By Katherine Unger Baillie
Forget birthstones and astrological signs; the month in which you were born may carry serious significance for your health.
A research project involving a team from Penn’s Perelman School of Medicine and School of Veterinary Medicine is teasing out a link between birth month and cardiac disease risk, looking at both humans and dogs. The main thrust: Being born in the summer heightens the risk of disease later in life.
“Dogs are more similar to humans than many other animal models,” says Mary Regina Boland, a biostatistician at Penn Medicine. “They’re pets, so they live in the same environment as we do, but they also can naturally develop cardiovascular disease.”
Boland had been examining the link between birth month and heart disease for a few years, relying on electronic health records, but encountered challenges when accounting for biases and disparities reflected in the data. So she turned to another source.
“I started wondering whether there were any animal models that could potentially support this,” Boland says.
Exploring datasets for pet dogs, Boland realized she needed colleagues in the veterinary world to help her navigate. She connected with two veterinary cardiologists at Penn Vet, Anna Gelzer and Marc Kraus. Together, they analyzed datasets from Penn Vet and the Orthopedic Foundation for Animals, an organization that supports research on inherited diseases in pets.
In a study published earlier this year in Scientific Reports, Boland, Gelzer, Kraus, and colleagues found a strong link between birth month and cardiac disease risk in canines: Those born in the summer months were predisposed to developing heart problems, with the risk soaring up to 74 percent higher than expected for dogs born in July.
In that work, as well as prior studies using human health records, researchers pointed fingers at air pollution as a likely culprit for this connection. It’s believed that exposure to fine air particulates—which are at their highest levels in the summer—somehow leads to harmful physiological changes in utero that may not manifest for decades.
Dogs prove a useful parallel subject to humans for these sorts of studies, the researchers note. “Their life spans are shorter, so if they’re going to develop a condition it will show up in a reasonably compressed timeframe compared to humans,” says Kraus.
That project is still in its early stages, but could have a variety of implications for reducing disease risk.
“For dog breeders, it’s pretty easy to control when puppies are born,” says Gelzer. “With June and July having the highest risk for heart disease, we could just advise to breed during months that wouldn’t result in these birthdays.”
When it comes to humans, dictating which month a baby will come into the world is not as straightforward, but insights gleaned from research in dogs have the potential to help uncover the molecular mechanisms that lead to birth-month effects.
For now, the Penn researchers are brainstorming ways to explore those mechanisms, such as statistical deep dives, genomic sequencing, or microbiome analyses, to potentially locate new intervention targets. They’ve also recently begun to explore connections between cancer risk and birth month, collaborating with Penn Vet’s Nicola Mason, a clinician and researcher who has applied immunotherapy approaches to treating cancer in dogs.
“This doesn’t mean there shouldn’t be any more summer babies,” Boland says, “but the findings we generate could be an entry into some very interesting questions about the drivers of these connections.”
Nanotechnology is enabling new materials and devices that work at sizes so small that individual atoms and molecules make a difference in their behavior. The field is moving so fast, however, that scientists from other disciplines can have a hard time using the fruits of this research without becoming nanotechnologists themselves.
With that kind of technology transfer in mind, the University of Pennsylvania’s Center for Targeted Therapeutics and Translational Nanomedicine has established the Chemical and Nanoparticle Synthesis Core.
Supported by the Perelman School of Medicine and its Institute for Translational Medicine and Therapeutics, the School of Engineering and Applied Science, and the School of Arts & Sciences’ Department of Chemistry, this core facility aims to help Penn researchers design and synthesize custom molecules and nanoscale particles that would be otherwise hard to come by.
“Based on a short survey we conducted, we found that many faculty members want to synthesize unique chemical compounds, such as imaging agents, drugs or nanoparticles, but they don’t have the expertise to produce these compounds themselves,” says Andrew Tsourkas, professor in Penn Engineering’s Department of Bioengineering and Director of the Chemical and Nanoparticle Synthesis Core. “As a result, these projects are often abandoned.”
Claire Mitchell, professor in the School of Dental Medicine’s Department of Anatomy & Cell Biology and the Perelman School of Medicine’s Department of Physiology, knows this story all too well. As one of the Core Facility’s first users, she’s restarting neuroscience research that had been long stymied by a lack of access to nanotech expertise.
Six years ago, Mitchell began a research project that investigated the role of the lysosomes on aging-related diseases, such as macular degeneration and Alzheimer’s. The organelles responsible for degrading cellular waste, lysosomes become less acidic as people and their cells age, and thus less capable of breaking down this waste.
Mitchell collaborated with a colleague at the University of Colorado, who developed nanoparticles that lysosomes would ingest. The nanoparticles help the lysosomes acidify, which leads to the more efficient degradation of cellular waste. They published preliminary findings that suggested that preventing the accumulation of these waste products may help prevent early signs of macular degeneration in retinal cells.
Mitchell’s next target was neurons; while getting the nanoparticles to a patient’s brain would be an additional challenge, she hypothesized that in vitro studies that would show their pH-lowering effect would offer a new therapeutic approach for the treatment of Alzheimer’s.
However, after Mitchell’s initial supply of nanoparticles ran out, she was unable to procure any more.
“My colleagues and I have tried a dozen or more potential research collaborators, but for synthetic chemists, our nanoparticles just aren’t very interesting on their own,” Mitchell says. “While we recognized their considerable potential, the relative simplicity of these nanoparticles made them less interesting for the chemists; they weren’t worth their time or effort to make.”
The nanoparticles in question are simply microscopic balls of polylactic acid (PLA), a plastic that is commonly used as a medium for 3D printing. The trick was getting them to the exact diameter necessary for Mitchell’s experiments: 300 nanometers.
A uniform size is key, as it allows the nanoparticles to enter the lysosomes and reduces off-target effects. While Mitchell and her lab members had access to the equipment and materials to make PLA nanoparticles, they needed professional help to achieve the necessary level of precision.
“We tried to make these nanoparticles ourselves, but we’re not chemical synthesis experts,” Mitchell says. “The Core Facility is a dream come true. Not having to reinvent the wheel allows us to focus on our neuroscience and the prevention of age-dependent damage to the cells.”
Mitchell’s forthcoming experiments with the PLA nanoparticles will investigate the link between microglial cells and the amyloid plaques that are a hallmark of Alzheimer’s. Microglial cells are the primary phagocytes of the brain; she and her colleagues hypothesize that acidifying their lysosomes will improve their ability to clear these plaques.
“Once we’re back to where we were six years ago, there’s huge opportunities to tweak these nanoparticles for new experiments,” Mitchell says. “There are lots of ways we can improve the nanoparticles’ design to enhance and improve this approach. The whole lab is excited that the Core will help us finally make these nanoparticles. It’s a great lesson to never give up.”
Image: Nanoparticles enhanced the degradation of cellular waste in light-sensing retinal cells, according to research by Penn Dental Medicine’s Claire Mitchell, an activity that may help prevent early signs of macular degeneration. (Image Courtesy of PLOS One)
By Katie Delach, Penn Medicine
Sticks and stones may break your bones, but modern medicine usually helps you get back to normal quickly. Though fractures and other injuries may case aches and pains and damaged ligaments and joints may never be exactly the same as they once were, the scars left by a traumatic brain injury (TBI) often manifest in less visible ways; ways that researchers and clinicians have only just begun to really understand.
“Injuries that cause visible physical disabilities—those that may result in paralysis, or the need for casts and wheelchairs—were long considered to be ‘diseases of the body,’ and diseases that result in disabilities such as personality changes, mood disorders, anxiety, insomnia, addiction, and trouble with memory and attention, were thought of as ‘diseases of the soul.’ But that’s changed,” says Ramon Diaz-Arrastia, associate director for Clinical Research in Penn’s Center for Neurodegeneration and Repair, the presidential professor of Neurology, and the director of the Traumatic Brain Injury Clinical Research Initiative at Penn Medicine. “We know now that brain injuries are not an injury of the soul. A traumatic brain injury (TBI) is a disease of the body—it affects the whole nervous system. The brain is a complex organ, and even though we can’t see its scars in the same way we can see them from other injuries, they are certainly there long after a patient has been treated and ‘recovered.’”
According to the CDC, in the United States alone, an estimated 2.5 million people sustain a TBI each year, and of them, 52,000 die and 280,000 are hospitalized. More than 2.2 million are treated and released from an emergency department, but the impact of a TBI can last well beyond a hospital visit, and without proper attention and care, can change the course of a person’s life.
It’s been 19 years since Amy Kraft’s brain injury and in some ways, she’s still recovering. Kraft, 35, was heading to a coffee shop with some friends after rehearsal for a school play when she was accidentally hit by a car. She was a sophomore in high school, a good student with a solid core group of friends, plans to attend college, and aspirations of being a journalist.
“I don’t remember anything from that day,” says Kraft, who is not a patient of Diaz-Arrastia’s but has become a strong advocate and resource for those with TBIs in the years following her injury, and will be participating in Penn Medicine’s Mind Your Brain conference this month. “The doctors told my parents if I didn’t come out of my coma within a week, it was likely that I would have serious brain damage. I woke up on day six. The first thing I remember is sucking water from a washcloth and seeing my grandmother standing at the foot of my hospital bed.”
In addition to her brain injury, Kraft also suffered a ruptured spleen, broken clavicle, broken ribs, broken femur and humerus, and a host of other injuries. When she was well enough, a neuropsychological exam revealed difficulty with short-term memory, problem-solving skills, and speech, and her math and reading skills were reduced to that of a sixth grader. But, in truth, the worst was yet to come, and there was no test anyone could give her that could predict it.
“I didn’t have any emotional issues at first. I was pretty calm and accepting of the whole thing, and just wanted to get out of rehab and get back to my friends and my life,” Kraft says, adding that she did her rehab exercises practically around the clock for nearly a month in an effort to try and speed her recovery. “Once my hair started growing, I started walking, my short-term memory came back…I looked fine, so nobody thought there could be something else going on.”
Little did she know then that it was only when she tried to go back to her life that the true extent of her injuries would be realized. Diaz-Arrastia says that some TBI patients make full mental and physical recoveries from their injuries and do not experience cognitive issues, but for a large number, the recovery may be only physical, and acclimating to daily life can be difficult.
“I suddenly just didn’t feel like I fit in. I was overwhelmed with feelings of inadequacy. I didn’t know how to fit in, and I didn’t know how to socialize,” Kraft explains. It wasn’t long before she turned to drugs and alcohol for relief. “I got into a bad place very quickly.” By the time she was 17, Kraft was “a black-out drinker,” and by the time she was 18, she was homeless and living out of her car.
Part of the problem, Kraft says, was she couldn’t understand what was happening to her. Her family, she says, couldn’t explain or understand the sudden changes in her behavior and didn’t know where to turn for help.
“For a lot of reasons it wasn’t uncommon 10 or 15 years ago for TBI patients to be sent home with zero follow-up, and zero resources or attention,” Diaz-Arrastia says. “Patients would come for follow-up care on their other injuries with specialists in orthopedics or trauma, but three or six months later those injuries were largely healed and almost all of the disability was related to the brain injury. Care that’s targeted at the TBI is certainly getting better, but it continues to be an unmet need.”
Recognizing the unmet need and the immense number of patients who could benefit from support services, Diaz-Arrastia has spent the past 18 months pulling together a team of clinical specialists who are focused specifically on these vulnerable and often overlooked families.
“Clinical care for TBIs has come a long way, but it’s still behind other neurological subspecialties,” says Megan Moyer, a nurse practitioner in neurology who heads up Penn’s TBI support group for patients and family members. “With a paucity of specialists focusing on these injuries, patients often are lost in the shuffle of the system, going to primary care for follow-ups, or seeing specialists only for other injuries that aren’t related to the TBI.”
Penn’s TBI support group started six months ago and, in that short time, has seen remarkable growth with patients and their family members attending meetings for the education as much as the support and knowledge that they aren’t alone.
Despite not having access to the resources, Amy Kraft was one of the lucky ones. When she realized that she was going to die if she didn’t make major changes, she took her first steps toward rehab—both for her substance abuse and her TBI. Today, she’s been sober for 16 years and was even able to still realize her dreams of becoming a journalist.
Still, even after getting clean, Kraft says she dealt with anxiety and insomnia for years. It wasn’t until a therapist suggested some of her struggles could be related to her TBI and started addressing it head on that her symptoms began to subside.
It’s a realization Moyer says she hears often from Penn patients.
“Patients who’ve experienced traumatic brain injuries and their family members need a place to go where they can realize they aren’t crazy, and they aren’t alone,” Moyer says. “We hear a lot of patients say they just didn’t know that a TBI could cause changes in mood or behavior or insomnia. So, for them, just being able to point to something and say ‘ah-ha, that’s why this is happening to me,’ makes a world of difference.”
Top photo: Amy Kraft and her family. Inset photo: Kraft recovering after a traumatic brain injury from a car accident. (Courtesy: Amy Kraft)