Saturday, July 28, 2012

Best #human #microbiome item of week: #MinaBissellToo #Cancer #TED

From Science Friday.
My wife just told me about a fascinating Science Friday episode that I missed today: Building Organs, On One Microchip At A Time : NPR.  The discussion was with Dr. Donald Ingber from Harvard who has been designing mock organ systems with microchips.

Of particular relevance to microbiome studies are the following sections
"One example was that we put human intestinal cells that have been studied and cultured for years, and the pharmaceutical companies actually use them for looking at absorption in dishes, but everybody knows they're not very good. They don't really mimic gut function. When we put them in our chip and when we give them peristaltic-like undulating stretching rhythmically and we trickle flow over them like in your gut, they start forming villi, which are like the finger-like projections that increase surface area for absorption in your intestine. 
And what really surprised me is that the proliferative cells, the cells that are dividing rapidly, are in the crypt, the bottom - like between your fingers, at the bottom of these fingers, which is exactly like in your intestine. Plus, they put out mucus on the top of it, which protects it, and now we can put microbes on top. If you put microbes - if you put bacteria on cells in a dish, we call it contamination, and you have to throw it out and sterilize it. But we put microbes on the top and they're perfectly happy. They're symbiotic. And this is important because - and I don't know if your show highlighted it, but over the last few months there's been a lot of news that the microbiome - the microorganisms that live in our body can be very important for various diseases. And so we now have ways to study that. And the microbiome in the human is different than the mouse. And so this is very exciting for new opportunities."

And then later
And I think other groups are looking at, you know, viral infections, for example. With our gut-on-a-chip, we're hoping to study Crohn's disease. Where it's known in Crohn's disease, there are three major contributors. One is inflammation, and we could add white blood cells, for example. The other is the microbiome, the microbes living in the gut. The other is peristaltic-like motions - again, mechanics. And so we can control all three of those.
Now I am sure there is some excessive enthusiasm for the power of their chip system here.  But it is fascinating and certainly will have many uses for testing models of function of host-microbe interacting systems.

The part I find most fascinating has nothing per se to do with the gut - what is most interesting is the concept that mechanical forces are fundamentally important to cell and organ function, development and regulation.  Here is one portion of what Ingber said:
We, you know, we actually - I've worked for 35 years in a strange - from a strange perspective in biology in that I've been - I was convinced that mechanical forces, that the forces due to breathing-like motions and stretching, you know, your muscles and the pulsations of blood through your vessels, that the stretching and the relaxing, the mechanical stresses are as important for regulating cell and tissue function as chemicals in genes. This is now getting more accepted in biology, but because of that, I felt that we had to create microenvironments that could mimic that - we had to develop microchips that can mimic that microenvironment. And what we 're finding consistently is that cells that people used before that they didn't think were very good are now recapitulating organ-like functions. 
And as I said at a meeting yesterday, you know, there are no bad cells, just like there are no bad kids. There are bad families. There are bad neighborhoods and so forth. But - and so you have to give it the right microenvironment. We've also - I guess another surprising thing in the lung - and this was surprising - is that not only did we mimic complex functions such as the entire inflammatory response if we put a bacteria in the airspace in our little breathing lung on a chip, we saw in human, white blood cells stick to the vessel migrate across and engulf them. And that is something we hope for. 
But when we started to do things like we looked at toxicities of airborne particulates like in smog, we found that they were absorbed across the airspace to the vessel, which was great, but we found that breathing motions, physiological breathing motions increase the efficiency of that by tenfold. Now that no one's even thought of before, nor have I. And so that was a prediction. And then we went back to animal models where we could control ventilation and we found exactly the same thing.

I have been thinking a lot about mechanical focuses and biology recently - especially since Mina Bissell came to visit UC Davis last year.  I wrote about her visit here: Mina Bissell, another of my science heroes, returns to #UCDavis (and also about her last visit before that here --- The Tree of Life: A eureka moment - but not of the good kind).  Mina has been focused on how mechanical forces are critical to cancer development.  The best way to learn about Mina's obsession is to watch one of her talks such as one that was recently posted at TED.

In the era of genomics and other ones the importance of mechanical forces and local environment has been ignored by many.  But it shouldn't be.  When I was a graduate student at Stanford, one professor there - Paul Green - was completely obsessed by mechanical forces and their effects of biological systems.  Sadly - Paul - who was an amazing teacher and person - died of pancreatic cancer just as I was finishing my PhD.  But every time I see something about mechanical forces I think of him and I think he would have really enjoyed this Science Friday as well as Bissell's work.

1 comment:

  1. Pretty interesting that a single cell type would not only duplicate villi, but be able to live with certain microbes, and that mechanical forces would be so important.

    This is a long way from the long term goal of gut on a chip, etc. Most of the immune system's cells are in the gut, and it's connected to the nervous system along with cells that express taste and smell genes. Nobody has a clue about what the latter is doing. I analyzed some unpublished material that showed HIV and SIV both showed lowered cannabinoid pathway expression, and both HIV and SIV very quickly show degeneration of villi. (That leads to lower surface area and absorption problems.) Perhaps there is a relationship? Conventional signalling may be able to override or also be present for healthy villi?

    Membrane gut architecture is complex. And that is connected to a network of lymph known as GALT.


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