amyotrophic lateral sclerosis
Posted on by Dr. Francis Collins
The blood-brain barrier, or BBB, is a dense sheet of cells that surrounds most of the brain’s blood vessels. The BBB’s tiny gaps let vital small molecules, such as oxygen and water, diffuse from the bloodstream into the brain while helping to keep out larger, impermeable foreign substances that don’t belong there.
But in people with certain neurological disorders—such as amyotrophic lateral sclerosis (ALS) and Huntington’s disease—abnormalities in this barrier may block the entry of biomolecules essential to healthy brain activity. The BBB also makes it difficult for needed therapies to reach their target in the brain.
To help look for solutions to these and other problems, researchers can now grow human blood-brain barriers on a chip like the one pictured above. The high-magnification image reveals some of the BBB’s cellular parts. There are endothelial-like cells (magenta), which are similar to those that line the small vessels surrounding the brain. In close association are supportive brain cells known as astrocytes (green), which help to regulate blood flow.
While similar organ chips have been created before, what sets apart this new BBB chip is its use of induced pluripotent stem cell (iPSC) technology combined with advanced chip engineering. The iPSCs, derived in this case from blood samples, make it possible to produce a living model of anyone’s unique BBB on demand.
The researchers, led by Clive Svendsen, Cedars-Sinai, Los Angeles, first use a biochemical recipe to coax a person’s white blood cells to become iPSCs. At this point, the iPSCs are capable of producing any other cell type. But the Svendsen team follows two different recipes to direct those iPSCs to differentiate into endothelial and neural cells needed to model the BBB.
Also making this BBB platform unique is its use of a sophisticated microfluidic chip, produced by Boston-based Emulate, Inc. The chip mimics conditions inside the human body, allowing the blood-brain barrier to function much as it would in a person.
The channels enable researchers to flow cerebral spinal fluid (CSF) through one side and blood through the other to create the fully functional model tissue. The BBB chips also show electrical resistance and permeability just as would be expected in a person. The model BBBs are even able to block the entry of certain drugs!
As described in Cell Stem Cell, the researchers have already created BBB chips using iPSCs from a person with Huntington’s disease and another from an individual with a rare congenital disorder called Allan-Herndon-Dudley syndrome, an inherited disorder of brain development.
In the near term, his team has plans to model ALS and Parkinson’s disease on the BBB chips. Because these chips hold the promise of modeling the human BBB more precisely than animal models, they may accelerate studies of potentially promising new drugs. Svendsen suggests that individuals with neurological conditions might one day have their own BBB chips made on demand to help in selecting the best-available therapeutic options for them. Now that’s a future we’d all like to see.
 Human iPSC-Derived Blood-Brain Barrier Chips Enable Disease Modeling and Personalized Medicine Applications. Vatine GD, Barrile R, Workman MJ, Sances S, Barriga BK, Rahnama M, Barthakur S, Kasendra M, Lucchesi C, Kerns J, Wen N, Spivia WR, Chen Z, Van Eyk J, Svendsen CN. Cell Stem Cell. 2019 Jun 6;24(6):995-1005.e6.
Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)
Stem Cell Information (NIH)
Svendsen Lab (Cedars-Sinai, Los Angeles)
NIH Support: National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences
Posted on by Dr. Francis Collins
Over the past couple of weeks, we’ve lost two legendary scientists who made major contributions to our world: Sir John Sulston and Stephen Hawking. Although they worked in very different areas of science—biology and physics—both have left us with an enduring legacy through their brilliant work that unlocked fundamental mysteries of life and the universe.
I had the privilege of working closely with John as part of the international Human Genome Project (HGP), a historic endeavor that successfully produced the first reference sequence of the human genetic blueprint nearly 15 years ago, in April 2003. As founding director of the Sanger Centre (now the Sanger Institute) in Cambridge, England, John oversaw the British contributions to this publicly funded effort. Throughout our many planning meetings and sometimes stormy weekly conference calls about progress of this intense and all-consuming enterprise, John stood out for his keen intellect and high ethical standards.
Posted on by Dr. Francis Collins
Matthew Disney grew up in a large family in Baltimore in the 1980s. While his mother worked nights, Disney and his younger brother often tagged along with their father in these pre-Internet days on calls to fix the microfilm machines used to view important records at hospitals, banks, and other places of business. Watching his father take apart the machines made Disney want to work with his hands one day. Seeing his father work tirelessly for the sake of his family also made him want to help others.
Disney found a profession that satisfied both requirements when he fell in love with chemistry as an undergraduate at the University of Maryland, College Park. Now a chemistry professor at The Scripps Research Institute, Jupiter, FL, Disney is applying his hands and brains to develop a treatment strategy that aims to control the progression of a long list of devastating disorders that includes Huntington’s disease, amyotrophic lateral sclerosis (ALS), and various forms of muscular dystrophy.
The 30 or so health conditions on Disney’s list have something in common. They are caused by genetic glitches in which repetitive DNA letters (CAGCAGCAG, for example) in transcribed regions of the genome cause some of the body’s cells and tissues to produce unwieldy messenger RNA molecules that interfere with normal cellular activities, either by binding other intracellular components or serving as templates for the production of toxic proteins.
The diseases on Disney’s list also have often been considered “undruggable,” in part because the compounds capable of disabling the lengthy, disease-causing RNA molecules are generally too large to cross cell membranes. Disney has found an ingenious way around that problem . Instead of delivering the finished drug, he delivers smaller building blocks. He then uses the cell and its own machinery, including the very aberrant RNA molecules he aims to target, as his drug factory to produce those larger compounds.
Disney has received an NIH Director’s 2015 Pioneer Award to develop this innovative drug-delivery strategy further. He will apply his investigational approach initially to treat a common form of muscular dystrophy, first using human cells in culture and then in animal models. Once he gets that working well, he’ll move on to other conditions including ALS.
What’s appealing about Disney’s approach is that it makes it possible to treat disease-affected cells without affecting healthy cells. That’s because his drugs can only be assembled into their active forms in cells after they are templated by those aberrant RNA molecules.
Interestingly, Disney never intended to study human diseases. His lab was set up to study the structure and function of RNA molecules and their interactions with other small molecules. In the process, he stumbled across a small molecule that targets an RNA implicated in a rare form of muscular dystrophy. His niece also has a rare incurable disease, and Disney saw a chance to make a difference for others like her. It’s a healthy reminder that the pursuit of basic scientific questions often can lead to new and unexpectedly important medical discoveries that have the potential to touch the lives of many.
 A toxic RNA catalyzes the in cellulo synthesis of its own inhibitor. Rzuczek SG, Park H, Disney MD. Angew Chem Int Ed Engl. 2014 Oct 6;53(41):10956-10959.
Disney Lab (The Scripps Research Institute, Jupiter, FL)
Disney NIH Project Information (NIH RePORTER)
NIH Support: Common Fund; National Institute of Neurological Disorders and Stroke