As an English major, I can guarantee that I won’t be called upon to inject a drug into a mouse brain. But for neuroscience honors candidate Alex Gogliettino ’17 of Branford, Conn., that’s a basic skill.

Already accepted into doctoral programs in neuroscience for next year, Gogliettino has spent hundreds of hours in a �ֲ���ý lab using a mouse model to analyze and interpret a possible treatment for an exceptionally rare autism-spectrum disorder in humans.

In preparation for his honors thesis research, he spent the past two summers working at , receiving support from a �ֲ���ý Summer Research Fellowship and the Kelsey Prize for Neuroscience Research, named for Professor Emeritus of Psychology John Kelsey.

This year, he’s brought all his �ֲ���ý training to bear on his thesis, “DNA Methylomics: Targeting TET1 as a Treatment for Intellectual Disability,” and as he explained it to me, this was my immediate thought: This is important, and I need to know more.

When somebody asks you about your thesis, what’s your elevator speech?

My adviser and I are basically knocking down a protein — that is, blocking it from being made in the brain — to try to enhance learning and memory in mice that have been genetically modified to have a certain intellectual disability.

The protein is the one in my thesis title: TET1, or “Ten-eleven translocation methylcytosine dioxygenase 1.”

We are also trying to better understand the molecular mechanisms that underpin learning and memory.

How do you make what you write accessible to students, like me, who are not in STEM fields?

That’s one of the biggest challenges in science: Communicating to individuals who are not necessarily involved in science what exactly you are doing.

My actual thesis delves deeply into the molecular biology, but in the first few pages I discuss what this topic means to me personally and how it is addressing a societal issue and a pressing biomedical issue, intellectual disability. I explain why I’m intrigued by it.

And why are you intrigued by it?

OK, this gets pretty philosophical. Humans have the capacity to recall just crazy amounts of detail from earlier parts of our lives. And that capacity really is what makes us who we are. We are what we can remember about our past. That’s just crazy, and it’s just a unique, really interesting puzzle.

And also, there are diseases of the brain, like Alzheimer’s and many others, where individuals can’t do that. And in rare disorders like the one I am studying, Pitt-Hopkins Syndrome, they have impaired language and memory function.

Can you go into a little more detail about Pitt Hopkins?

Individuals with this disease are missing a functional copy of a single gene known as Transcription Factor 4.

Pitt Hopkins is an extremely rare disease. There are only about 500 people in the world that we know of. Individuals with Pitt Hopkins Syndrome often do not develop language — spoken or sign.

My project is based on Pitt Hopkins research being done at �ֲ���ý by my thesis adviser, Andrew Kennedy. We think one of the reasons is a disruption in their capacity for verbal memory.

How is your relationship with your adviser, Andrew Kennedy?

He’s new, and I didn’t really meet him until this year.

Last year, I was taking a neuroscience class, and my professor, Nancy Koven, was saying how �ֲ���ý was hiring a new professor and we should go to the research talk that each candidate gives. I went and I thought that he was asking really interesting questions about learning and memory.

So I just emailed him, a cold email saying, “I would love to work with you.” He emailed me back and said, “That would be cool. Here are the projects that you can work on.”

Alex Gogliettino’s thesis adviser is Assistant Professor of Chemistry Andrew Kennedy, shown teaching an organic chemistry lab on Feb. 9, 2017, in Dana Chemistry Hall. (Josh Kuckens/�ֲ���ý College)

I really like working with him. He’s always available through email, phone, etc. He’s only 33 and has just finished his post-doc so he knows what’s like to be an undergrad.

More important, he also went to a small college, Providence College, so he knows what the relationship between a small-college professor and a student is. He really cares and understands that this whole thing is a learning experience.

What is your thesis routine?

The most important part was to make sure I familiarized myself with the literature, so I started reading last May. That’s probably one of the hardest parts of a project like this: wrapping your head around what is actually happening in the field, where the barriers to new knowledge are, and what we know vs. what we don’t know. That is a really important part of science.

Last semester, almost every morning from around 9 to 12, I would write. I would have the most energy in the morning, and writing is very taxing, that’s the best time for me.

The spot where I wrote really didn’t matter. I would just go somewhere I was comfortable and could work for three hours. It would depend. I would mix it up. First floor of the library sometimes. Then the third floor, then the second floor. And sometimes in my room at my desk.

Was going through the literature daunting?

When you start familiarizing yourself with the field, the first pieces of literature you are going to read are pretty intense. Honestly, reading a scientific paper in an unfamiliar field takes about five hours to go through. You’ve got to just take your time and start as early as you possibly can.

I started out with reading review articles, which are not necessarily studies per se, but are reviewing the literature. They give you a scope of the field. They give you perspective, help you familiarize yourself with the jargon and, again, tell you what’s known and what’s not known about the field.

And once I started to get a feel for that, I started delving deep into the hard-core research papers. It was daunting, a little bit, but I would just take my time.

What has been most enjoyable about working on your senior thesis?

The most interesting part are the questions we are asking about our ability to recall things from the past, and how that fits into the bigger picture of understanding how the brain gives rise to consciousness. That is the coolest part.

The most difficult?

I think the most difficult part is that this work is technically difficult and very time-consuming. That’s not negative, just challenging.

Working with animals requires a good amount of dexterity and injecting drugs into a mouse brain is pretty hard. In the grand scheme of cognitive neurobiology research, it’s pretty simple surgery, but at the undergraduate level it is probably one of the most challenging things that I would do.

Neuroscience major Alex Gogliettino ’17 of Branford, Conn., poses in a Carnegie Science Hall laboratory on Feb. 28, 2017. The red light helps create a calm environment for the lab’s  work with mice. Since mice cannot see red light, they behave as they would in their preferred, darkened environment. (Josh Kuckens/�ֲ���ý College)

Also, another component of my thesis involves working with big data and doing computer-science work, so I had to teach myself a lot of computer science stuff, too. That was tough and challenging, but you grow and learn a lot from it.

What advice would you give to your younger self?

Especially with lab theses, there is only a certain amount of control when you run the experiments. And there is a lot of stuff you can’t control. That is just going to happen.

One of the most important parts of doing thesis, and being involved with science at all, is just understanding that nothing is ever going to be perfect. You are going to mess up and you are going to fail. But don’t be discouraged or shy away from that. Just learn from your mistakes and move on. Be a little too optimistic at times because you need that positive energy to keep going, because there will be a lot of roadblocks to be found, but you can overcome them.

Plans for next year?

I hope to continue doing neuroscience research for the next five years, at least.

I’ve been accepted to a couple neuroscience Ph.D. programs, at Washington University and Vanderbilt, and am heading to Stanford for interviews this week.

I have the potential opportunity to work with a professor who advised Professor Kennedy, doing the same sort of work at a research university that we’re doing here at �ֲ���ý.

Interviews are just a great time to talk science with professors and be immersed in an environment where everyone is as passionate about studying neuroscience as you are.

The malfunctioning of a single human gene causes an autism-spectrum disorder called Pitt Hopkins Syndrome.

The syndrome has profound impacts on intellectual development and cognition, mobility, breathing, digestion and other functions. Notably, it affects communication: Most people with Pitt Hopkins are unable to use language, even sign language.

In recent years, a handful of researchers have made great strides in understanding Pitt Hopkins. And one of them teaches at �ֲ���ý.

Assistant Professor of Chemistry Andrew Kennedy, who joined the �ֲ���ý faculty in August, is among the disorder’s first and leading researchers. And the work that he’s doing with his �ֲ���ý students may be bringing a therapeutic approach to Pitt Hopkins within reach.

Pitt Hopkins is extremely rare. Fewer than 600 cases have been diagnosed worldwide. Until this decade, Pitt Hopkins research was minimal, although its genetic connection was discovered in 2007.

Kennedy’s Pitt Hopkins research is a facet of his broader investigation into how cognition, specifically memory formation, is affected by so-called epigenetic factors — biochemical mechanisms that control how genes are organized.

“I don’t know what it’s like caring for someone with a developmental disability, but I imagine it requires hope,” he says. “Hope includes uncertainty, and it requires investigation and effort, probably setbacks and imperfect outcomes. But at the core there has to be hope.”

Kennedy’s research has attracted about $427,000 in grant support to �ֲ���ý in all. His broader investigation is being funded by a $339,300, three-year grant from the INBRE Investigator program, part of the award from the National Institutes of Health, administered by the Mount Desert Island Biological Laboratory.

That investigation is focusing on ways that, in non-diseased brains, a process called DNA methylation affects long-term memory formation.

In addition, �ֲ���ý has received $88,000 from the , a volunteer nonprofit established by families of children with the disorder, to support Kennedy’s Pitt Hopkins–specific research.

“Pitt Hopkins syndrome, although rare, is a ruinous disease,” says Matt Auer, vice president of academic affairs and dean of the �ֲ���ý faculty. “When Andrew applied for the �ֲ���ý chemistry appointment, his postdoctoral research on DNA methylation and its impact on long-term memory formation got the attention of my colleagues in chemistry and neuroscience.

“We were thrilled when Andrew accepted our offer to join �ֲ���ý. After just one semester, he is emerging as a key interdisciplinary bridge-builder in the sciences at the college.”

Founded in 2012, the Pitt-Hopkins Research Foundation essentially inaugurated Pitt Hopkins research when it reached out to J. David Sweatt, a neurobiologist then at the University of Alabama at Birmingham.

“After just one semester, Andrew is emerging as a key interdisciplinary bridge-builder in the sciences at the college.”

The first molecular neurobiologist in the U.S. to investigate the disorder, Sweatt hired Kennedy as a postdoctoral research associate in 2012, and the pair went on to create the first mouse model of Pitt Hopkins — a fundamental advance, as it gave them and other scientists a basis for further study of the disorder.

With the team of Sweatt and Kennedy, “we got really, really lucky,” says Audrey Davidow Lapidus, foundation president. “It was like hitting the jackpot twice. The two of them really spearheaded some amazing research.” (Sweatt now chairs the pharmacology department at the Vanderbilt University School of Medicine.)

Lapidus and her husband, Eric Lapidus, are the parents of Calvin, who was diagnosed with Pitt Hopkins at 13 months and is now 5 years old. “He has profound developmental delays,” his mother says. “He still cannot walk. He likely will never talk. Some of the other kids with this disorder have severe seizures and breathing episodes, like apneas and hyperventilation.”

The failure of a single gene — TCF4 on chromosome 18 — is the root cause of Pitt-Hopkins, but that failure has a ripple effect. Because TCF4 produces a protein that helps other genes to be read, “it’s a compounding problem,” says Kennedy. “It’s not just one gene not working, it’s a whole family of genes that TCF4 controls not working correctly.”

Assistant Professor of Chemistry Andrew Kennedy in his lab in Carnegie Hall on Dec. 14, 2016. (Josh Kuckens/�ֲ���ý College)

Sweatt and Kennedy capitalized on the fact that there are drugs that “affect gene expression in kind of a wholesale way, called epigenetic modifiers,” says Kennedy. He works specifically with a category of modifiers called histone deacetylase inhibitors, or HDAC inhibitors.

They correlated genes known to be affected by HDAC inhibitors with the genes involved with Pitt Hopkins. One drug in particular emerged from this detective work: Vorinostat, marketed as a cancer treatment under the brand name Zolinza.

“We treated the Pitt Hopkins mice with the drug, and it profoundly improved their capability of learning and remembering,” Kennedy says.

“And this went across every type of behavior that we looked at, whether it be maze-solving, object association, or even object location memory.”

It was an electrifying discovery — all the more so because Vorinostat has already been approved by the U.S. Food and Drug Administration, albeit for a different use. “So there’s a possibility that we can now look at this in a clinically controlled trial setting,” hopefully within five years, says Kennedy.

“Single-gene disorders are a sort of Rosetta Stone for figuring out larger issues like autism, Alzheimer’s, and schizophrenia.”

At �ֲ���ý, Kennedy’s PHRF-funded work will pursue the Vorinostat angle from two directions. First, he and his students will continue to scrutinize specific genes affected by Vorinostat. Second, they will investigate the potential of other FDA-approved HDAC inhibitors for treating Pitt Hopkins.

“We’d like to pick one with the least number of side effects before going into a clinical trial,” because Vorinostat does have side effects, Kennedy says. “We want to know exactly which horse to put our money on before going to clinical trial.”

Moreover, the INBRE-funded study will have a bearing on the Pitt Hopkins work. HDAC inhibitors require ongoing use to be effective, but therapies that target DNA modification, specifically DNA methylation patterns, may have longer-lasting effects on cognition.

What are the students in Kennedy’s charge doing? “They’re going to be trying different therapies on mice, and then giving them tasks to learn and seeing if they do any better than control mice. This is all based on the hypothesis that the epigenome [the complex of chemical compounds that can control the genome] can be targeted to improve learning and memory.”

With a collection of model molecules in the foreground, Assistant Professor of Chemistry Andrew Kennedy is shown in his Dana Chemistry Hall office on Dec. 14, 2016. (Josh Kuckens/�ֲ���ý College)

At the same time, genetic material from the treated mice will be sent away for sequencing. “We’ll be looking exactly at the changes in the genome that occur by going into the neurons and assessing what changed there.”

While the number of known Pitt Hopkins cases is only in the hundreds, the work being done by Kennedy and other scientists in the field reaches beyond that single disorder: a growing body of scientific evidence shows that single-gene disorders like Pitt Hopkins hold clues to understanding afflictions that are vastly more common.

“They hold so much promise for unlocking treatments for other cognitive disorders,” says Lapidus. “They are a sort of Rosetta Stone for figuring out larger issues like autism, Alzheimer’s, and schizophrenia.”

She points out that the initial PHRF grant to Sweatt’s lab at Alabama was followed in 2014 by a research grant of more than $1.8 million from the U.S. National Institute of Mental Health. “They recognize that this is really important, especially with regard to figuring out what we can do about autism.”

Researchers like Sweatt and Kennedy, she says, are “not just researching a rare disorder in some little bubble. This really does have larger ramifications.”

But it’s nevertheless true, as Kennedy points out, that researching an orphan disease “means there are fewer resources and less awareness. Tasks such as organizing a clinical trial, which require large numbers and control groups to be meaningful, can be daunting with such a small population.”

“It can also be hard on the parents that have to wait on the pace of scientific research,” he adds, “but it’s clear that the fact that research is occurring produces hope.”