Now celebrating its 10th anniversary, the guiding spirit of San Diego’s Diabetes Research Connection can be seen in the labs across the country, including one run by developmental geneticist Duc Dong at 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 some day 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 that plagues transplanted cells.
Early work in zebrafish showed enough promise that the small initial grant quickly turned into a $1 million award from the WM Keck Foundation, and the team now expects to publish their work soon.
That’s not bad for an idea that Dong said drew laughter from a mentor when he proposed it one decade ago.
“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. 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.”
dr Alberto Hayek, diabetes researcher and co-founder of Diabetes Research Connection
The DRC donation, while it was not massive, provided just enough of a spark to get the lab exploring an unpopular direction, one that is already 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 and other major organizations who, after a 30-year career, said he found himself disappointed that it took so very long for smart, young scientists to explore their most out-of- the box ideas. The average age of a first grant from the National Institutes of Health, he noted, is 44.
He brought this frustration up with his friend and local attorney David Winkler, who also has Type 1 diabetes, and the idea of the 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 CC 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.
Forming their nonprofit organization in 2012, it took a few years to figure out the model. But now, in a decade, the 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 to date received about $12 million in follow-on 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, and several years of work, the researcher said, has been required to convince peer reviewers that the goal has truly been accomplished. 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.
“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 added, is that it can cause a transformation without first shifting cells into a “pluripotent” type, one that can become any cell. While pluripotency is an amazing attribute of cellular biology, studies have also found that inducing a transformation from that being-anything state can increase the chances of a malignant mutation that causes a cancerous tumor to form.
There is no reason, he said, why the technique could not be used to coax transformations into other types of cells such as those found in the brain and the heart.
“What we’re proving is that you don’t need stem cells as an intermediary; you can reprogram into almost anything that 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.
Though Glass and the Venter institute have made international headlines for their feats of synthetic biology, creating living cells from their constituent chemical compounds, the idea of building an insulin-producing bacteria, Hayek said, simply did not resonate with any of the big funding sources .
Not at first, anyway.
A small DRC grant, he said, provided just enough evidence that the idea was possible to garner $1.2 million in follow-on funding.
“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.”
That model’s key is scrutiny from people who are themselves engaged in Type 1 research. Tapping Hayek’s contacts, DRC spent its first few years putting together a scientific review committee of experts who vet every out-of-the-box idea. For 2022, the group consists of 74 scientists working in labs nationwide.
The whole group screens all applications, choosing only those that seem both original but also not obviously impossible for some fundamental reason. From there, three-member panels who are selected because their own work is directly related to the idea proposed then provide a second level of inspection. If two of the three agree that a proposal is worth pursuing, a grant of up to $50,000 is made.
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 the DRC’s main constraint.
The organization’s initial aim was to pursue a crowdfunding model. The reasoning went that the estimated 1.6 million Americans affected by Type 1 diabetes nationwide would jump at the chance to throw a few hundred bucks at interesting grants that — who knows — might just end up helping them directly someday. While that avenue remains active on its website — diabetesresearchconnection.org — the kickstart approach has so far represented only about 6 percent of grant revenue. The organization has also pursued individual donors, even creating its own “Dance for Diabetes,” an annual fundraising event in the fall that has fallen to the coronavirus pandemic the past two years.
They’ve done what they can to give donors confidence, separately funding overhead expenses so that 100 percent of donations go directly to funded scientists, and they’ve created a feedback loop between those who receive grants and those who fund them. Scientists file regular reports for donors to read, allowing them to keep abreast of the work they helped make happen.
The model, Winkler said, should scale well as funding increases, and he bristles at any suggestion that Type 1 is largely solved by automated insulin pumps which can check for low blood sugar and dispense compensating 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 biological cure.”