Pharyngula

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].

Comments

  1. #1 Brownian, OM
    August 30, 2008

    I used to fundraise for diabetes research. Dash of cold water or not, it’s a pretty promising big deal.

    Thanks for the post, PZ.

  2. #2 Becca
    August 30, 2008

    So wait, they’re taking *immunodeficient mice* to try to test run a mechanism to cure a *disease of autoimmunity*?

    I know I know, you warned us…
    as kewl basic science “let’s reprogram cells” experiment = WIN
    but as diabetes progress = FAIL

  3. #3 Nerd of Redhead
    August 30, 2008

    I recall seeing a news headline about this on one of the web news sites. I didn’t read the article, as I was at work, and was just finishing my coffee break.
    The interesting question would be what happens to the converted cells in someone had a real case of type 1 diabetes. Would the immune system attack and kill the converted cells? Interesting lead though.

  4. #4 Craig Messerman
    August 30, 2008

    Thanks for the excellent summary, PZ. At the risk of blowing minds too early, I read some passages of Joel Garreau’s Radical Evolution to my sophomore high school biology students this week. It documents our path up The Curve toward The Singularity where humans and technology reach some sort of nexus. It’s based mainly on Moore’s Law and the fringey ideas of Ray Kurzweil, but I was wondering if there is a comparable function for medical advancement. Can it be considered exponential too, or is it more linear compared to computer technology? This cell reprogramming is an excellent example of the types of medical advances I’m preparing my students to deal with as they travel up The Curve. (And although most won’t understand it, even after a whole year of biology, my students will be reading this post!)

  5. #5 Holbach
    August 30, 2008

    Ah, the pancreas; developed for you by evolution, explained and improved for you by science!

  6. #6 Sigmund
    August 30, 2008

    Its also important to note that this work could not be done without the use of animal research.

  7. #7 Sili
    August 30, 2008

    So we don’t need to drop our shares in Novo Nordisk like hot coal?

    So diabetes is an autommune disease? Then I fail to see how growing new ?-cells will help if the immunesystem goes on to kill them immediately.

  8. #8 raven
    August 30, 2008

    So diabetes is an autommune disease? Then I fail to see how growing new ?-cells will help if the immunesystem goes on to kill them immediately.

    That might not be a problem. There is a similar procedure that involves harvesting allogenic islet cells and injecting them into patients with small amounts of anti-transplant drugs.

    The cells end up in the liver and function normally. They don’t always replace all injectable insulin and how long they last (years at least) is questionable. But partial insulin is vastly superior to no insulin at all.

  9. #9 David Marjanovi?, OM
    August 30, 2008

    So diabetes is an autommune disease?

    Tpe 1 dibetes is, ys.

    Then I fail to see how growing new ?-cells will help if the immunesystem goes on to kill them immediately.

    This technique does not grow new ? cells. It merely makes other cells produce insulin. That’s all.

  10. #10 Timothy Wood
    August 30, 2008

    wow. it’s not a cure.. but i’m impressed nonetheless. (whoa. that rhymed).

  11. #11 LisaJ
    August 30, 2008

    Fantastic post PZ. This is a great step forward. Just three transcription factor, wow. Ah, I love science.

  12. #12 Holbach
    August 30, 2008

    LisaJ @ 11

    Oh yes, Science! I posted this quote a short while ago and do so again in case you missed it. It is by the great Darwin’s friend, Thomas Henry Huxley, and so apt even today!
    “Science is simply common sense at its best- that is, rigidly accurate in observation, and merciless to fallacy in logic.” Ah!

  13. #13 Holbach
    August 30, 2008

    LisaJ @ still here I hope! Here is another “bookish” gem by our pal Christopher Morley;

    “Be assiduous in the library, because for you it is the place of paradise.” Another ah!

  14. #14 Sili
    August 30, 2008

    I was thinking type I, yes. Thank you for the clarification.

    nd ’ll hv to wrst m drss frm m cld, dd hnds.

  15. #15 Zachary B.
    August 30, 2008

    Great post P.Z., thanks for the explanation.

  16. #16 LisaJ
    August 30, 2008

    Thanks for the uplifting quotes again Holbach!

    Also, you will be happy to know that I have decided to forgo reading more science articles, at least until this evening, and have instead just picked up my copy of Richard Dawkins’ The Blind Watchmaker. I love the feeling of cracking open a new book!

  17. #17 Holbach
    August 30, 2008

    LisaJ @ 16

    Nothing better than cracking open a new book by Richard Dawkins, even if The Blind Watchmaker came out in 1986! I have read that at least four times; real good stuff in there! Have all of Richard’s books, for he is a great guy to have around! Sure as hell want to meet him before I croak, or at least get his signature in all his books before he croaks! I have all of Stephen Jay Gould’s books, but alas, he is gone, much too early. And my good friend Carl Sagan who I met at Cornell University in 1993 when I was passing through Ithaca, New York, and who died in December, 1996. Had a good cry for that wonderful guy and still am moved when I watch him on “Cosmos”. So many scientists have died whose books I have read and keep, and I cherish them as valued scientists, and as writers who will keep alive the love and need for science. Isaac Asimov, Richard Feynman, and so many more scientists and writers of science who sit on my shelves and remind me of my unequivocal regard and thanks for having come by.
    But I ramble, as I am wont to do when I discuss books and science, so I’ll give you a rest, and before I do, go over to the post, “Pop sc book meme” and check out my comment to Mrs Tilton @ 124. There is a another quote on books that is just incredible for it’s time!

  18. #18 LisaJ
    August 30, 2008

    Holbach: Yes, I am just getting to The Blind Watchmaker now, as I had quite a late introduction to Dawkins’ novels, and alot of other science books. I will say though that The God Delusion, which I read just this past January (I actually stumbled onto Pharyngula because Richard recommended it in TGD), really helped me to open my eyes that last little bit that they needed. I haven’t believed in god for a number of years, but thought that I needed to believe in ‘something bigger’ (no idea what I thought that was though) to find meaning in my life. TGD really showed me that I could just let go of all of this belief in a higher being crap for good and not be ashamed about it. It’s amazing how much my confidence in my own abilities, and my productivity, has increased over the past year since coming to this realization, and how much more fulfilling life is to really be living it for yourself. Ah books, they’re the best… well, books AND science of course :)

  19. #19 Stephen Couchman
    August 30, 2008

    @ 4. Yep, this is how the Singularity gets here, one awesome unraveling at a time. People like to trash transhumanists as pie-in-the-sky thinkers, but who can blame us for being optimistic with results like these?

  20. #20 Quiet Desperation
    August 30, 2008

    But can they reprogram it to run Linux?

    Oh, sorry, thought I was on Slashdot for a moment.

  21. #21 SC
    August 30, 2008

    Awesome.

    Another front on which to attack diabetes:

    http://www.farmland.org/programs/farm-bill/default.asp

  22. #22 One Eyed Jack
    August 30, 2008

    This type of research is the future of medicine. Much like antibiotics and vaccines catapulted medical treatments, regenerative cell technology will be another milestone in medicine.

    That is, unless we continue to elect small minded anti-intellectuals like GWB to office.

  23. #23 Monado
    August 30, 2008

    I know people with diabetes. I am getting my hopes up for 15 years hence!

  24. #24 Alan Kellogg
    August 30, 2008

    I think it’s cool.

    Let’s keep in mind that autoimmune diseases have triggers, and I’ve heard scientists have found ways to ‘turn off’ autoimmune disorders. Lupus for example. I could be wrong; like another poster here I remember facts but forget names, dates, and page numbers. (But no diagnoses of Autism or Autism Spectrum Disorder yet. Raised in the 50s and 60s, I don’t think High Functioning Autism had been invented yet.)

  25. #25 JohnnieCanuck, FCD
    August 30, 2008

    This may not be the end of Diabetes, but it is the beginning of the end. Chills up my spine.

    Congratulations to the researchers and their supporters.

  26. #26 slang
    August 31, 2008

    So, if I understood this right, they turned to a cell that shared most of its development path with the cell type that they needed. IE, if the desired cell type was the top of the ladder, and stem cells are the bottom of the ladder, in this research they took a cell that was one rung below the desired type, instead of figuring out how the entire ladder works?

  27. #27 John C. Randolph
    August 31, 2008

    I have a couple of friends who are diabetic. I sure hope we can relegate diabetes to the history books in my lifetime.

    -jcr

  28. #28 Freidenker
    August 31, 2008

    Amazing stuff. As an undergrad biology major, doing research like this is a breathtaking aspiration.

  29. #29 Alan Kellogg
    August 31, 2008

    Slang, #26

    It’s called cheating. Scientists do it all the time. An alternative term is, creativity. Some would call it a shortcut. If there is no substantial reason to do everything step by step, why do everything step by step?

  30. #30 slang
    August 31, 2008

    Alan, hey, I’m all for it! When we find enough pieces of the puzzle, we can complete the puzzle.

  31. #31 Tocarde
    August 31, 2008

    Just wanted to point out that the reason immunodeficient mice were used is not because diabetes is an auto-immune disease but because they used a virus as a carrier for the transcription factor.
    Using immunodeficient mice allows the pancreatic cells to be infected by the virus and not killed by the immune system.

  32. #32 DustWolf
    August 31, 2008

    Wouldn’t it be easier to just reprogram one stem cell, grow a culture and implant that?

  33. #33 Nerd of Redhead
    August 31, 2008

    My guess is that they don’t have the proper sequence and timing of all the growth factors to go from a stem cell to a pancreas beta-cell. They have a few, and tried it on an “advanced intermediate” with success.

  34. #34 Alethea
    September 1, 2008

    @Slang and Alan: I heard Doug Melton talk about this work at the International Society for Stem Cell Research back in June in Philadelphia. They and others of course are trying to work out all the steps on the ladder! It’s just painfully inefficient – and they and patients are also looking for expediency. So we developmental biologists can either wait – or try to fill in the blanks in parallel.

    Cellular reprogramming is a very interesting subject that dovetails onto the idea of “dedifferentiation” – a topic that is a little anathema to developmental biologists – but works very well with the concept of induction overall. Some cells are more refractory than others to inductive signals, but it may be possible to *force* cells to listen to their environment in some way. Stem cells are already very receptive to such cues, and working out the signals and the concept of cellular identity is fascinating.