Remote cell reprogramming for diabetes treatment

Since I’m not that long in diabetes business, two new Cell papers from Collombat and Kubicek labs looked quite sensational for me. Both are the products of multi-centered collaborations, and both report regeneration of insulin-producing beta-cells in vivo with small molecules.

As I learned from introductions, reprogramming of pancreatic alpha cells (glucagon-secreting) into beta cells is a sort of a Holy Grail of regenerative medicine for diabetes treatment. Naturally, first attempts to reprogramming were performed with aid of transcription factors. But pretty soon small molecules kicked in. These were kinase inhibitors and chromatin-altering probes from Stuart Schreiber lab, resveratrol (of course!), and peptide hormone betatrophin. OK, the last one doesn’t count, and it’s not a small molecule anyway. What’s unusual about the latest Cell papers, is that they describe reprogramming by small molecules acting pretty high upstream from direct gene regulation [1]. Both papers involve messing with GABAA receptor signaling.

Let’s start with the Kubicek lab paper, which found that common (yet Nobel-winning) malaria drug, artemisinin, can make pancreatic alpha cells to secret insulin. The authors identified artemisinin and its metabolite dehydroartemisinin from a library of 280 existing drugs [2]. After they found that the drugs induce insulin secretion, they identified gephyrin as the most likely target. Then, via electrophysiology and a series of inhibitory tests, they linked gephyrin-mediated activity to GABAA receptor signaling. Known agonists of GABAA, however, didn’t increase insulin secretion as much as artemisinin (after 72 h treatment of cells). The drug then increased mass of beta cells islets in zebrafish, healthy and diabetic mice (while reducing basal glucose level in the last ones). Finally, it altered gene expression in human alpha cells and increased insulin secretion by the islets. Frankly, the figure 7A-C, which is supposed to convince in the last effect, raises some questions as data look cherry-picked from different donors. But authors do address that by briefly mentioning donor-to-donor variability. And it’s not surprising at n = 6 sample size.

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The paper from Collombat lab branches from the screening results of the first one. Once researchers noticed that activation of GABA signaling correlates with alpha-to-beta conversion, they thought “why not injecting plain ol’ GABA into mice?” And miraculously this simple idea worked. Just look at the jaw-dropping figures 1B-D! Figure S7C,G (below) can somewhat give you the feeling, but go check out the main paper, you won’t be disappointed.

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Figure S7 fragment showing increase in insulin-producing cells from rat pancreas. I assume scale bars, if they were present, would be equal (Ben-Othman et al paper)

Here are the main results: daily injections of GABA at 250 μg/kg over three months convert pancreatic alpha cells into beta. But what’s even more exciting is that the new alpha cells are continuously being produced to compensate for those that were converted into beta! They even caught small fraction of cells in some transitional state, where they secret both glucagon and insulin. I particularly liked the discussion section where authors warn that before you, all excited, rush to inject diabetic patients with GABA think why there’s not enough beta cells in the first place. Yes, it is patient’s immune system that attacks her own beta cells. So before this approach makes into clinic one needs to figure out that autoimmune component of type 1 diabetes.

In a sum we have two great papers with rock-solid mouse data and some exciting preliminary results in human beta cells. Let’s see where it will end up. Regardless of the future success, isn’t it amazing how small, simple, and seemingly well-known molecules like GABA (and artemisinin for that matter) can upturn human cells identity?


[1] OK, authors do not strictly claim reprogramming as the identity of cells doesn’t change completely from alpha to beta, but their secretory activity is definitely flipped.

[2] Side note: check out this sexy acoustic liquid handler they used.

 

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Molecular tribology

It’s hard to imagine more intriguing title in Angewandte Chemie International Edition than “Astringent Mouthfeel as a Consequence of Lubrication Failure“. The first impression doesn’t deceive, and the paper is really interesting and fun to read. Somehow manifestations of molecular interactions in the macroscopic world never stop amusing me. And this communication is exactly about such emergent effect. Continue reading “Molecular tribology”

Catching gravitational waves

OK, seems like I am on a track of rebuilding my daily routine under new circumstances of the offline life. So it’s a good time to incorporate some blogging activity in it.

While I was away, some fascinating things happened. First of all I mean the direct observation of gravitational waves, which were theoretically predicted by Einstein in 1915 (or Poincare in 1905, if you stretch your definition of “prediction”). As with all fundamental physics experiments, the measurement was not a trivial one. It required construction of two interferometers each having two orthogonal 4 km-long tubes to detect distortion of the spacetime by a fraction of a proton diameter. Continue reading “Catching gravitational waves”

High-level scientific miscommunication

There’s a scandal growing in the field of CRISPR due to a lawsuit and patent war between pioneers of the technology. And then this paper in Cell appeared and made the things worse… I don’t want do discuss in details the story behind, because there are plenty of better information sources all over the internet. What I want to bring up today is the problem of communication in the highest level of science, among respected professors.

Continue reading “High-level scientific miscommunication”

Nanopharmacology: [atomic] force awakens

Studying membrane proteins is not easy. The broad scope of the problem clearly deserved a Noble prize in 2012. Thanks to these advances, today scientists can determine structures of some membrane proteins (e.g., G protein-coupled receptors). But some of them are so huge and complex that X-Ray crystallography and NMR spectroscopy don’t help. Continue reading “Nanopharmacology: [atomic] force awakens”

What’s so special about synthesis?

On Tuesday a piece form Phillip Ball appeared in Nature, with provocative question ‘Why synthesize?’ addressed to organic chemists, and particularly to adepts of total synthesis. And, you know what, after reading it, I didn’t feel like the author answered the question − for each argument he provides a counterargument. So the take home message I got was the following:

even though molecule-building is sure to remain a crucial part of the chemical enterprise, conventional organic synthesis need not be the only, or even the best, way to do it

When I started learning about organic chemistry, the book “Organic synthesis: the science behind the art” was one of the strongest inspiration sources for the subsequent choice of the major. This perception of the organic synthesis as the art is something that triggered my interest but what’s causing awkward feelings nowadays.

Like architecture, chemistry deals in elegance in both design and execution.

What exactly is meant by “elegance” of synthesis? “Beauty is in the eyes of the beholder” says the old proverb. So isn’t it disturbing that organic chemists themselves are the only ones who appreciate the elegance of total synthesis?

In my current opinion arranging synthetic steps in a reasonable manner is an engineering and project management problems, but by no means is it the art. There’s no more elegance in designing the synthetic scheme than in designing any other sophisticated multi-step experiment. So why don’t call microbiology the art, too? Why setting up the culturing of stubborn microorganisms producing natural products is different? After all, it’s often the same trial and error process yield a couple milligrams of the product in the end.

For me the synthesis is a means, not the goal. It’s a chemist’s way of solving problems. But other scientists may be interested in solving the same problems, too. So indeed, the synthesis is not the only and often not the best way to do it. That’s why chemists should focus on how to make it the best way. In this I’m staying with George Whitesides’s philosophy that simplicity should be the major goal. But that doesn’t make organic chemists unique among other scientists. That’s why I’d rephrase the following quote from Phillip Ball:

We need to avoid romanticizing an imagined bygone age […]

We [organic chemists] need to avoid romanticizing an imagined uniqueness of our field and train a broader look on problem solving.

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