“The more I narrow in, the broader the science becomes”

As PhD researcher Alexandra Ekshteyn, who goes by Sasha, approaches the end of her PhD in the Jordanova lab, something slightly unexpected is happening. Her research question is becoming more specific, but the science she draws on to answer it is getting broader.

“You imagine that toward the end of a PhD, you keep narrowing things down until you arrive at this very specific conclusion,” Sasha says. “For me, it has almost been the opposite. The mechanism I’m looking at is getting more specific, but the research I’m pulling from is coming from a much wider range of fields than I expected.”

Her PhD focuses on HINT1-related Charcot-Marie-Tooth disease (CMT), a rare inherited neuropathy affecting the peripheral nerves. The Jordanova lab helped identify HINT1 as a disease gene more than a decade ago, but many questions about what the protein actually does, and why losing its function damages peripheral nerves, remain unanswered.

That search has taken Sasha well beyond the traditional CMT literature. “I’m looking at other neuropathies and neurodegenerative diseases, of course,” she says. “But I also find myself reading a lot of cancer research and even heart disease research. These can seem like completely different diseases, but sometimes the underlying cellular pathway is very relevant to what we are seeing.”

A thousand ways to kill a neuron

HINT1 is expressed throughout the body and has been linked to several cellular processes. Yet a loss of functional HINT1 produces a very specific neurological phenotype, raising an obvious question: why are peripheral nerves particularly vulnerable?

Earlier transcriptomics work in the Jordanova lab provided one clue. Researchers saw changes in pathways associated with the actin cytoskeleton, the internal network that helps cells maintain their shape, organize their contents, and move material from one place to another.

“At first, it looked like something we might investigate with a few experiments and then move on,” Sasha says. “That did not turn out to be the case.”

The deeper she looked, the more evidence she found that HINT1 may be involved in maintaining a healthy actin cytoskeleton. And that is where apparently unrelated research fields started becoming unexpectedly useful.

“There’s a phrase I’ve heard a lot: there are a thousand ways to kill a neuron,” she says. “Neurons are very specific cells in a very specific environment, so there are lots of little things that can go wrong.”

But there is another way to look at that complexity, she adds: “There may be a thousand ways to kill a neuron, but that is still a finite number. And I’m willing to bet that some of those mechanisms overlap with ways to kill a tumor cell or damage a heart cell.”

Cancer researchers may be asking a completely different biological question, but they can still be studying the same signaling pathway, protein interaction, or piece of cellular machinery. Their tools and findings can therefore offer clues for understanding what is happening in a peripheral nerve.

“That has actually informed some of the last steps of my PhD,” Sasha says. “Once you get to a question that nobody in your immediate field has answered yet, there isn’t always someone doing exactly the same thing whose work you can follow. You have to look further.”

Looking outside your own field

For Sasha, that increasingly means thinking of interdisciplinarity not simply as collaboration between neighboring specialties, but as actively looking for useful ideas in places where you might not initially expect to find them.

She points to examples far beyond CMT. Connections between the gut and the brain have reshaped parts of neuroscience, while ideas borrowed from fields such as topology and origami have even influenced the design of medical devices.

“You see people making very deliberate connections much further outside their own area than you might expect,” she says. “And often it is really useful.”

That is particularly relevant in CMT, which is not one disease caused by one gene. It is a genetically heterogeneous group of neuropathies involving many different genes and proteins. As researchers learn more about them, however, common biological themes are beginning to emerge.

“Different genes can end up affecting the same pathways, the same cellular structures, or the same processes,” Sasha says. “So what we learn from one form of CMT can potentially inform what we do with another.”

When neuroscience tools are built for the brain

Looking ahead, Sasha also sees a more practical limitation that needs addressing: many of the newest tools in neuroscience are still designed primarily for the central nervous system.

“For our group, that can be frustrating,” she says. “You talk to a company about doing neuroscience and they are very excited, until you explain that you are working with peripheral nerve rather than brain tissue.”

Spatial omics is one example. These technologies can map molecular information while preserving where it is located within tissue, giving researchers a much richer picture than simply measuring which genes or proteins are present. But protocols have often been optimized around brain tissue, which behaves very differently from a peripheral nerve sample.

“There has been huge progress in recent years, especially in spatial methods,” Sasha says. “But I would really like to see the tools available for peripheral nervous system research catch up with what already exists for the CNS.”

Doing so could open up an important source of material that researchers already have: archived patient biopsies. Peripheral nerve biopsies were historically collected as part of the diagnostic process and many remain stored in paraffin blocks. They represent actual affected human tissue, but were often collected years before today’s technologies existed.

“Some of those samples are literally sitting in a drawer,” Sasha says. “If we can apply these newer methods to them, suddenly we can bring that patient tissue back into the research.”

For families still waiting

Better technologies also matter for a more immediate reason. Despite enormous advances in genetics, some people with CMT still do not know the genetic cause of their condition.

For those families, Sasha says progress can sometimes feel frustratingly slow: “It can feel like a game of hurry up and wait. But we as researchers do have a pipeline. We go from sample to variant, to model, to mechanism, and hopefully eventually to treatment.”

New sequencing approaches can uncover variants that older technologies missed. New disease models can help researchers investigate genes whose role was previously unclear. And every new disease mechanism adds to the accumulated knowledge researchers can use when approaching the next unsolved case.

For families who already have a genetic diagnosis, meanwhile, a different set of questions begins. “Being able to put a name to it can already be a big deal,” Sasha says. “Especially with a rare disease, where people may have spent a long time feeling that nobody really knows what is happening.”

A genetic answer can clarify inheritance and connect people with relevant information or patient communities. But identifying the gene is only the start of the scientific problem. Researchers still need to understand how a particular variant changes cells, why that leads to peripheral nerve degeneration, and whether that mechanism can be altered.

Many genes, fewer mechanisms

That is where Sasha thinks the diversity of CMT may ultimately become an advantage.

There are many CMT genes, but there may be far fewer underlying biological processes through which those genes cause damage. If several forms of the disease converge on the same pathway, discoveries made in one rare subtype could become relevant to many others.

“Our group and other groups are gradually making our way through these mechanisms,” Sasha says. “And every new thing we learn can inform the next.”

The trajectory she would like to see is straightforward, even if achieving it is anything but. A family without an answer gets a genetic diagnosis. A newly identified gene gets a disease model. The model reveals a mechanism. And once researchers understand that mechanism, they can begin asking whether there is something they can actually change.

“Best-case scenario, we cure CMT and we can all go home,” Sasha laughs. For the next few years, she will settle for continued progress: “For the patient who doesn’t have an answer, hopefully we find a gene. For the gene, we build a model. For the model, we find a mechanism. And from those mechanisms, hopefully we can move toward something actionable.”

As she reaches the end of her PhD, the picture in front of her has not become as neatly contained as she once expected. Her own research question has narrowed, but the scientific landscape around it has expanded, pulling in ideas from other diseases, other tissues, and other fields. Increasingly, those connections are where the next clues seem likely to come from.