What Makes People Social? The Answer May Be Found in Petri Dish Brains Made from Teeth.

Research being done with brain organoids ("mini brains" deriving from cells, such as teeth) from those with autism and Williams syndrome is providing insight into what makes humans social. 

Sometimes the Tooth Fairy gives more than a dollar underneath your pillow.

In the case of Dr. Alysson Muotri, associate professor of pediatrics and cellular and molecular medicine at UC San Diego School of Medicine and a noted expert on autism, the Tooth Fairy gave new insight into what may make humans social. Through Dr. Muotri's Fairy Tooth Kit Collection campaign, donated baby teeth from both those with autism and those unaffected were collected for research. 

A tiny brain was then created in a petri dish from the teeth.

These miniature brains may provide a window into the human spectrum of sociability, helping us better understand why certain individuals like those with autism have diminished social skills. It may also help us understand how humans evolved to be as social as we generally are.

Called Brain or Cerebral Organoids, Dr. Muotri and his team were able to create these so-called mini-brains by extracting the pulp cells in the teeth and converting them into brain cells. This is done through the induced pluripotent stem cell (iPS) technique, a reprogramming of cells to be in a stem cell-like state. These neural progenitor cells are able to create networks similar to the developing cortex of a human brain. 

Dr. Muotri's research showed that the organoids using cells from those with autism had fewer neural connections than those unaffected. 

While autism is generally associated with low degrees of sociability, Williams syndrome is a rare genetic disorder where those affected have an extremely high level of sociability to the point of talking with strangers. It is often referred to as the "opposite of autism."

Dr. Muotri and his team of researchers at the University of California San Diego, along with researchers at the Salk Institute of Biological Studies, examined organoids grown from those affected by Williams syndrome. The team noticed that instead of former fewer neural connections like the autism organoids, the organoids contained an abnormally high level of neural connections.

Organoids derived from cells unaffected by a neurobiological disorder were right in the middle. In other words, the level of neural connections in the mini-brains correlated with the sociability of person. The higher the sociability (from autism to unaffected to Williams Syndrome), the greater the neural connections in the cerebral organoid.  

Speaking to New Scientist, Dr. Muotri said:

“The differences are striking, and go in opposite directions. In Williams syndrome, one of the cortical layers makes large projections linking into many other layers, and these are important for sociality. By comparison, autism-linked brains are more immature, with fewer synapses."

The connection between synapses and sociality was also found by the research team when examining donated brains from those who had autism or Williams syndrome. In addition, another research team working with brain organoids recently found that patients with idiopathic autism overproduced inhibitory neurons.

In the December 2015 issue of the journal Developmental Biology, researchers Madeline Lancaster and Iva Kelava explored both the promise and challenges of cerebral organoids. In the article, Dishing out mini-brains: Current progress and future prospects in brain organoid research, they argue that brain organoids can successfully model neurodevelopmental conditions such as idiopathic autism and the brain organoids "model early human embryonic and fetal brain development to a remarkably high degree."

While the work on brain organoids is quite new, there appears to be a great deal of promise in the research with unlocking some of the secrets of the brain.

"Brain organoids (and organoid systems in general), which adequately model tissue development and physiology, are a relatively new development, and the field has exploded in the last several years. Thus, it is easy to envisage that in 10–20 years from now (or even less) we will be able to almost fully mimic development of certain tissues in vitro. In addition, further improvements in the technique might allow us to model adult brain physiology and disorders of the adult and ageing brain."

Madeline Lancaster is a leading researcher in working with brain organoids and is credited with discovering the method of growing neurons in a petri dish long enough to develop characters is the human brain. 

"I'm mainly interested," she told MIT Technology Review, "in figuring out what it is that makes us human.”

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Yale scientists restore brain function to 32 clinically dead pigs

Researchers hope the technology will further our understanding of the brain, but lawmakers may not be ready for the ethical challenges.

Still from John Stephenson's 1999 rendition of Animal Farm.
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  • Researchers at the Yale School of Medicine successfully restored some functions to pig brains that had been dead for hours.
  • They hope the technology will advance our understanding of the brain, potentially developing new treatments for debilitating diseases and disorders.
  • The research raises many ethical questions and puts to the test our current understanding of death.

The image of an undead brain coming back to live again is the stuff of science fiction. Not just any science fiction, specifically B-grade sci fi. What instantly springs to mind is the black-and-white horrors of films like Fiend Without a Face. Bad acting. Plastic monstrosities. Visible strings. And a spinal cord that, for some reason, is also a tentacle?

But like any good science fiction, it's only a matter of time before some manner of it seeps into our reality. This week's Nature published the findings of researchers who managed to restore function to pigs' brains that were clinically dead. At least, what we once thought of as dead.

What's dead may never die, it seems

The researchers did not hail from House Greyjoy — "What is dead may never die" — but came largely from the Yale School of Medicine. They connected 32 pig brains to a system called BrainEx. BrainEx is an artificial perfusion system — that is, a system that takes over the functions normally regulated by the organ. Think a dialysis machine for the mind. The pigs had been killed four hours earlier at a U.S. Department of Agriculture slaughterhouse; their brains completely removed from the skulls.

BrainEx pumped an experiment solution into the brain that essentially mimic blood flow. It brought oxygen and nutrients to the tissues, giving brain cells the resources to begin many normal functions. The cells began consuming and metabolizing sugars. The brains' immune systems kicked in. Neuron samples could carry an electrical signal. Some brain cells even responded to drugs.

The researchers have managed to keep some brains alive for up to 36 hours, and currently do not know if BrainEx can have sustained the brains longer. "It is conceivable we are just preventing the inevitable, and the brain won't be able to recover," said Nenad Sestan, Yale neuroscientist and the lead researcher.

As a control, other brains received either a fake solution or no solution at all. None revived brain activity and deteriorated as normal.

The researchers hope the technology can enhance our ability to study the brain and its cellular functions. One of the main avenues of such studies would be brain disorders and diseases. This could point the way to developing new of treatments for the likes of brain injuries, Alzheimer's, Huntington's, and neurodegenerative conditions.

"This is an extraordinary and very promising breakthrough for neuroscience. It immediately offers a much better model for studying the human brain, which is extraordinarily important, given the vast amount of human suffering from diseases of the mind [and] brain," Nita Farahany, the bioethicists at the Duke University School of Law who wrote the study's commentary, told National Geographic.

An ethical gray matter

Before anyone gets an Island of Dr. Moreau vibe, it's worth noting that the brains did not approach neural activity anywhere near consciousness.

The BrainEx solution contained chemicals that prevented neurons from firing. To be extra cautious, the researchers also monitored the brains for any such activity and were prepared to administer an anesthetic should they have seen signs of consciousness.

Even so, the research signals a massive debate to come regarding medical ethics and our definition of death.

Most countries define death, clinically speaking, as the irreversible loss of brain or circulatory function. This definition was already at odds with some folk- and value-centric understandings, but where do we go if it becomes possible to reverse clinical death with artificial perfusion?

"This is wild," Jonathan Moreno, a bioethicist at the University of Pennsylvania, told the New York Times. "If ever there was an issue that merited big public deliberation on the ethics of science and medicine, this is one."

One possible consequence involves organ donations. Some European countries require emergency responders to use a process that preserves organs when they cannot resuscitate a person. They continue to pump blood throughout the body, but use a "thoracic aortic occlusion balloon" to prevent that blood from reaching the brain.

The system is already controversial because it raises concerns about what caused the patient's death. But what happens when brain death becomes readily reversible? Stuart Younger, a bioethicist at Case Western Reserve University, told Nature that if BrainEx were to become widely available, it could shrink the pool of eligible donors.

"There's a potential conflict here between the interests of potential donors — who might not even be donors — and people who are waiting for organs," he said.

It will be a while before such experiments go anywhere near human subjects. A more immediate ethical question relates to how such experiments harm animal subjects.

Ethical review boards evaluate research protocols and can reject any that causes undue pain, suffering, or distress. Since dead animals feel no pain, suffer no trauma, they are typically approved as subjects. But how do such boards make a judgement regarding the suffering of a "cellularly active" brain? The distress of a partially alive brain?

The dilemma is unprecedented.

Setting new boundaries

Another science fiction story that comes to mind when discussing this story is, of course, Frankenstein. As Farahany told National Geographic: "It is definitely has [sic] a good science-fiction element to it, and it is restoring cellular function where we previously thought impossible. But to have Frankenstein, you need some degree of consciousness, some 'there' there. [The researchers] did not recover any form of consciousness in this study, and it is still unclear if we ever could. But we are one step closer to that possibility."

She's right. The researchers undertook their research for the betterment of humanity, and we may one day reap some unimaginable medical benefits from it. The ethical questions, however, remain as unsettling as the stories they remind us of.