Reprogramming the pancreas

Blogging on Peer-Reviewed Research

Wow…so have you heard about this result?

One goal of regenerative medicine is to instructively convert adult cells into other cell types for tissue repair and regeneration. Although isolated examples of adult cell reprogramming are known, there is no general understanding of how to turn one cell type into another in a controlled manner. Here, using a strategy of re-expressing key developmental regulators in vivo, we identify a specific combination of three transcription factors (Ngn3 (also known as Neurog3) Pdx1 and Mafa) that reprograms differentiated pancreatic exocrine cells in adult mice into cells that closely resemble β-cells. The induced β-cells are indistinguishable from endogenous islet β-cells in size, shape and ultrastructure. They express genes essential for β-cell function and can ameliorate hyperglycaemia by remodelling local vasculature and secreting insulin. This study provides an example of cellular reprogramming using defined factors in an adult organ and suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.

This is a big deal, I think, so allow me to translate.

First, a little caveat: this is a recent result published in Nature, and it is basic science, not clinical work. Before you start thinking it’s a new treatment for diabetes, I have to dash a little cold water on you and warn you that this has a long, long way to go before it can be applied to humans…but it does open the door to some future strategies that might be applied.

The pancreas is a fairly complicated organ. It’s made up of a variety of different cells that we can toss into a couple of different classes. There are garden variety support cells — mesenchyme, connective tissue, components of the circulatory system, and the ductwork of the organ — that provide building services for the other cell types. Then there are exocrine cells, cells that produce quantities of important substances that are piped directly into the digestive tract via ducts. Among the most important materials exported by this route are bicarbonate buffers to neutralize stomach acids and enzymes like amylase to digest sugars. Finally, the class of cells that most people are familiar with, because they are the subject of a common disease, are the endocrine cells. These are cells that generate hormonal signals that are secreted into the blood stream, and the most familiar of these are the beta (β) cells, which are organized into clumps called islets and which secrete insulin…and if something goes awry with the β cells, the resulting disease is called diabetes.

What the researchers did was identify a small subset of transcription factors, the genes Ngn3, Pdx1 and Mafa, that are sufficient to switch on the insulin production genes in non-insulin-producing cells of the pancreas. They can turn exocrine cells into β cells, which produce insulin, and these cells reduce the effects of diabetes.

The way they did this was to insert the transcription factors (and a gene that makes a glowing protein, GFP, as a marker) into adenoviruses, and then inject the virus directly into the pancreases of genetically immunodeficient (to reduce immune response complications) adult mice. The viruses infected a subset of the pancreatic cells, preferentially the exocrine cells, and started pumping out the transcription factors. As is common in these kinds of genetic engineering experiments, the use of viral transfection is perhaps the scariest part of the story; viruses aren’t trivial to keep in check. However, they report that they also did later PCR tests of adjacent tissues and found no evidence that the virus spread beyond the target organ; they also found that inducing the expression of the 3 transcription factors in other kinds of cells, like muscle, seems to do nothing. These genes are only potent in pancreatic cells that are already primed to be competent to respond to the signals generated by the transcription factors.

The virus is also not needed for long term maintenance of these cells. The virus in the pancreas, as determined by PCR, is cleared away after about 2 months. It seems that all it takes is a brief jolt of expression of Ngn3, Pdx1 and Mafa to switch susceptible cells into the β cell state, and that the developmental program is then self-sustaining.

The authors also made diabetic mice by injecting them with streptozotocin, which kills islet β cells, and then gave them the viral cocktail injection. It did not cure their diabetes, but it did give them significantly greater glucose tolerance, and they did measure increased blood insulin levels. One reason the treatment may not be as effective as it could be is that it simply converts random, scattered exocrine cells into single β cells that are not organized into the islets of the normal pancreas.

A lot of attention has been paid to embryonic stem cell and adult stem cell technologies, and those are both important and provide research and treatment opportunities that must not be neglected, but this is a third way: mastering the developmental control genes of the cell so that we can reprogram mature cells into any cell type we need. While injecting a person’s pancreas with a collection of viruses to rebuild missing cell types might be a little hazardous and crude, there may come a day when we can collect a few cells from an individual by a scraping or biopsy, grow them in a dish to get enough, tickle their transcription factors to cause them to differentiate into the cell, tissue, or organ type we want, and transplant the final, immunocompatible product right back into the patient.

This is the direction developmental medicine can take us — I hope you’re all ready to support it.

Zhou Q, Brown J, Kanarek A, Rajagopa J, Melton DA (2008) In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature Aug 27. [Epub ahead of print].

Banking with Jesus is a bad idea

Integrity Bank in Georgia decided to build their business model on Christian principles.

Integrity’s employees regularly prayed before meetings or in branch lobbies with customers, while the bank gave 10 percent of its net income to charities.

“We felt if we prayed and obeyed God’s word and did what He asked, that He would help us be successful,” the bank’s founder, Steve Skow, told the Journal-Constitution in 2005.

Chalk this one up to another example of how religion fails and we really ought to base our decisions on reality: the bank failed. You really can’t rely on that God fella, you know.

Perhaps one contributing factor was their obedience to that other Christian principle, greed.

CEO Steve Skow earned $1.8 million that year, while senior lender and executive vice president Doug Ballard earned $847,222. A typical community bank CEO, banking consultants said, earn roughly $300,000 per year.

And say…isn’t there something in the Bible that prohibits lending at interest, too?

Create dollars for education by clicking

I mentioned this before, but time is running out and the full allotment of money hasn’t been used up yet. If you go to the Big Think site and watch a video about inspiring scientists, Pfizer will spend a dollar on DonorsChoose. The videos are actually pretty good, they aren’t just commercials, and it’s an easy way to donate to a worthy cause by investing nothing but a tiny amount of time.

Surprise! McCain doesn’t persuade me to switch my vote with his VP choice

So McCain has picked Sarah Palin as VP. Supposedly she has some credibility as a good choice for dealing with energy issues, but near as I can tell she’s of the drill-in-marginal-areas school, not someone who’s going to pursue alternative energy sources, and is going to be a favorite of the oil companies — Dick Cheney with a less evil face. Worst of all, from my perspective, she also has a history of pandering to creationist ignorance, promoting the bogus ‘teach the controversy’ nonsense in the absence of any real scientific controversy.

Guess I won’t be voting Republican this year.

Greg & PZ’s Excellent Party

Scienceblogs.com is about to hit one of those arbitrary round-number milestones: sometime soon, someone will make the one millionth comment. Our generous Seed overlords wish to mark this event with celebrations all over the world, and are planning to bestow upon us small sums of money for the purpose of purchasing refreshments at gatherings of bloggers and readers near the places where our physical forms abide.

In other words, we get to have a party and Seed will pay for the beer.

So Greg Laden and I are going to organize a joint party — if I tried to have one in Morris, the contrast with my readership would make me look sad — so we’re going to get together somewhere in the Twin Cities area some evening.

The best time for me will be the evening of Thursday, 18 September, because that’s when I’ll be driving through on my way to Madison anyway. Now we’re looking for a nice venue: something with seating for a throng, that’s not too noisy (we’ll provide the noise, instead of a football game on the big screen or a band on the stage), and with good food and beer, somewhere near the Twin Cities, and where some of you readers might actually show up. Make suggestions here and at Greg’s place and we’ll pull it together.

The recent bigfoot flap…a little late

I’ve spent my evening curled up with a wracking cough and nasty pains in places I didn’t know I could hurt — I think I sprained my diaphragm — and while stumbling dumbly through the web, I belatedly found the story of the recent Georgia bigfoot. I know, it’s last week’s news, but I’m feeling a little addled.

Anyway, it brought back old memories. Way back when I was a teenager, I used to build balsa wood model airplanes in my grandparents’ attic. It was a good deal: my family didn’t have to deal with the smell, I didn’t have to worry about my brothers and sisters stomping on a delicate wing, and Grandma would bring me cookies and milk. There was also a stack of my grandfather’s manly men magazines to browse while I was waiting for that last coat of dope to dry. I don’t know if the genre is still around today, but in the 60s and 70s, at least, there were these magazines like Argosy and Saga that were full of manly stories of manly fellows braving dangers and hunting and exploring, with the occasional woman in a bikini lolling on the beach as the manly frogmen fought vicious sharks, and such like. One of the stories I recall most vividly was the Minnesota Iceman, which the article claimed was the most amazing evidence for the existence of bigfoot ever. There were several accompanying photographs of the poor guy in full color, frozen in a defensive pose, one arm thrown up over his head, with a bright splash of red over one eye, where he had been purportedly shot.

It made an impression. I recall reading up on cryptozoology quite a bit after that, trying to figure out whether it was real or not. I regretfully came to the conclusion eventually that it was a complete fraud, largely because I couldn’t find any legitimate scientific sources that had anything to say about it, and even in my teens I knew that Argosy was not a credible source of scientific information. Curiously, I now learn that creationists haven’t figured that out; Answers in Genesis uses the Minnesota Iceman as an example of scientific fakery ala Piltdown Man, accusing “experienced zoologists and scientific journals” of going out on a limb for a bogus missing link. At least now I can place their scientific expertise as somewhere significantly below mine…at the age of 15.

The Minnesota Iceman was a fake by a disreputable carnie. What about the Georgia Bigfoot? The lesson learned there is that people have gotten stupider since the 1960s. This bigfoot corpse was a graceless fake that was exposed within hours by the clever dicks at the JREF, and was concocted and promoted by a pair of blustering oafs named Rick Dyer and Matt Whitton, who have taken the unfortunate Southern redneck stereotype and amplified it into an embarrassment. It’s a rubber suit stuffed with dead animal parts. If I’d seen the photos of this thing at an impressionable age, I would not have been at all impressed — they were pathetic. The most thorough (if rather rambling) account is at a bigfoot site, and it’s damning. The creators weren’t just con-artists, they were stupid, incompetent con-artists…and people still fell for it. That’s the most depressing part of this story. The frauds don’t even have to try anymore, and the suckers line up to give them their money.