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<h4 class="author-name"><a href="/author/duncangeere/">Duncan Geere</a></h4>
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<time class="post-full-meta-date" datetime="2018-04-17">17 April 2018</time>
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<h1 class="post-full-title">Simulating the Human Body</h1>
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<p>In 1537 Swiss physician Paracelsus came up with a method to craft a tiny model human: Fill a gourd with human semen, and put it in the womb of a horse to putrefy. The resulting transparent form must be fed with human blood for forty weeks and kept warm by the horse, after which point a miniature child should grow.</p>
<p>History does not record if Paracelsus' attempts were successful, and the lack of miniature children running around the world today suggests they probably weren't. But our fascination with the idea of creating model people, simplified versions of our human ecosystems, has endured -- we long to make computer brains, synthetic hearts, to watch full-fledged organs grow in labs. The instinct to simulate is part of our instinct to study and understand, and biological physicists continue to pursue the dream of model humans, with systems that perform like our own.</p>
<hr>
<p>Testing on rats is the classic way we've done this - we share a large amount of genetic material with all mammals, including rats, and almost all human genes known to be associated with diseases have counterparts in the rat genome. But there are also major differences -- circadian rhythms play a big role in pharmacology and toxicology, and rats are nocturnal. Another key motivation for researchers is to overcome traditional challenges with drug trials.</p>
<p>Another alternative is to test drugs on parts of an organ, or the entire thing, in test tubes. This preserves the organ's structure and layout, but requires both careful handling and a regular supply of fresh organs. Plus, when an organ is studied away from the body, it's easy to miss interactions between it and other parts of the body. For example, a drug that seems safe when tested on heart and liver cells separately might reveal a lethal transformation when it travels through a whole human test subject.</p>
<p>Today, the cutting edge of our attempts to model the insides of our bodies lies in the creation of "organs on chips". These are generally a piece of glass, silicon or polymer about the size of a computer memory stick.</p>
<p>Each chip can model a specific organ system, like the lungs, bone marrow, or intestines. Tiny tunnels run through the clear polymer chip, arranged to mimic normal - or even diseased - organ structures, so researchers can study what happens inside in great detail. These are abstractions, meaning that they won’t necessarily look like the real thing - in the same way that a subway map represents a city without actually looking like it. As long as they connect up in the right places, they’re accurate.</p>
<p>Fluids and gases containing living human cells can then be piped down those channels, kept moving by mechanical or electrical stimulation and continually monitored by sensors or microscopes at key locations. Controlled, sterile conditions allow cell growth and other processes to happen without outside influence, and it"s even possible to simulate mechanical processes like beating hearts, or varying stresses like flexing muscles.</p>
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<p class="instructions-description">Select two inputs to try and find the four human organs that it's possible to replicate—or just experiment and see what you can create.</p>
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<p>Organs on chips, more commonly called “microphysiological systems”, have vast potential. Several private pharmaceutical companies are funding research, and the idea has caught not just the attention of the National Institute of Health, but also of the Department of Defense’s Defense Advanced Research Projects Agency (Darpa). Harvard’s Wyss institute created the first successful organ chip, a miniature lung, in 2010, earning it a $37 million Darpa grant. Darpa, which has funded multiple microphysiological systems, says it’s interested in how these simulations of body parts can help defense departments create vaccines, respond to pandemics, or even prepare bioterrorism countermeasures as quickly as possible.</p>
<hr>
<p>Wikswo's team is using this model to study brain inflammation - which some neuroscientists call a "silent killer". There is no pain involved in brain inflammation, but it contributes to conditions like Alzheimer’s and Parkinson’s disease, and may also be behind a much wider range of problems - from poor cognition to conditions like schizophrenia or depression. Additionally, drug makers can use the model to address the challenge of how to get drugs through this barrier and directly into the brain. The simplicity of the models doesn’t undermine their effectiveness, either.</p>
<p>“There are variations in melatonin, cortisol, and all sorts of other hormones that differ from organ to organ,” says Wikswo. “What we’re claiming is that organs on chips, and the technology for which they are developed, will allow you to re-create these variations in vitro.”</p>
<p>By getting human cells involved in drug development earlier in the pipeline, new treatments can be brought to market more rapidly, Wikswo says. A recent estimate from the Tufts University Center for the Study of Drug Development, funded by the pharmaceutical industry (which has an interest in inflating that figure), puts the cost of successfully developing a single new drug at $2.5 billion or more over the course of about 12 years. The real picture is complex, but advancements in efficiency or accuracy are crucial to lowering costs - and organs on chips can help.</p>
<hr>
<p>A key question is how well these chips work together. In order to avoid the aforementioned problem of missed interactions between different organs, it's useful to be able to feed a drug through a complete biological system. So, if you patched together enough different organ chips, would you get a tiny human like the one imagined by Paracelsus? In a sense yes, says Wikswo. These different human organ chips talk amongst themselves as they would in a “real” human body, and that makes it a safer way to quickly study new disease treatments than using rats or tissue samples alone.</p>
<p>While we may view these collections of glued-together chips as “little humans” for the purpose of medical modeling, they aren’t really “people”—no mind, no plasticity, no environment, no learning. Wikswo and his team are now working toward creating a brain on a chip with multiple regions -- “collections of neurons of one flavor, talking [using electrons] through synapses to nearby neurons of another flavor,” he says. “We’re getting ready to put the neurons on electrode rays, so we can see how the neurons respond, in their electrical behavior, to drugs crossing barrier. We’re ratcheting up the realism, by including electrons.”</p>
<p>However, even a chip-based model of multiple brain systems would not be particularly intelligent—it would be too small. “A micro-brain is the size of a mouse brain, and mice are not particularly intelligent,” Wikswo suggests. “There will be people successfully building neural nets on electrodes in two or three dimensions, which can do computations—but that is not a fully-functioning brain. I don’t think anyone is talking about building a functioning brain.”</p>
<p>For now, recreating simple, specific human bodily systems seems to be the most valuable path to improving our drug development process and getting a better grasp of what's happening inside of our bodies. “Genomics has brought us a very clear understanding of the individual parts,” Wikswo says. “But physiology is all those parts, working together.”</p>
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