Peter Dempsey, PhD, professor of pediatrics-developmental biology in the CU School of Medicine, and Justin Brumbaugh, PhD, assistant professor of molecular, cellular, and developmental biology at CU Boulder, recently published a paper in the journal Nature Cell Biology showing the importance of the H3K36 methylation process in regulating plasticity and regeneration in intestinal cells.

“The intestine has an enormous ability to regenerate itself after injury, and it does this through a model of dedifferentiation,” Dempsey explains. “The cells dedifferentiate back into a type of regenerative stem cell after injury, and those stem cells eventually recover the intestine and turn back to normal cells.”

Finding the switch

Scientists have been looking for a long time for the “switch” that turns regular intestinal cells back into regenerative stem cells, Brumbaugh says. Using animal models, he, Dempsey, and the rest of their research team found that H3K36 methylation — a biochemical process that occurs within the H3 histone protein — is responsible for turning that plastic state on and off. Their research was funded by a grant from the CU Cancer Center.

“If you think about it, those cells that are normally in the intestine have to maintain their identity so they’re functional,” Brumbaugh says. “You have to be sure that they don’t flip when they’re not supposed to, because you lose their specialized function — which is also a hallmark of cancer. There has been other research on histone modifications, because epigenetics makes sense to study in this context. It makes sense that you have this form of regulation that will prevent reversion and lock in cell fate.”

Next steps

With H3K36 methylation identified as the process responsible for the switch between normal cells and regenerative cells, the researchers say the next step is to look for ways to target the process to turn it off or on as needed to treat colorectal cancer and intestinal conditions that can lead to cancer.

“H3K36 methylation seems to be directly involved in differentiating the cells, but if you take it away, the cells revert to this regenerative stem cell state,” Dempsey says. “That regenerative state is important when you have injury and repair, but there also are certain colorectal cancers that have exactly this regenerative gene signature. Chronic colitis, inflammatory bowel disease, is a repetitive injury system, and leads to a higher risk of colorectal cancer. We think we have a mechanism that could be directly applied to those types of cancers, and that’s something we want to study.”

Outside of colon cancer, the methylation process also may have implications for resistance to chemotherapy and radiation, Dempsey says.

“When the cells switch into this regenerative stem cell state, they become more resistant to certain treatments, and that’s a problem,” he says. “If you have a patient who’s not a colon cancer patient but is undergoing chemotherapy or radiation therapy, one of the side effects of those therapies is that you get destruction of intestinal stem cells. In some patients, if it’s not dosed correctly, you can actually strip the whole lining of the intestine. If you could understand how to turn that state back on, you may be able to get the cells to be more protected.”

Future applications

Brumbaugh emphasizes that the recently published research is just the first step in understanding a process that could have a significant role in treating diseases in the future.

“As stem cell biologists, we want to understand the nuts and bolts of this process, because if you do, then you can manipulate it,” he says. “You might want to manipulate it for drug testing, for disease modeling — even if it’s not something where we have a direct therapy that we’re applying to patients, if we can understand how a disease works, then that provides options and opportunities to inform therapies.

“This would be far off in the future, but creating certain cell types for transplantation therapies is something that is very exciting in the stem cell arena,” he adds. “We’re not anywhere close to that, but if you understand how to manipulate the process, you can start thinking about these types of things.”

Now, applied physicists at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have invented a new type of interferometer that allows precise control of light’s frequency, intensity and mode in one compact package.

Called a cascaded-mode interferometer, it is a single waveguide on a silicon-on-insulator platform that can create multiple signal paths to control the amplitude and phase of light simultaneously, a process known as optical spectral shaping. By combining mechanisms to manipulate different aspects of light into a single waveguide, the device could be used in advanced nanophotonic sensors or on-chip quantum computing.

Published in Science Advances, the research was led by postdoctoral fellow Jinsheng Lu, who works in the lab of Federico Capasso, the Robert L. Wallace Professor of Applied Physics and Vinton Hayes Senior Research Fellow in Electrical Engineering. Federal support for the work included award No. FA9550-23-1-0699 from the Air Force Office of Scientific Research under. Devices were made at Harvard’s Center for Nanoscale Systems, supported by the National Science Foundation under award No. ECCS-2025158.

“Conceptually, this is a very big step forward compared to the state of the art for commercial high-speed modulators that are particularly used for communications,” Capasso said.

The most widely used such devices, known as Mach-Zehnder interferometers, work by splitting a beam of light down two paths to toggle its output. Despite their widespread use, Mach-Zehnder interferometers have their limitations — they are not very good at simultaneously controlling different aspects of light. Today, multiple interferometers are needed in succession to make up for these limitations, taking up space and restricting the amount of signal that can travel through.

The new cascaded-mode interferometer is a reimagining of a Mach-Zehnder device integrated into a single-chip waveguide. Rather than the traditional split beam, the new interferometer has a unique, nanoscale pattern of gratings etched into the waveguide that control the energy exchange between different modes of light.

This makes the new interferometer able to control the spectrum of light passing through by finely adjusting the intensity and characteristics of different colors. Light can move through in different patterns, or transverse modes. And the device allows for precise, sharp lines of color, or light waves with distinct features.

In the paper, the team not only demonstrates the capabilities of their new interferometer but also lays out the theoretical framework for extending the physics of the device to many different modes of light.

In one, what looks like a pointillist painting illustrates a young zebra finch’s myriad attempts to sound more like an adult, capable of wooing a mate. In another, squiggly lines trace the ebb and flow of chemical signals in the reward circuit of the bird’s brain.

“Their songs don’t sound like much at first,” said Mooney, who has studied birdsong for four decades.

That’s because some things take considerable practice to master. Nobody walks onto a tennis court for the first time and plays a match worthy of Wimbledon, or takes up the piano and becomes a virtuoso overnight.

Likewise, in zebra finches, chicks don’t start out life with the vocal chops to make their signature trills, chirps and peeps. It takes them a while to get the hang of it.

“The amount of effort that a juvenile bird makes to achieve vocal mastery is immense,” Mooney said. “It takes them about one month of solid practice every day, up to 10,000 renditions a day.”

Young finches keep at it hour after hour, day after day, even when no one is listening. Their motivation for mastery comes from within. And now, new research sheds light on the brain signals underlying their intrinsic desire to learn their songs; it also holds implications for understanding human learning and neurological disorders.

Thanks to new tools and techniques, including advances in machine learning and the ability to track subtle and rapid chemical fluctuations in the brain, Mooney and Duke neurobiology professor John Pearson are beginning to disentangle the molecular signals that drive learning for its own sake.

In new research published March 12 in the journal Nature, the team put male juvenile zebra finches into individual soundproof rooms where they could practice their songs at will.

In zebra finches, only the males sing; young birds learn their courtship song early in life by first listening closely to their dad and memorizing his song. Then, like babies learning to talk, they begin to babble, their squeaks slowly becoming more song-like. By practicing their songs and listening to the results, gradually they figure out how to produce the right notes and rhythms to match their mental template of their dad’s song.

It takes a zebra finch chick about three months from hatching to become proficient singers.

To Mooney, a longtime rock ‘n’ roll fan, the males’ practice sessions are a bit like the obsessive recording process for The Beatles. “The Beatles might have done a hundred takes” before they were satisfied, Mooney said. Similarly, “these birdsong data sets get so big so fast.”

That’s where Pearson’s team came in. To get a handle on the data, they developed a machine learning model that can analyze the thousands of song renditions and score each attempt.

“This way we can track learning on a moment-by-moment basis,” Pearson said.

“Some tries were a little better, and some were a little worse,” he added. Generally the longer the birds worked at it, the better they got.

As the birds gradually mastered their tunes, the team also measured the level of dopamine released in the birds’ basal ganglia, a part of the brain involved in learning new motor skills.

Dopamine is one of the brain’s chemical messengers, transmitting important signals about learning, reward and motivation from one neuron to another.

To monitor dopamine, the researchers used tiny sensors made from genetically modified proteins that glow when particular neurochemicals are released in the brain. The technology makes it possible to track brain activity that is largely invisible to common methods based on measuring electrical signals.

What they found surprised them. Whenever a bird practiced, dopamine levels in the bird’s basal ganglia started to ramp up. It didn’t matter whether they hit all the notes or missed the mark. In other words, any effort at singing activates signals in the brain’s reward pathways.

The birds’ dopamine surged more when a bird performed better than was typical for their age. The signal was slightly weaker when they regressed.

The better they performed for their age, the more dopamine increased, said first author Jiaxuan Qi, who did the work as part of her Ph.D. in neurobiology at Duke.

Dopamine has long been known to play an important role in how humans and other animals learn from external rewards and punishments.

Take, for example, a child studying because they want to get a good grade or avoid a scolding. Or consider a rat learning to press a lever for food.

But birds don’t need carrots or sticks to learn how to sing. Because the birds were alone during their practice sessions, singing away in a soundproof room, they weren’t getting any external feedback on how they were doing.

“Nobody’s telling the bird if he’s an honor student or going to be sent to detention,” Mooney said.

Instead, the findings suggest that dopamine acts like an internal “compass” to steer their learning.

The team’s research helps explain how learning still occurs even in the absence of external incentives. The researchers also found that dopamine isn’t the only chemical signal required for such learning.

Qi was able to show that another chemical messenger called acetylcholine can trigger dopamine release in the bird’s brain when it is singing. It works by binding to a different part of the neurons, giving the bird an extra dopamine boost when it belts its ballad.

When the birds were given drugs that blocked dopamine or acetylcholine signaling in the basal ganglia, the birds made less progress, Qi added.

“Learning basically comes to a halt,” Mooney said. “The bird still sings a lot, but he doesn’t seem to be able to learn from it.”

The potential implications go beyond bird brains, Mooney said.

“These findings translate across species,” Pearson said. “The brain regions and neurochemicals involved — namely the basal ganglia, dopamine and acetylcholine — are shared by mice, primates, humans. Essentially every animal with a backbone.”

Studying how birds learn to sing can help researchers better understand how humans learn other motor skills such as talking or juggling or playing an instrument. In that sense, Mooney said, “birdsong learning is very similar to what children do when they spontaneously acquire these remarkable skills.”

Dopamine signaling problems in the basal ganglia have also been linked to a number of diseases, including Parkinson’s and schizophrenia.

“It’s really important that we understand these regions, and the bird is a means of getting at those principles,” Pearson said.

“Of all the scientific frontiers that remain, the brain is probably the most poorly understood, and it’s fundamental to being human,” Mooney said.

This research was supported by grants from the National Institutes of Health (5R01 NS099288, RF1 NS118424, F32 MH132152 and F31 NS132469).