Testing new drugs with 'ALS-on-a-chip'

October 10, 2018, Massachusetts Institute of Technology
ALS on a chip with hiPS-derived optogenetic motor neruons from an ALS patient (green) and hiPS-derived skeletal muscle cells (purple) was established to represent ALS pathology. Credit: Tatsuya Osaki/MIT

There is no cure for amyotrophic lateral sclerosis (ALS), a disease that gradually kills off the motor neurons that control muscles and is diagnosed in nearly 6,000 people per year in the United States.

In an advance that could help scientists develop and test new drugs, MIT engineers have designed a microfluidic chip in which they produced the first 3-D human tissue of the interface between and . The researchers used from either healthy subjects or ALS patients to generate the neurons in the model, allowing them to test the effectiveness of potential drugs.

"We found striking differences between the healthy cells and the ALS cells, and we've been able to show the effects of two drugs that are in clinical trials right now," says Roger Kamm, the Cecil and Ida Green Distinguished Professor of Mechanical and Biological Engineering at MIT and the senior author of the study.

MIT postdoc Tatsuya Osaki is the lead author of the paper, which appears in the Oct. 10 issue of Science Advances. Sebastien Uzel, a former MIT graduate student, is also an author of the paper.

3-D junctions

Scientists began developing tissue models of the connections between motor neurons and , also called neuromuscular junctions, decades ago. However, these were limited to two-dimensional structures, which do not fully replicate the complex physiology of the tissue.

Kamm and his colleagues developed the first version of their 3-D neuromuscular junction model two years ago. The model consists of neurons and muscle fibers that occupy adjacent compartments of a microfluidic chip. Once placed in the compartments, the neurons extend long fibers called neurites, which eventually attach to the muscles, allowing the neurons to control their movement.

The neurons are engineered so that the researchers can control their activity with light, using a technique called optogenetics. The muscle fibers are wrapped around two flexible pillars, so when the neurons are activated by light, the researchers can measure how much the muscle fibers contract by measuring the displacement of the pillars.

In the 2016 version of the model, the researchers used mouse cells to grow the neurons and muscles, but differences between species can affect drug screening. In the new study, they used induced from humans to generate both the muscle cells and the neurons. After demonstrating that the system worked, they began to incorporate neurons generated from induced pluripotent stem cells from a patient with sporadic ALS, which accounts for 90 percent of all cases.

This ALS model showed significant differences from the neuromuscular junctions created from . The neurites grew more slowly and seemed to be unable to form strong connections with the muscle fibers, Kamm says.

"You can see that the healthy neurites are going directly to the individual myotubes and then activating them. However, the ALS neurons don't seem to be able to connect very well," he says.

This translated to weaker muscle control: After two weeks, the muscles innervated by ALS motor neurons were generating only about one-quarter the force produced by muscles controlled by healthy neurons. This also suggested that ALS motor attacked healthy skeletal muscle tissues.

Promising drugs

The researchers then used their model to test two drugs that are now in clinical trials to treat ALS—rapamycin and bosutinib. They found that giving both of the drugs together restored most of the strength that had been lost in the ALS motor units. The treatment also reduced the rate of cell death normally seen in the ALS motor unit.

Working with a local biotech company, Kamm and his colleagues hope to collect induced pluripotent stem cells from 1,000 ALS patients, allowing them to perform larger-scale studies. They also plan to scale up the technology so they can test more samples at a time, and to add more types of cells, such as Schwann cells and microglial cells, which play supportive roles in the nervous system.

This tissue model could also be used to study other muscular diseases such as spinal muscular atrophy, which affects nerve cells found in the spine.

Explore further: New knowledge on how neurons talk to muscles

More information: T. Osaki el al., "Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons," Science Advances (2018). advances.sciencemag.org/content/4/10/eaat5847 , DOI: 10.1126/sciadv.aat5847

Related Stories

New knowledge on how neurons talk to muscles

October 2, 2018
Researchers at Karolinska Institutet in Sweden have discovered a new way in which nerve cells can control movement. In a study on zebrafish published in the journal PNAS they show that the contact between neurons and muscles ...

New microfluidic chip replicates muscle-nerve connection

August 3, 2016
MIT engineers have developed a microfluidic device that replicates the neuromuscular junction—the vital connection where nerve meets muscle. The device, about the size of a U.S. quarter, contains a single muscle strip and ...

Artificial muscles promise to speed up testing of treatments for muscle diseases

May 9, 2018
Artificial muscles grown from human stem cells could pave the way forward for treating muscle diseases, according to new research led by UCL.

Therapeutic antibodies protected nerve–muscle connections in a mouse model of Lou Gehrig's disease

February 20, 2018
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, causes lethal respiratory paralysis within several years of diagnosis. There are no effective treatments to slow or halt this devastating disease. Mouse ...

Stem cells may be the key to staying strong in old age

June 6, 2017
University of Rochester Medical Center researchers have discovered that loss of muscle stem cells is the main driving force behind muscle decline in old age in mice. Their finding challenges the current prevailing theory ...

New role for motor neurons discovered

January 13, 2016
A new study presented in the journal Nature could change the view of the role of motor neurons. Motor neurons, which extend from the spinal cord to muscles and other organs, have always been considered passive recipients ...

Recommended for you

Research shows signalling mechanism in the brain shapes social aggression

October 19, 2018
Duke-NUS researchers have discovered that a growth factor protein, called brain-derived neurotrophic factor (BDNF), and its receptor, tropomyosin receptor kinase B (TrkB) affects social dominance in mice. The research has ...

Good spatial memory? You're likely to be good at identifying smells too

October 19, 2018
People who have better spatial memory are also better at identifying odors, according to a study published this week in Nature Communications. The study builds on a recent theory that the main reason that a sense of smell ...

How clutch molecules enable neuron migration

October 19, 2018
The brain can discriminate over 1 trillion odors. Once entering the nose, odor-related molecules activate olfactory neurons. Neuron signals first accumulate at the olfactory bulb before being passed on to activate the appropriate ...

Scientists discover the region of the brain that registers excitement over a preferred food option

October 19, 2018
At holiday buffets and potlucks, people make quick calculations about which dishes to try and how much to take of each. Johns Hopkins University neuroscientists have found a brain region that appears to be strongly connected ...

Gene plays critical role in noise-induced deafness

October 19, 2018
In experiments using mice, a team of UC San Francisco researchers has discovered a gene that plays an essential role in noise-induced deafness. Remarkably, by administering an experimental chemical—identified in a separate ...

Brain cells called astrocytes have unexpected role in brain 'plasticity'

October 18, 2018
When we're born, our brains have a great deal of flexibility. Having this flexibility to grow and change gives the immature brain the ability to adapt to new experiences and organize its interconnecting web of neural circuits. ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.