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Thanks for the Memories

It’s my third time meeting with Mike Yassa ’02. Once again, I park my car in the same underground garage, climb the same flights of steps, turn past the same fountain, and walk the same path toward his office in Ames 216A on the Homewood campus. When I arrive, he’s wrapping up a phone call, so for a few minutes, my eyes flit around his office, taking in what’s now become a familiar scene: his miraculously uncluttered desk, scattered photos of his wife and young daughter, yellow padded chairs, matching yellow wall adorned with a black metal seahorse. Just like the other times we’ve spent together, he and I will sit and chat for about an hour. We’ll talk about his life, his work, and his family.

Despite the similarities of each visit, my brain will reliably record each meeting as a separate event—each a new memory that’s distinct from those of my previous visits. Forming these unique accounts seems like a simple undertaking—something most young, healthy people take for granted. But the process actually involves a complicated interaction between cells within a spot near the center of the brain called the medial temporal lobe. It’s a dance that Yassa has been focused on learning more about for several years, both to understand what happens in healthy brains as well as in the brains of those whose memories fade away, either through normal aging or memory disorders such as Alzheimer’s disease.

He’s had his own multiple experiences at Johns Hopkins: coming here first for his undergraduate education, then starting his graduate career [at Hopkins], and finally returning for a faculty position here last winter, moving into the campus’s newest student residence hall, Charles Commons. Besides laying down his own unique memories, he’s also making big gains in the learning and memory field—and providing students with research experiences they’ll never forget.

Chasing Neuroscience

In our first meeting, Yassa told me that it was his father who originally had the idea to come to Johns Hopkins. A pediatrician who decided later to pursue public health, Alfred Yassa took a job as a faculty member at Johns Hopkins’ Bloomberg School of Public Health in 1994. For years, he worked [remotely] in the Middle East, starting up public health programs that focused on family planning and smoking cessation, among other initiatives, in Oman and Jordan.

Mike Yassa spent his high school years in American embassy academies, listening to his father expound on the wonders of Johns Hopkins. When it came time to make a decision about college, it was an easy choice. Sight unseen, except for photos of the university that his dad brought back from visits, he applied through the early application process and got in.

“I came to Hopkins in ’98, and except for just a few years away, I’ve never really left,” he tells me with a grin hovering above his neatly trimmed goatee.

Yassa started out intending to get a broad science background so that he could apply to medical school, an objective that seemed a given in his family. But he quickly discovered a tenacious affinity for neuroscience. Even while putting together medical school applications, gathering reference letters, and taking the MCAT, Yassa was eating, sleeping, and breathing his neuroscience classes. “Any free time I had, I was in the lab. And when I wasn’t there, I was reading neuroscience articles,” he says. “It became a really positive power that possessed my life.”

Not wanting to disappoint his parents, Yassa initially kept his leanings to himself. But after he’d started research as a sophomore in a neuroscience lab, taken all the requirements for the neuroscience program by accident, and realized he was ready to declare it as a major, Yassa broke the news to his father. Both Yassas saw the advantages that a career in research could have over medicine. Rather than touching individual lives, as a doctor might, he could take a research approach through neuroscience—potentially helping hundreds of thousands of people at once.

Yassa’s single‑minded focus earned him a spot in Johns Hopkins’ new neuroscience honors society in his senior year. During a lunch for society members with famed Johns Hopkins neuroscientist Vernon Mountcastle, Yassa asked a question that confirmed what he’d already suspected: What one big thing will revolutionize our understanding of the brain?

Mountcastle’s answer was functional MRI, or fMRI, a way to track what parts of the brain are active during tasks by following blood flow. Yassa was already very familiar with fMRI—he was using the technology in his undergraduate research project at Johns Hopkins’ medical school.

“I told my father, ‘[Mountcastle] is a guy who’s seen the field change over the last 50 years. If he thinks this is the next big thing, then maybe I should try to pursue this. ‘”

The Winding Path to Memory

During my second visit to Yassa’s office, I sat in on one of his frequent video chat sessions with Craig Stark, his former graduate school mentor and good friend. After Stark and his wife and research associate, Shauna Stark, flashed into view on Yassa’s screen, the three chatted over the tinny‑sounding computer speakers about the most recent results from ongoing experiments, tweaks in study designs, and the pros and cons of recruiting study subjects from retirement communities and churches. There’s no hint of the former student‑mentor dynamic now—only the close relationship of two respected colleagues who are working together to solve the same problems.

Yassa met Stark three years after finishing his undergraduate degree at Johns Hopkins. After graduation, Yassa accepted a job as a senior research technologist at the same Hopkins lab where he’d worked as an undergraduate. It was still fun to dabble in fMRI and to help other researchers at the School of Medicine design their experiments—for a while, at least. After a couple of years, Yassa says that he started hitting a wall.

“I realized that I had my own questions, but it’s not like I had my own grant,” he told me. “I knew I couldn’t really go o and do my own research with just a bachelor’s degree.”

His next step became clear after meeting one day with Stark, then a Hopkins professor in the Krieger School of Arts and Sciences, who had developed software that Yassa was using to process fMRI data. When Yassa stopped by to ask Stark some questions about the software, the two got into a deep discussion about Yassa’s work, scribbling notes about experimental design and plotting data on the surface of a glass desk with a dry erase marker. “It left me wanting more,” Yassa remembers.

When Stark asked him if he planned to apply to Hopkins’ graduate program, Yassa already knew that the answer was yes. That fall, in 2005, he started his graduate work with Stark as his mentor.

With the hint of a chuckle in his voice, Stark told me later over the phone that from early on, he knew Yassa wasn’t the typical grad student. “I could tell that Mike thought in a very big‑picture kind of way,” he said. “Nothing seems impossible to him.”

Rather than wait placidly for assignments from his mentor, Stark remembers, Yassa had his own ideas. Stark’s lab had long focused on understanding learning and memory using young, healthy undergraduates as study subjects. But Yassa had a different thought: What about looking at these processes through the lens of aging and memory loss? He reasoned that getting a better understanding of the gradual memory deterioration that takes place with normal aging—as well as the more drastic decline with memory‑robbing diseases such as Alzheimer’s—could provide a new way of looking at the basics of how learning and memory work. The new focus could also give Stark’s lab a way to collaborate with Michela Gallagher at Arts and Sciences, an international powerhouse in the field of aging‑related memory research in animals.

Yassa’s aging‑related memory work quickly ramped up. To fully develop his research, he needed funding—but Stark remembers feeling harried with the pressures of running the lab, with no time to work on grant proposals to fund new research areas.

“I was busy with other stuff, and the deadline for the grant Mike wanted wasn’t too far away. Mike said, ‘Let me have a crack at it,’” Stark recalls, with incredulity still audible in his voice. “I figured it would be a good learning experience for him.”

Normally, Stark explained, professors don’t have mentees help them write grants until their postdoctoral years. At the time, Yassa was only a second‑year graduate student.

Patiently, and not expecting much, Stark says that he waited a couple of weeks for Yassa to turn in a draft. To his surprise, the grant proposal was so well reasoned and well‑written that it needed only the lightest of edits. When they eventually heard back from the grant committee at the National Institutes of Health (NIH), Stark remembers, he got the biggest surprise of all: the grant, for $100,000, had been funded in the first round of reviews. “The NIH wasn’t funding a heck of a lot then,” Stark told me. To get research funded so quickly and easily “was practically unheard of,” he added.

Yassa’s “eternal optimism” wasn’t just an advantage in getting grant funding, Stark says. It’s also played a key role in his subsequent research success. Not long after getting that grant, Stark accepted a new position at the University of California, Irvine, and brought Yassa with him. There, Yassa set his sights on using an MRI technique called diffusion tensor imaging to get pictures of the perforant path—a tiny stretch of nerve cells, about 2 millimeters wide, in the medial temporal lobe that’s thought to play a key role in encoding and retrieving memories. It delivers and pulls information out of the brain’s seahorse‑shaped structure that stores memories, known as the hippocampus (a structure that Yassa plays homage to in the seahorse art on his office wall).

Yassa and Stark, among other researchers, had hypothesized that the perforant path is one of the first structures to degrade with the normal cognitive decline of aging, as well as the more drastic decline of early Alzheimer’s. But examining it in living, breathing humans had never been done before. The resolution of images that researchers had been able to obtain just wasn’t good enough to see the minuscule structure, much less confirm its degradation.

“Mike just wasn’t willing to take ‘that’s not going to work’ as an answer,” Stark says. Set on his goal, Yassa spent months in the lab, varying parameters on the MRI scanner and working with a physicist to push the machine’s limits. One day in late 2009, the researchers finally got their breakthrough: An image of Stark’s brain revealed the fabled structure. Knowing now how to wield this tool, the researchers embarked on an odyssey of scanning dozens of volunteers, young and old, to see how their perforant paths compared. Sure enough, the researchers found that those in older volunteers had less integrity compared to those in the younger volunteers.

The finding wasn’t just a curiosity—it had real world significance. Volunteers with more degraded perforant paths couldn’t remember words on a list as well as those with perforant paths in better shape. In another study, published in Proceedings of the National Academy of Sciences earlier this year, Yassa and Stark pushed the limits on their technique even further, using it to catch a glimpse of how new memories are retrieved. The scientists were especially interested in the phenomena known as pattern separation and pattern completion. Just as I’m able to remember each of my visits to Yassa’s lab as separate events, pattern separation involves teasing apart memories that have features in common. Pattern completion is the flip side of that coin—using old memories to fill in gaps in new experiences, such as using my previous trips to the Homewood campus for other projects to figure out how to get to Yassa’s office the first time.

Yassa explains that in their follow‑up study, the research team asked college students and senior citizens to view pictures of a series of objects, indicating whether these objects were more likely to be found inside or outside—a ploy to get their brains to unconsciously lay down new memories of these pictures while in the scanner. Later, outside the scanner, the volunteers viewed some of the same pictures, interspersed with similar pictures (for example, a tractor in the first set of photos in a different orientation) and pictures that were completely new. Yassa, Stark, and their colleagues asked the volunteers to distinguish which pictures were the old ones, which were new, and which were similar.

The scientists found that younger volunteers were generally better at identifying the similar items for what they were—even when they were very similar to old pictures. However, older volunteers, with more degraded perforant paths, were more likely to say that similar items were old ones.

“We showed that the perforant path seems to play a big role in pattern separation,” Yassa told me. “It’s as if previous information interferes with current learning and inhibits it. As we age, and the perforant path degrades, it gets harder to learn and retrieve information and pull things apart as well as we did in our younger days.”

Getting a better handle on exactly what the perforant path and the structures it interacts with are doing and how they degrade could help older people retain their memories far longer into old age, Yassa believes. “Maybe this infrastructure degrades down to 80 percent fidelity, but if we can figure out a way to tweak it so it acts like 100 percent—maybe by taking a drug—people could remember more for longer,” he explained.

That’s exactly what Yassa and collaborator Michela Gallagher have in mind for future studies. Several years ago, Gallagher’s lab showed that in aged animals that showed memory deficits, a population of nerve cells in a region of the hippocampus, known as the CA3, was hyper‑ active. Other researchers, who’d seen increased activity in the same general area using less precise methods, had assumed that this increased activity was just the brain trying to overcompensate for degeneration. However, when Gallagher and her colleagues quieted these CA3 cells, the animals’ memories improved.

After joining forces with Yassa and Stark, the team showed last year that people with amnestic mild cognitive impairment (aMCI), a memory problem thought to be the initial stage of Alzheimer’s disease, also have hyperactivity in the CA3 region. The study used an FDA‑approved drug for epilepsy, called levetiracetam, that had previously been shown to improve memories in aged animals. The researchers found similar benefits in human patients: Levetiracetam lowered hippocampal overactivity and improved memory performance in a neuroimaging task. Gallagher says that she and Yassa currently have a grant proposal under review to use these imaging methods to run a larger clinical trial of levetiracetam to confirm its effects.

Paying It Forward

In my third trip to see Yassa, I paid a visit to his lab on Ames’ first floor. It bustled with about half a dozen students—all conspicuously young. “That’s right,” he confirmed later. “I’ve staffed my lab with undergraduates.”

His young work force, he says, isn’t a temporary placeholder until he recruits his first graduate students, a consequence of starting his faculty position midyear. On the contrary: It’s a permanent solution, an homage to the opportunities he was given as an undergraduate student here. He credits his strong undergraduate research program, along with the independence he had in Stark’s lab, for enabling him to achieve so much so early in his career. Though he just started his first faculty position in January of this year, at age 30, his curriculum vitae already lists 20 peer‑reviewed papers. And rather than land his first job after a lengthy postdoctoral fellowship, the norm for most faculty members, Yassa was invited to interview at Johns Hopkins even before he defended his graduate thesis.

Wanting his students to have the same chance to make their mark, Yassa has each lab member leading work on an independent project. They’re trying to answer a wide range of questions related to the lab’s overarching theme of learning and memory, such as whether people’s cultural backgrounds might bias whether they’re better at remembering the faces of members of their own race—a project led by junior Allen Chang. Or whether study subjects show the same age‑related deficits in pattern separation with words or music clips—a project led by junior Maria Ly, who recently won one of Johns Hopkins’ coveted Provost Undergraduate Research Awards to fund her work.

As if Yassa doesn’t get enough time with undergraduates during the day, he also lives with them at night. That’s because his family, including his wife, Manuella ’06, and their 16‑month‑old daughter, Isabella, resides in Johns Hopkins’ Charles Commons. Opened in 2006, the dorm houses sophomores and juniors, along with a handful of resident and graduate assistants. The Yassa family lives in a three‑bedroom apartment built just for the resident faculty member. Their tidy home teems with pink toys belonging to Isabella, including a play kitchen, a plush rocking horse, and a polka‑dotted, toddler‑sized chair.

Living in a dorm might not seem like the most natural choice for a new faculty member with a young family—but Manuella told me that it’s been the perfect fit. Having graduated from the same undergraduate neuroscience program that Mike did, four years later, she said that the neighborhood was already familiar before they made the move. “It’s like coming home,” she added.

Besides already knowing her way around, she and her husband listed a slew of other benefits for their unique living arrangement: a five‑minute commute, being able to eat meals as a family, and built‑in babysitters for Isabella. “Everyone in the building sees her and knows her,” Mike says.

As part of their living arrangement, the family is in charge of organizing the “Charles Commons Connections” events, which bring together faculty and students from across the campus to socialize outside of class. They’ve held faculty dinners, fireside chats with faculty—complete with a fake cardboard fireplace—and most recently, an ice cream social to welcome students back to the academic year.

Despite heavy rain outside, throngs of raincoat‑clad students straight from class crowded the lobby, loading tiny paper Dixie cups with their favorite flavors. Within a few minutes, the remnants of Isabella’s melted sweet potato ice cream were on Mike’s shirt. “Worse stuff has happened to this shirt,” he joked with the dorm’s newest students.

It’s a fresh new year—and a new chance to make memories.