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From zebrafish to bacteria, La Jolla scientists’ novel ideas have received a spark from area charity

Geneticist Duc Dong at Sanford Burnham Prebys in La Jolla performs research on cell transformation in zebrafish.
An early grant from Diabetes Research Connection helped developmental geneticist Duc Dong at Sanford Burnham Prebys in La Jolla perform groundbreaking research on cell transformation in zebrafish. The work could one day provide a new source of replacement cells for the human body.
(Eduardo Contreras / The San Diego Union-Tribune)

Diabetes Research Connection has provided $2.4 million in its 10 years to early-career scientists across the country who are conducting maverick research on Type 1 diabetes.

As it celebrates its 10th anniversary, the guiding spirit of the nonprofit Diabetes Research Connection can be seen in labs across the country, including one run by developmental geneticist Duc Dong at the Sanford Burnham Prebys medical research institute in La Jolla.

The charity, which focuses on Type 1 diabetes, provided the researcher and his postdoctoral fellow Joseph Lancman with a $47,000 grant in 2016 to pursue a wild idea: transforming one type of cell into another with the goal of someday being able to make beta cells, the kind that live in the pancreas and make the hormone insulin to control blood sugar. Such an ability would be a real victory because the cells would come from a person’s own body and would not be subject to rejection, a common problem with transplanted cells.

Early work in zebrafish showed enough promise that the small initial grant quickly turned into a $1 million award from the W.M. Keck Foundation, and the team now expects to publish its work soon.

That’s not bad for an idea that Dong said drew laughter from a mentor when he proposed it a decade ago.

The donation from Del Mar-based DRC, while not massive, provided enough of a spark to get the lab exploring an unpopular direction — one that is yielding results that most didn’t expect.

“People like to fund things that are obvious, but if you only fund what’s obvious, you’re less likely to get science that’s unexpected,” Dong said. “DRC is one of those that’s changing the way we think.”

The effort started with the dissatisfaction of Dr. Alberto Hayek, a well-known diabetes researcher at UC San Diego in La Jolla and other major organizations who, after a 30-year career, said he found himself disappointed that it took so long for smart young scientists to explore their most out-of-the-box ideas. The average age of recipient of a first grant from the National Institutes of Health is 44, he noted.

He brought up that frustration with his friend and local attorney David Winkler, who has Type 1 diabetes, and the idea of DRC was born: Why not come up with a way to find the best crazy ideas and raise money to give the best a little spark of cash?

“Funding very, very young people — graduate students all the way up to some professors — it was pretty clear that was the place where we should focus,” Hayek said.

The pair joined forces with pediatric diabetes researcher C.C. King and pathology professor Nigel Calcutt, both at UC San Diego, and Amy Adams, a writer and business owner whose son has Type 1 diabetes.

A decade since its founding in 2012, DRC has funded 48 research projects, allocating a total of $2.4 million in donations received. As was the case for Dong, grants of no more than $50,000 have sometimes proved to be the spark that has led to much larger investments from the government or much larger charities.

All told, DRC grantees have received about $12 million in follow-up funding after their initial grants.

The work with zebrafish in Dong’s lab has so far used genetic manipulation techniques to transform muscle cells into those found in the gut. Several years of work have been required to convince peer reviewers that the goal has truly been accomplished, he said. Skepticism has been fierce, he said, because current understanding of cell transformation has demonstrated such transformations only among cells that are closely related. Gut cells, he said, are a kind of interim landing spot on the longer journey to insulin-producing beta cells, though making it to that destination will require more funding.

Researcher Duc Dong (center) stands with David Winkler (left) and C.C. King of Diabetes Research Connection.
From left, David Winkler, chief financial officer of Diabetes Research Connection; researcher Duc Dong, a DRC grant recipient; and C.C. King, DRC chairman and president, stand in the zebrafish room at Sanford Burnham Prebys in La Jolla.
(Eduardo Contreras / The San Diego Union-Tribune)

“I think we are one or two steps away from making beta cells, and we’ve been wasting the last few years trying to convince people that we can,” Dong said.

A key reason why his technique is different, Dong said, is that it can cause a transformation without first shifting cells into a “pluripotent” type that can become any cell. Studies have found that inducing a transformation from that be-anything state can increase the chances of a malignant mutation that causes a cancerous tumor to form.

There is no reason the technique could not be used to coax transformations into other types of cells, such as those found in the brain and heart, he said.

“What we’re proving is that you don’t need stem cells as an intermediary; you can reprogram into almost anything you want,” Dong said.

Another collaboration is with Yo Suzuki, a young postdoc working in the lab of geneticist John Glass at the J. Craig Venter Institute just down Torrey Pines Road in La Jolla. It involves creating bacterial cells capable of sensing glucose levels and releasing insulin, duplicating the function of islet cells in a much different form.

A small DRC grant provided just enough evidence that the idea of building insulin-producing bacteria was possible to spur $1.2 million in other funding, Hayek said.

“These are examples of the kinds of dreams we want to make reality, the type of things that nobody else would be able to fund,” Hayek said. “The key is that we have a way to make sure that the work is credible, so it’s really hard to punch holes in our model.”

The key is scrutiny from people who are engaged in Type 1 research. Tapping Hayek’s contacts, DRC spent its first few years putting together a scientific review committee that vets every out-of-the-box idea. The group now consists of 74 scientists working in labs nationwide.

Developmental geneticist Duc Dong shows gut cells, which glow bright green under laser light, in zebrafish tissue.
Developmental geneticist Duc Dong shows gut cells, which glow bright green under laser light, in zebrafish tissue in his lab on the Sanford Burnham Prebys campus in La Jolla. Dong’s research on reprogramming cells could lead to better treatments for diseases including Type 1 diabetes.
(Eduardo Contreras / The San Diego Union-Tribune)

While it can take a year or more to get most other grants, DRC has stayed committed to a quick turnaround.

“We can process the entire grant and fund it in as little as 12 weeks,” Winkler said. “That’s almost unheard of, but we’re able to do it because we’ve kept it relatively simple.”

Donations remain DRC’s main constraint. The organization’s initial aim was to pursue a crowdfunding model. The reasoning was that the estimated 1.6 million Americans affected by Type 1 diabetes would jump at the chance to help fund grants that might end up helping them someday.

While that avenue remains active on DRC’s website, diabetesresearchconnection.org, it so far has represented only about 6 percent of grant revenue. The organization also has pursued individual donors and even created the “Dance for Diabetes,” an annual fundraising event that has fallen to the COVID-19 pandemic the past two years.

Scientists file regular reports for donors to read, allowing them to keep abreast of the work they helped make happen.

Winkler objects to any suggestion that Type 1 diabetes is largely solved by automated insulin pumps that can check for low blood sugar and dispense insulin continuously.

“This disease, even though it’s much better than it was when I was diagnosed in 1960, it’s still a pain in the neck,” Winkler said. “If anybody says T1D has been cured by automated insulin devices, they’re wrong.

“It’s better, but we need a biologic cure.” ◆