CELEBRATING FEDERAL COBRE SUPPORT

Dustin Updike, Ph.D., and his research group at the MDI Biological Laboratory are uncovering new truths about germ cells — the egg and sperm cells that are uniquely able to divide and differentiate into all other cell types.

The scientists are focusing on tiny, transparent C. elegans roundworms to illuminate some mysterious structures that are found inside their germ cells. Made of RNA and protein, the blob-like formations are called germ granules.

One early discovery at the Updike lab: how granules defend germ cells’ prolific capabilities — their “totipotency.”

Certain proteins in the granules, they found, prevent the germ cells from changing into specific cell types and losing their capacity for self-renewal. That stabilizes the organism’s fertility and supports genetic processes needed to regenerate damaged tissues.

“We see these granules and processes in roundworms, but the same things are happening in all animals, including humans,” Updike says. “That’s giving us insights into how fertility and cellular regeneration can be encouraged… or discouraged.”

Updike says it was support from the federal “Centers of Biomedical Research Excellence” program — COBRE for short — that propelled his work into new frontiers of basic cell science.

“It doubled the size of my staff,” he says. “It supported my lab and the institute’s infrastructure. It allowed me to get that work done.”

COBRE (pronounced COE-bree) is part of a National Institute of General Medical Sciences program, called the Institutional Development Award (IDeA), that funds biomedical science and education in geographic regions outside the more established research centers. Over the course of three decades, it’s cultivated the work of institutions and early-to-mid-career scientists in 23 states and Puerto Rico.

In 2013, here on rural Mount Desert Island, Updike joined three other scientists in the Laboratory’s new Kathryn W. Davis Center for Regenerative Biology and Aging to pursue — and win — what would become the center’s first COBRE award: a $13 million grant.

Updike says that as an early-career scientist, the influx of support allowed him to build a solid base of staff, equipment, research and publication. And it laid the groundwork for subsequent efforts to win more traditional funding.

“In these IDeA states like Maine, the program incentivizes research institutions and colleges and universities to hire new faculty,” Updike says. “And the expectation is they’ll be good enough and have enough resources to grow and then apply for independent funding.”

It worked for Updike. With help from COBRE-backed coaches and mentors, (including experts in writing grant applications) he won a coveted federal R01 grant within two years.

“And because of that I was booted off of the COBRE program,” he jokes. “‘Graduated’ is the nicer term — and that allowed us to recruit someone else under the same COBRE grant.”

Over time COBRE funding has provided $23 million to support innovative work by nine principal investigators at the Laboratory and built a platform for MDIBL’s emergence as an international hub for research on aging, regeneration and tissue repair.

“COBRE established a critical mass of research scientists at MDIBL,” says

Iain Drummond, Ph.D., the Davis Center’s director and the Principal Investigator for the grant. “It’s funded nine of our 11 labs — all top-notch, all internationally competitive. The foundation provided by COBRE will serve as a springboard for the maturation of the Laboratory.”

And it’s led to six other major National Institutes of Health grants, such as Updike’s R01 award, totaling more than $9 million. COBRE has also worked in partnership with private donors to the Laboratory: science-funding stalwarts such as Kathryn Davis and Wistar and Martha Morris, who have provided gifts of more than $10 million over the last decade. (See This is Why, page 14)

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Now, a final phase of the Laboratory’s COBRE journey will focus on enhancing its scientific and technical resources, such as bioinformatics, cloud computing, microscopy, and an expanded roster of animal models. (See The Next Phase, page 11)

Meantime, there are still three earlycareer scientists on campus whose investigations and advancement are directly supported by the earlier phases of the Laboratory’s COBRE grants.

Jarod Rollins, Ph.D., is researching how lifespan-extending interventions such as dietary restriction regulate gene expression, protecting cells and tissues from age-related decline. COBRE funding, he says, is like an aerialist’s safety net.

“With money comes security, which provides the freedom to take risks, and that’s what you have to do if you want to make big discoveries and have a big impact,” Rollins says. “The COBRE funding has allowed our team to endure the failures. And, let’s be honest, failures are necessary to be truly innovative.”

COBRE’s wide scope has also fostered a culture of collaboration across disciplines at the Laboratory, sparking new scientific insights and creating real excitement among the researchers.

“It’s a kind of cross-fertilization that wouldn’t exist anywhere else,” says James Godwin, Ph.D. He studies the role scarring plays in inhibiting regeneration in humans and how animals such as axolotl salamanders can regenerate tissues, organs and limbs. But he also works closely with scientists at the Laboratory whose focus is on aging.

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“With money comes security, which provides the freedom to take risks, and that’s what you have to do if you want to make big discoveries and have a big impact. The COBRE funding has allowed our team to endure the failures. And, let’s be honest, failures are necessary to be truly innovative.”

In 2019, he, Rollins and Sam Beck, Ph.D. — another COBRE recipient — organized the 2019 RegenAge symposium. It was a first-of-its kind event on the interface between these fields and one of several COBREsupported symposia that have brought the world to the Laboratory’s doorstep.

“The ability to regenerate is linked to age, but these fields are usually quite disconnected,” Godwin says. “So the opportunity to collaborate and share ideas with colleagues at MDIBL who are thinking about aging and longevity is a dream.”

Central to the scientific enterprise, COBRE is helping MDIBL and its scientists penetrate some of nature’s closely-held secrets.

Back in 2013, a paper in the journal Cell identified nine “hallmarks of aging,” such as the degradation of gene structures and expression, cellular senescence, and a decline in stem cell persistence.

The “geroscience hypothesis” holds that since aging plays a role in disorders such as Alzheimer’s, cancer, diabetes and heart disease, slowing the rate of aging should slow their onset.

The concept has stimulated development of some promising anti-aging drug candidates, but biological commonalities that may underpin the hallmarks of aging have remained a mystery… until now. Recent work at the Laboratory proposes a unified theory that links the hallmarks.

Beck’s been researching Hutchinson- Guilford progeria syndrome, a rare genetic condition that accelerates aging in children. With COBRE support, Beck made a deep computational dive into large-scale, publicly available genomic data related to the disease, and then validated his analysis with mouse models.

He found that disrupting the architecture of a part of the cell’s nucleus that carries genetic information, the chromatin, leads to a loss of the functional identity of aging cells and ultimately to agerelated degenerative disease. This means that, for instance, pancreatic cells partly lose their function as pancreatic cells.

The finding opens a door to the development of drugs that prolong healthy lifespan by protecting, or even restoring, aging chromatin architecture.

“COBRE gave me the opportunity to come here and establish the research program,” Beck says.

And the work helped him win an R01 grant last summer, making Beck the Laboratory’s latest COBRE “graduate.” That funding will support the next stage of his career, at Boston University. Beck says he’ll still work closely, though, with MDIBL colleagues such as Godwin.

In 2021, Beck and Godwin co-published research linking chromatin disruption and the misexpression of a specific set of genes, revealing new areas for inquiry into how to slow aging at the cellular level.

“Dr. Godwin is a top-notch investigator with a deep understanding of inflammation and genetics,” Beck says. “We hope our interdisciplinary research can yield new insights into the pathophysiology of aging, as well as effective therapeutic strategies against aging and age-related diseases.”

By assembling outstanding research teams and promoting creative collaborations, COBRE has launched the Laboratory and its scientists on a growth trajectory, creating new opportunities and elevating their respective roles on the global stage.

“Most, if not all, of the scientific output generated by the MDIBL over the last decade has been touched either directly or indirectly by COBRE support,” says Alejandro Sánchez Alvarado, Ph.D. He’s Chief Scientific Officer of the Stowers Institute for Medical Research and a founding member of the board of outside advisors for the MDI Biological Laboratory’s COBRE grants.

“To say that COBRE transformed research activities at the MDIBL would be an understatement.”