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Organ Models on Chips

Why do we test new drug candidates on animals? The simple answer is that there’s nothing else like an animal. There are clearly chemical and biological features of living systems that we don’t yet understand, or even realize exist – the discovery of things like siRNAs is enough proof of that. So you’re not going to be able to build anything from first principles; there isn’t enough information. Your only hope is to put together something that matches the real thing as closely as possible, using original cells and tissues as much as possible.
The easiest way to do that, by far, is to just give your compounds to a real animal and see what happens. But you have to think carefully. Mice aren’t humans, and neither are dogs (and nor are dogs mice, for that matter). Every species is different, sometimes in ways that make little difference, and sometimes in ways that can mean life or death. Animal testing is the only way to access the complexity of a living system, and the advantages of that outweigh the difficulties of figuring out the all differences when moving on to humans. But those difficulties are very real nonetheless. (One way around this would be to make animals with as many humanized tissues and systems as possible, although that’s not going to make anyone any happier about testing drugs on them. The other way is try to recapitulate a living system in vitro.
But the cells in a living organ are different than the cells in a culture dish, both in ways that we understand and in ways that we don’t. The architecture and systematic nature of a living organ (a pancreas, a liver) is very complex, and subject to constant regulation and change by still other systems, so taking one type of cell and growing it up in a roller bottle (or whatever) is just not going to recapitulate that. Liver cells, for example, will still do some liver-y things in culture. But not all of the things, and not all of them in the same way. And the longer they’re grown in culture, the further they can diverge from their roots.
There has been a huge amount of work over the years trying to improve this situation. Growing cells in a more three-dimensional culture style is one technique, although (since we don’t make blood vessels in culture tubes) there’s only so far you can take that. Co-cultures, where you try to recreate the various populations of cell types in the original organ, are another. But those are tricky, too, because all the types of cell can change their behaviors in different ways under lab conditions, and their interactions can diverge as well. Every organ in a living creature is a mixture of different sorts of cells, not all of whose functions are understood by a long shot.
Ideally, you’d want to have many different such systems, and give them a chance to communicate with each other. After all, the liver (for example) is getting hit with the contents of the hepatic portal vein, full of what’s been absorbed from the small intestine, and is also constantly being bathed with the blood supply from the rest of the body, whose contents are being altered by the needs of the muscles and other organs. And it’s getting nerve signals from the brain along with hormonal signals from the gut and elsewhere, with all these things being balanced off against each other all the time. If you’re trying to recreate a liver in a dish, you’re going to have to recreate these things, or (more likely) realize that you have to fall short in some areas, and figure out what differences those shortfalls make.
The latest issue of The Economist has a look at the progress being made in these areas. The idea is to use the smallest cohorts of cells possible (these being obtained from primary human tissue), with microfluidic channels to mimic blood flow. (Here’s a review from last year in Nature Biotechnology). It’s definitely going to take years before these techniques are ready for the world, so when you see headlines about how University of X has made a real, working “(Organ Y) On a Chip!”, you should adjust your expectations accordingly. (For one thing, no one’s trying to build, say, an actual working liver just yet. These studies are all aimed at useful models, not working organs). There’s a lot that has to be figured out. The materials from which you make these things, the sizes and shapes of the channels and cavities, the substitute for blood (and its flow), what nutrients, hormones, growth factors, etc. you have in the mix (and how much, and when) – there are a thousand variables to be tinkered with, and (unfortunately) hardly any of them will be independent ones.
But real progress has been made, and I have no doubt that it’ll continue to be made. There’s no reason, a priori, why the task should be impossible; it’s just really hard. Worth the effort, though – what many people outside the field don’t realize is how expensive and tricky running a meaningful animal study really is. Running a meaningful human study is, naturally, far more costly, but since the animal studies are the gatekeepers to those, you want them to be as information-rich, as reproducible, and as predictive as possible. Advanced in vitro techniques could help in all those areas, and (eventually) be less expensive besides.

19 comments on “Organ Models on Chips”

  1. Biotech Capitalist says:

    The promise of these ideas is great. I am a little concerned that there is so much hype and money flowing into it despite very little (or no?) data. Has there been a single compound which exhibited a toxic or adverse response in a human but did not show up in animal tox studies which these organ-on-chips predicted even retrospectively? Does the blog readership know of any?

    1. David Cockburn says:

      How about a tox problem in animals which didn’t cause a problem in humans.
      If I remember rightly, omeprazole caused hyperplasia of ECL cells in rats due to gastrin drive but didn’t cause a problem in humans.

  2. Anonymous says:

    It looks some big shots’ startup in trouble, and it’s time to pump up hype.

  3. Anonymous says:

    It looks some big shots’ startup in trouble, and it’s time to pump up hype.
    That right “there are a thousand variables to be tinkered with, and (unfortunately) hardly any of them will be independent ones.”

  4. Eric says:

    I really like the idea behind these studies, but it’s so far away from any practical application. I don’t see this having much impact on drug development during my career.
    On a more philosophical level – to mimic what happens in a human requires a circulatory system, a nervous system, an endocrine system, etc – all of the pieces are needed. If you use living tissue to build this, haven’t you in essence created an animal?

  5. Anonymous says:

    test

  6. Andre says:

    Derek, many thanks for your thoughtful and profound analysis of the current state of the organ-on-a-chip technology. In my opinion, the rational is admirable but the problems are huge. At present, we can talk at best of having seen prototypes of tissues-on-a-chip. Typically, one or two cell types are seeded in these chips. For example, Ingber’s lung-on-a-chip recapitulates the alveolar-capillary interface. Human alveolar epithelial cells are cultured on top of a flexible, porous, ECM-coated membrane
    and human capillary endothelial cells on the bottom. This is it. Similarly, the kidney chip recreates the proximal tubule epithelia interface with the endothelia. As we all know, a functional kidney is far more complex. Just think about the glomerular filtration, which would require the recreation of a fenestrated endothelium contacting a podocytes. This structure would need to be connected to a proximal tubule and then to a loop of Henle, etc. It is difficult for me to imagine how this all should be accomplished in vitro. Do we have unlimited supplies of the carefully validated human renal cell types to feed these chips? Can we expect these complex chips to become available in sufficient numbers for high-throughput drug testing? I do not want to spoil the party, but I believe that there is lots of hype and false promises driving this area of bioengineering. The everyday reality in drug discovery and development is however that we cannot abandon animal testing for years to come. Unfortunately, animal rights activists in Europe are using these false and overinflated promises as a proof that we do no longer need animal testing (for details, go to http://www.stopvivisection.eu/en/content/billionaires-backing-wyss-spinout-aims-retire-animals-rd). Personally, I would prefer to see more money being invested in developing more precise animal models of human diseases.

  7. Andre says:

    @1:
    A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice.
    Huh D, Leslie DC, Matthews BD, Fraser JP, Jurek S, Hamilton GA, Thorneloe KS, McAlexander MA, Ingber DE.
    Sci Transl Med. 2012 Nov 7;4(159):159ra147.
    The device was used to reproduce drug toxicity-induced pulmonary edema observed in human cancer patients treated with interleukin-2 (IL-2) at similar doses and over the same time frame.

  8. Biotech Capitalist says:

    @7 Andre In that paper the IL-2 induced edema in the lung-on-a-chip is similar to their mouse model in Figure 4B. Part of the allure of organs on a chip is the potential to replace costly animal tests with (hopefully) less costly chips. The second and to me the most interesting feature is the ability to get sophisticated human physiology in a preclinical setting. That is the excitement of organs on chips. There are elements of biology and toxicology in humans that no animal faithfully represents. If these could be modeled, then that is pretty cool. I haven’t seen a human-specific phenomenon modeled with an organ-on-a-chip yet.

  9. Meagain says:

    I believe @5 Anonymous phrased it perfectly!

  10. steve says:

    What would be interesting would be to see what happens when a drug enters clinical trials based on these types of safety assays and patients die because of an unpredicted toxicity. You wonder how many animal rights activists show more concern about the mice that were saved than the human patients that were lost.

  11. Mark Thorson says:

    Does China possess a competitive advantage in pharmaceutical development with their abundance of condemned prisoners? They haven’t shown it yet, but we shall see.

  12. colintd says:

    If you want accurate models of all the complexities of a human, some might argue that the most viable approach is the production of virtually anencephalic bodies (most likely from embryos), with just a brainstem to deal with respiration and very basic responsiveness.
    This approach is obviously unattractive in terms of timescales, space and cost (chip based solutions obviously have wonderful scaling potential on that front). And clearly not great for any brain related disease. But, would it be a viable alternative to primate models and where we are dealing with complex interactions?
    I must confess I instinctively have very very large moral difficulties about this approach, but thinking in more details I’m struggling to pin down exactly why this is the wrong ethically, compared with trying to cobble together a human surrogate on a chip.
    Is it the process of denying the potential to develop as a conscious human? But if that is the limit, does it apply to all embryonic cell lines? What about if we tweaked a germ line to stop higher brain development, but left bodies otherwise viable? Could these “bodies” be used for transplants.
    If we’re unhappy with doing this with human cell lines, would this be ethical to do with primates?
    Just a thought/question….

  13. Morten G says:

    @12 What about brain-dead humans unsuitable for organ transplant? Still feels icky though.

  14. johnnyboy says:

    Speaking as someone who works with animal models every single day, I am 100% convinced that this will never be realizable, and the technology will just remain a hype-y sideshow. At least not until we know and intimately understand every molecular pathway of every cell of every tissue. And if and when we ever get there, it’s rather unlikely that we’ll need body-on-chip technology anymore…

  15. Anonymous says:

    @12 But even then with an anencephalic body you wouldn’t be able to measure BBB penetration.
    13@ that sounds at least more reasonable/ethical than the suggestion I always hear of using inmates… I think the problem though is that those organs short term can be used to directly save lives. Sure long term the data generated to create new drugs could save more lives, but I think the availability of organs is already way too low.

  16. Mark Thorson says:

    At least on paper, China is supposed to be transitioning to a policy of no organ transplants from prisoners. (From a previously very liberal policy, including timing executions to the schedule of the recipient.) So they will soon have a surplus of human capital, so to speak. Be a shame to let all of that go to waste . . .

  17. Scott says:

    I think this discussion is missing the value of organs-on-a-chip. They don’t have to be used directly in drug discovery (hit and tox screening) to be useful for drug discovery. Before we get to that point, they’re a tool for teasing apart the molecular pathways that later become drug targets. They act synergisticly with animal models which are more complex but are decidedly not human to understand the normal (and abnormal) function of tissues and allow us to understand the difference between human and animal systems in a more physiological setting than a typical 2D culture dish. Increasing the level of physiological modelling of in vitro systems has all sorts of incremental value without reaching the height of replacing animal models.

  18. john says:

    Does anyone know of drug(s) that passed in animals but failed pulmonary toxicity in humans?

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