the effects of inflammation and aging. On the flip side, we hope to develop mechanisms to selectively deplete telomeres in cancer cells to stop them from dividing,” said Dr. Opresko.
A number of studies have shown that oxidative stress—a condition where damaging molecules known as free radicals build up inside cell—accelerates telomere shortening. Free radicals can damage not only the DNA that make up telomeres, but also the DNA building blocks used to extend them.
Oxidative stress is known to play a role in many health conditions, including inflammation and cancer. Damage from free radicals, which can be generated by inflammation in the body as well as environmental factors, is thought to build up throughout the aging process.
The goal of the new study was to determine what happens to telomeres when they are damaged by oxidative stress. The researchers suspected that oxidative damage would render telomerase unable to do its job.
“Much to our surprise, telomerase could lengthen telomeres with oxidative damage,” Dr. Opresko said. “In fact, the damage seems to promote telomere lengthening.”
Next, the team looked to see what would happen if the building blocks used to make up telomeres were instead subjected to oxidative damage. They found that telomerase was able to add a damaged DNA precursor molecule to the end of the telomere, but was then unable to add additional DNA molecules.
The new results suggest that the mechanism by which oxidative stress accelerates telomere shortening is by damaging the DNA precursor molecules, not the telomere itself. “We also found that oxidation of the DNA building blocks is a new way to inhibit telomerase activity, which is important because it could potentially be used to treat cancer.”
Dr. Opresko and her team are now beginning to further explore the consequences of oxidative stress on telomeres, using a novel photosensitizer, developed by Marcel Bruchez at Carnegie Mellon University that produces oxidative damage selectively in telomeres. “Using this exciting new technology, we’ll be able to learn a lot about what happens to telomeres when they are damaged, and how that damage is processed,” she said.
Imagine being in an accident that leaves you unable to feel any sensation in your arms and fingers. Now imagine regaining that sensation, a decade later, through a mind-controlled robotic arm that is directly connected to your brain.
That is what 28-year-old Nathan Copeland experienced after he came out of brain surgery and was connected to the Brain Computer Interface (BCI), developed by researchers at the University of Pittsburgh and UPMC. In a study published online today in Science Translational Medicine, a team of experts led by Robert Gaunt, Ph.D., assistant professor of physical medicine and rehabilitation at Pitt, demonstrated for the first time ever in humans a technology that allows Mr. Copeland to experience the sensation of touch through a robotic arm that he controls with his brain.
“The most important result in this study is that microstimulation of sensory cortex can elicit natural sensation instead of tingling,” said study co-author Andrew B. Schwartz, Ph.D., distinguished professor of neurobiology and chair in systems neuroscience, Pitt School of Medicine, and a member of the University of Pittsburgh Brain Institute. “This stimulation is safe, and the evoked sensations are stable over months. There is still a lot of research that needs to be carried out to better understand the stimulation patterns needed to help patients make better movements.”
This is not the Pitt-UPMC team’s first attempt at a BCI. Four years ago, study co-author Jennifer Collinger, Ph.D., assistant professor, Pitt’s Department of Physical Medicine and Rehabilitation, and research scientist for the VA Pittsburgh Healthcare System, and the team demonstrated a BCI that helped Jan Scheuermann, who has quadriplegia caused by a degenerative disease. The video of Scheuermann feeding herself chocolate using the mind-controlled robotic arm was seen around the world. Before that, Tim Hemmes, paralyzed in a motorcycle accident, reached out to touch hands with his girlfriend.
But the way our arms naturally move and interact with the environment around us is due to more than just thinking and moving the right muscles. We are able to differentiate between a piece of cake and a soda can through touch, picking up the cake more gently than the can. The constant feedback we receive from the sense of touch is of paramount importance as it tells the brain where to move and by how much.
For Dr. Gaunt and the rest of the research team, that was the next step for the BCI. As they were looking for the right candidate, they developed and refined their system such that inputs from the robotic arm are transmitted through a microelectrode array implanted in the brain where the neurons that control hand movement and touch are located. The microelectrode array and its control system, which were developed by Blackrock Microsystems, along with the robotic arm, which was built by Johns Hopkins University’s Applied Physics Lab, formed all the pieces of the puzzle.
In the winter of 2004, Mr. Copeland, who lives in western Pennsylvania, was driving at night in rainy weather when he was in a car accident that snapped his neck and injured his spinal cord, leaving him with quadriplegia from the upper chest down, unable to feel or move his lower arms and legs, and needing assistance with all his daily activities. He was 18 and in his freshman year of college pursuing a degree in nanofabrication, following a high school spent in advanced science courses.
He tried to continue his studies, but health problems forced him to put his degree on hold. He kept busy by going to concerts and volunteering for the Pittsburgh Japanese Culture Society, a nonprofit that holds conventions around the Japanese cartoon art of anime, something Mr. Copeland became interested in after his accident.
Right after the accident he had enrolled himself on Pitt’s registry of patients willing to participate in clinical trials. Nearly a decade later, the Pitt research team asked if he was interested in participating in the experimental study.
After he passed the screening tests, Nathan was wheeled into the operating room last spring. Study co-investigator and UPMC neurosurgeon Elizabeth Tyler-Kabara, M.D., Ph.D., assistant professor, Department of Neurological Surgery, Pitt School of Medicine, implanted four tiny microelectrode arrays each about half the size of a shirt button in Nathan’s brain. Prior to the surgery, imaging techniques were used to identify the exact regions in Mr. Copeland’s brain corresponding to feelings in each of his fingers and his palm.
“I can feel just about every finger—it’s a really weird sensation,” Mr. Copeland said about a month after surgery. “Sometimes it feels electrical and sometimes its pressure, but for the most part, I can tell most of the fingers with definite precision. It feels like my fingers are getting touched or pushed.”
At this time, Mr. Copeland can feel pressure and distinguish its intensity to some extent, though he cannot identify whether a substance is hot or cold, explains Dr. Tyler-Kabara.
Michael Boninger, M.D., professor of physical medicine and rehabilitation at Pitt, and senior medical director of post-acute care for the Health Services Division of UPMC, recounted how the Pitt team has achieved milestone after milestone, from a basic understanding of how the brain processes sensory and motor signals to applying it in patients
“Slowly but surely, we have been moving this research forward. Four years ago we demonstrated control of movement. Now Dr. Gaunt and his team took what we learned in our tests with Tim and Jan—for whom we have deep gratitude—and showed us how to make the robotic arm allow its user to feel through Nathan’s dedicated work,” said Dr. Boninger, also a co-author on the research paper.
Dr. Gaunt explained that everything about the work is meant to make use of the brain’s natural, existing abilities to give people back what was lost but not forgotten.
“The ultimate goal is to create a system which moves and feels just like a natural arm would,” says Dr. Gaunt. “We have a long way to go to get there, but this is a great start.”
The Pierre-and-Marie-Curie University (French: Université Pierre-et-Marie-Curie; abbreviated as UPMC), also known as Paris VI, is a university located on the Jussieu Campus in the Latin Quarter of the 5th arrondissement of Paris, France.
It was established in 1971 following the division of the University of Paris (Sorbonne), and is a principal heir to its Faculty of Sciences. The French cultural revolution of 1968, commonly known as “the French May”, resulted in the division of the world’s second oldest academic institution, the University of Paris, into thirteen autonomous universities.
UPMC is the largest scientific and medical complex in France, active in many fields of research with scope and achievements at the highest level, as demonstrated by the many awards regularly won by UPMC researchers, and the many international partnerships it maintains across all five continents. Several university rankings have regularly put UPMC at the 1st place in France, and it has been ranked as one of the top universities in the world. The ARWU has ranked UPMC as the 1st in France, 6th in Europe and 37th in the world and also 5th in the field of mathematics, 41st in the field of physics, 14th in the field of natural sciences and between 51st to 75th in the world in the field of engineering, technology and computer science.
It has more than 125 laboratories, most of them in association with the Centre national de la recherche scientifique (CNRS). Some of its most notable institutes and laboratories include the Institut Henri Poincaré, Institut d’Astrophysique de Paris, Laboratoire d’informatique de Paris 6 (LIP6), Institut de mathématiques de Jussieu (shared with University Paris-Diderot) and the Laboratoire Kastler-Brossel (shared with École Normale Supérieure)