Motor neurons, shown with their axons (nerve fibres) coloured green, growing on a spinal cord organ chip developed by scientists at Cedars-Sinai Medical Center, Los Angeles. | Photo Credit: The Svendsen Lab./Cedars-Sinai Medical CenterThe New York Yankees’ baseball team’s Lou Gehrig wipes away a tear while speaking at a tribute function held for him at the Yankee Stadium in New York on July 4, 1939, a month after he was diagnosed with amyotrophic lateral sclerosis. The disease is also known as Lou Gehrig’s disease. | Photo Credit: Murray Becker/APALS-on-chip model provides insights into the diseaseUsing stem cells from patients with amyotrophiclateral sclerosis (ALS), also known as Lou Gehrig’s disease, scientists at Cedars-Sinai Medical Center, Los Angeles, US, have created a lifelike model of the mysterious and fatal disease that could help identify a cause of the illness as well as effective treatments.In a study published in a recent issue of the journal Cell Stem Cell, the researchers detailed how they created “ALS on a chip”, a laboratory model that mimics the key features of the disease. This specialised laboratory chip has already thrown up clues about the non-genetic causes of the disease, said the authors.The work builds on previous studies where adult cells from ALS patients were reverted to stem cells. The cells were then pushed forward to produce motor, or muscle-controlling, neurons, which die in the disease, causing progressive loss of the ability to move, speak, eat, and breathe. This work was published in the journal Neuron in 2023.In the present work, motor neurons from ALS patients were seeded into the top channels of microengineered chips. Cells that make up the blood-brain barrier were seeded into the bottom channels of the chips. The two channels were connected through a porous membrane that allowed investigators to flow fluids through the chips in order to mimic blood flow.The researchers then created a second group of the specialised chips using cells from individuals who did not have ALS. Using specialised technologies, the researchers then analysed more than 10,000 genes in the motor neurons in both groups of chips.“In our early work, we couldn’t detect many differences between the motor neurons of patients with ALS and those from healthy individuals,” said Clive Svendsen of Regenerative Medicine Institute at Cedars-Sinai and the senior author of the study. “But those studies employed traditional lab culture that is static like a pond. In the body, blood vessels provide constant fluid flow to bring in nutrients and take away waste and may even provide other types of support to motor neurons,” he added.In the specialised chips, the motor neurons matured more completely than they would have in a static dish, and investigators could detect distinct differences in the cells from patients with ALS. “We were intrigued to find that signalling for glutamate, a chemical that sends excitatory messages between neurons, was altered in the ALS motor neurons,” Svendsen said. Excessive release of glutamate has long been considered a possible cause of ALS, and one of the few drugs approved to treat the disease targets this neurotransmitter.The team’s next task, Svendsen said, was to determine whether this increased glutamate signalling directly leads to the dysfunction or death of the cells or if glutamate is only one piece in a much larger puzzle that underlies the cause of ALS.Also Read | Cell and gene therapy for Lou Gehrig’s diseaseSingle grains of a scandium-zinc quasicrystal have 12 pentagonal faces. | Photo Credit: Yamada et al., International Union of Crystallography Journal (2016)Now we know why quasicrystals existQuasicrystals are a type of solid that scientists once thought could not exist. When first discovered in 1984 by Daniel Shechtman, they seemed to defy physics. While atoms in quasicrystals are arranged in a lattice as in crystals, the pattern of atoms is neither periodic nor does it repeat like it does in conventional crystals, extending to infinity in each direction. The pattern in a quasicrystalline solid can continuously fill all the available space, but it lacks translational symmetry.According to the crystallographic restriction theorem, crystals can possess only two-, three-, four-, and sixfold rotational symmetries. But quasicrystals can have other symmetry orders, fivefold, for example. Scientists at one time thought that the atoms inside crystals could only be arranged in sequences repeating in each direction, but fivefold symmetry precluded such patterns.A study from the University of Michigan explains why quasicrystals exist. The work, which is the first-ever quantum-mechanical simulation of quasicrystals, was published in a recent issue of Nature Physics. The simulation method by the Michigan group, led by Wenhao Sun, suggests that quasicrystals, like crystals, are fundamentally stable materials despite their similarity to disordered solids like glass. Until this work, it was unclear why quasicrystals existed or how they formed. The hurdle was that density-functional theory—the quantum-mechanical method for calculating a crystal’s stability—relies on patterns that infinitely repeat in a sequence, which quasicrystals lack. “Quasicrystals have forced us to rethink how and why certain materials can form,” Sun said.Materials arrange into crystals such that the chemical bonds achieve the lowest possible energy. Such structures are called enthalpy-stabilised crystals. But materials that take other forms, such as glass, have high entropy, meaning there are a lot of different ways for its atoms to be arranged. Glass is an entropy-stabilised solid.Quasicrystals are a puzzling intermediate between glass and crystal. They have locally ordered atomic arrangements like crystals, but like glass, they do not form long-range, repeating patterns. To determine if quasicrystals are enthalpy- or entropy-stabilised, the researchers scooped out smaller nanoparticles from a larger simulated block of quasicrystal. They then calculated the total energy in each nanoparticle, which is related to its volume and surface area. This does not require an infinite sequence because particles have well-defined boundaries.By repeating the calculations for nanoparticles of increasing sizes (selected from randomly sampled scoops), the total energy inside a larger block of quasicrystal could be extrapolated. Using this method, the study discovered that two well-studied quasicrystals—one, an alloy of scandium and zinc and the other of ytterbium and cadmium—are enthalpy-stabilised.Also Read | Breakthrough in crystallographyHumans have higher rates of cancer than non-human primates. Here, a chimpanzee at the Indira Gandhi Zoological Park in Visakhapatnam, in 2022. | Photo Credit: K.R. DEEPAKWhy are humans more susceptible to cancer?A tiny genetic mutation in an immune protein called Fas ligand (FasL) in humans makes the protein vulnerable to being disabled by plasmin, a tumour-associated enzyme. This mutation is not found in non-human primates, such as chimpanzees, new research from the Comprehensive Cancer Center at the University of California, Davis, has revealed. The study was published in Nature Communications.“The evolutionary mutation in FasL may have contributed to the larger brain size in humans,” said Jogender Tushir-Singh, senior author of the study. “But in the context of cancer, it was an unfavourable trade-off because the mutation gives certain tumours a way to disarm parts of our immune system.” FasL is an immune cell membrane protein that triggers apoptosis, programmed cell death. Activated immune cells, including CAR-T cells made from a patient’s immune system, use apoptosis to kill cancer cells.The UC Davis team found that in human genes, a single evolutionary amino acid change—serine instead of proline at position 153—makes FasL more susceptible to being cut and inactivated by plasmin. The protease enzyme plasmin is often elevated in aggressive solid tumours like triple negative breast cancer, colon cancer, and ovarian cancer.This means that even when human immune cells are activated and ready to attack the tumour cells, one of their key death weapons, FasL, can be neutralised by the tumour environment, reducing the effectiveness of immunotherapies.The findings may help explain why CAR-T and T-cell-based therapies can be effective in blood cancers but often fall short in solid tumours. Blood cancers often do not rely on plasmin to metastasise (spreading of cancer from one location to others), whereas tumours like ovarian cancer rely heavily on it. Significantly, the study also showed that blocking plasmin or shielding FasL from cleavage can restore its cancer-killing power. That finding may open new doors for improving cancer immunotherapy.CONTRIBUTE YOUR COMMENTS