Medical research

Scientists are creating organs on chips to study the human body better

Recreating simple, specific human bodily systems seems to be the most valuable path to improving our drug development process.

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 40 weeks and kept warm by the horse, after which point a miniature child should grow.

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.

Testing on rats is the classic way we’ve simulated human biology. 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 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 it requires both careful handling and a regular supply of fresh organs – and when an organ is studied away from the body, it’s easy to miss interactions between it and other parts of the body. 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.

Today, the state of the art in attempts to model the insides of our bodies lies in the creation of “organs on chips”. They are generally a piece of glass, silicon, or polymer about the size of a computer memory stick.

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: 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 same way as the real thing, they’re accurate.

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.

Organs on chips, more commonly called “microphysiological systems,” have vast potential, catching the attention (and financial backing) of not only the National Institutes of Health, but also of the Defense Advanced Research Projects Agency, or 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.

Image: Eden Brackenbury
Image: Eden Brackenbury

Enter John Wikswo, a founding director of Vanderbilt Institute for Integrative Biosystems Research and Education. Wikswo recently led a research team in creating an advanced model of the blood-brain barrier. The blood-brain barrier is a vital part of the brain system: it consists of specialized cells that surround the brain’s veins and arteries, and it acts a bit like security at a nightclub. Nutrients and other important things are allowed through, but substances like pathogens and toxins that will be harmful to the brain are stopped in their tracks.

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 be behind a much wider range of problems, from poor cognition to schizophrenia and depression.

Drug makers can use the model to address the challenge of how to get drugs “past” this barrier and directly into the brain. “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.”

By getting human cells involved in drug development earlier in the pipeline, Wisko explains, new treatments can be brought to market more rapidly. Recent estimates place the cost of successfully developing a single new drug at $2.5 billion or more over the course of about 12 years. Advancements in efficiency or accuracy are crucial to lowering those costs.

Image: Eden Brackenbury
Image: Eden Brackenbury

But how well do these chips work together? In order to avoid the problem of missed interactions between different organs, it’s useful to be able to feed a drug through a complete biological system. If you patched together enough different organ chips, would you get a tiny human like the one Paracelsus envisioned? 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.

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 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.”

But 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 says. “There will be people successfully building neural nets on electrodes in two or three dimensions, who can do computations – but that is not a fully-functioning brain. I don’t think anyone is talking about building a functioning brain.”

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.”

This article was first published on How We Get To Next.

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Swara Bhasker: Sharp objects has to be on the radar of every woman who is tired of being “nice”

The actress weighs in on what she loves about the show.

This article has been written by award-winning actor Swara Bhasker.

All women growing up in India, South Asia, or anywhere in the world frankly; will remember in some form or the other that gentle girlhood admonishing, “Nice girls don’t do that.” I kept recalling that gently reasoned reproach as I watched Sharp Objects (you can catch it on Hotstar Premium). Adapted from the author of Gone Girl, Gillian Flynn’s debut novel Sharp Objects has been directed by Jean-Marc Vallée, who has my heart since he gave us Big Little Lies. It stars the multiple-Oscar nominee Amy Adams, who delivers a searing performance as Camille Preaker; and Patricia Clarkson, who is magnetic as the dominating and dark Adora Crellin. As an actress myself, it felt great to watch a show driven by its female performers.

The series is woven around a troubled, alcohol-dependent, self-harming, female journalist Camille (single and in her thirties incidentally) who returns to the small town of her birth and childhood, Wind Gap, Missouri, to report on two similarly gruesome murders of teenage girls. While the series is a murder mystery, it equally delves into the psychology, not just of the principal characters, but also of the town, and thus a culture as a whole.

There is a lot that impresses in Sharp Objects — the manner in which the storytelling gently unwraps a plot that is dark, disturbing and shocking, the stellar and crafty control that Jean-Marc Vallée exercises on his narrative, the cinematography that is fluid and still manages to suggest that something sinister lurks within Wind Gap, the editing which keeps this narrative languid yet sharp and consistently evokes a haunting sensation.

Sharp Objects is also liberating (apart from its positive performance on Bechdel parameters) as content — for female actors and for audiences in giving us female centric and female driven shows that do not bear the burden of providing either role-models or even uplifting messages. 

Instead, it presents a world where women are dangerous and dysfunctional but very real — a world where women are neither pure victims, nor pure aggressors. A world where they occupy the grey areas, complex and contradictory as agents in a power play, in which they control some reigns too.

But to me personally, and perhaps to many young women viewers across the world, what makes Sharp Objects particularly impactful, perhaps almost poignant, is the manner in which it unravels the whole idea, the culture, the entire psychology of that childhood admonishment “Nice girls don’t do that.” Sharp Objects explores the sinister and dark possibilities of what the corollary of that thinking could be.

“Nice girls don’t do that.”

“Who does?”

“Bad girls.”

“So I’m a bad girl.”

“You shouldn’t be a bad girl.”

“Why not?”

“Bad girls get in trouble.”

“What trouble? What happens to bad girls?”

“Bad things.”

“What bad things?”

“Very bad things.”

“How bad?”

“Terrible!!!”

“Like what?”

“Like….”

A point the show makes early on is that both the victims of the introductory brutal murders were not your typically nice girly-girls. Camille, the traumatised protagonist carrying a burden from her past was herself not a nice girl. Amma, her deceptive half-sister manipulates the nice girl act to defy her controlling mother. But perhaps the most incisive critique on the whole ‘Be a nice girl’ culture, in fact the whole ‘nice’ culture — nice folks, nice manners, nice homes, nice towns — comes in the form of Adora’s character and the manner in which beneath the whole veneer of nice, a whole town is complicit in damning secrets and not-so-nice acts. At one point early on in the show, Adora tells her firstborn Camille, with whom she has a strained relationship (to put it mildly), “I just want things to be nice with us but maybe I don’t know how..” Interestingly it is this very notion of ‘nice’ that becomes the most oppressive and deceptive experience of young Camille, and later Amma’s growing years.

This ‘Culture of Nice’ is in fact the pervasive ‘Culture of Silence’ that women all over the world, particularly in India, are all too familiar with. 

It takes different forms, but always towards the same goal — to silence the not-so-nice details of what the experiences; sometimes intimate experiences of women might be. This Culture of Silence is propagated from the child’s earliest experience of being parented by society in general. Amongst the values that girls receive in our early years — apart from those of being obedient, dutiful, respectful, homely — we also receive the twin headed Chimera in the form of shame and guilt.

“Have some shame!”

“Oh for shame!”

“Shameless!”

“Shameful!”

“Ashamed.”

“Do not bring shame upon…”

Different phrases in different languages, but always with the same implication. Shameful things happen to girls who are not nice and that brings ‘shame’ on the family or everyone associated with the girl. And nice folks do not talk about these things. Nice folks go on as if nothing has happened.

It is this culture of silence that women across the world today, are calling out in many different ways. Whether it is the #MeToo movement or a show like Sharp Objects; or on a lighter and happier note, even a film like Veere Di Wedding punctures this culture of silence, quite simply by refusing to be silenced and saying the not-nice things, or depicting the so called ‘unspeakable’ things that could happen to girls. By talking about the unspeakable, you rob it of the power to shame you; you disallow the ‘Culture of Nice’ to erase your experience. You stand up for yourself and you build your own identity.

And this to me is the most liberating aspect of being an actor, and even just a girl at a time when shows like Sharp Objects and Big Little Lies (another great show on Hotstar Premium), and films like Veere Di Wedding and Anaarkali Of Aarah are being made.

The next time I hear someone say, “Nice girls don’t do that!”, I know what I’m going to say — I don’t give a shit about nice. I’m just a girl! And that’s okay!

Swara is a an award winning actor of the Hindi film industry. Her last few films, including Veere Di Wedding, Anaarkali of Aaraah and Nil Battey Sannata have earned her both critical and commercial success. Swara is an occasional writer of articles and opinion pieces. The occasions are frequent :).

Watch the trailer of Sharp Objects here:

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This article was published by the Scroll marketing team with Swara Bhasker on behalf of Hotstar Premium and not by the Scroll editorial team.