Research Roundup: New CRISPR, ALS, Colon Cancer, Asthma and More

row of test tubes with dropper depositing pink liquid

There are plenty of great scientific research stories out this week. Here’s a look at just a few of them.

CRISPR to Treat a Genetic Disease in Prenatal Mice

Researchers with Children's Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania used CRISPR-Cas9 and base editor 3 to edit the genes of mice in utero to treat for a mouse model of hereditary tyrosinemia type 1, a lethal liver disease. They published their research in the journal Nature Medicine.

William Peranteau, a pediatric and fetal surgeon at CHOP’s Center for Fetal Diagnosis and Treatment, and his team injected CRISPR editing components into pregnant mice’s placenta. The pups who received the treatment were born with stable amounts of edited liver cells for up to three months with no evidence of off-target editing mistakes. They had improved liver function and better rates of survival.

The entire field of CRISPR gene editing in the context of human embryos has been rocked by the scandal of a Chinese researcher who used the technique to modify the embryos of seven couples, then implanted them, with the resultant birth of a set of twins and at least one other pregnancy.

This research, which is in animal studies and very early, shows that the technique has promise in treating genetic diseases in utero, although doing so in human beings, at least ethically, is still down the road. “This is not a panacea for curing every genetic disease that’s out there,” Peranteau told Wired. “At some point in the future—not tomorrow or the next day, years from now—I think in utero editing would provide hope for families that today have none.”

A New Type of CRISPR

Since its discovery not long ago—technically in about 2012, although CRISPR itself was identified in the 1980s—there have been a number of innovations and approaches to improve CRISPR-Cas9 gene editing. Researchers with Cornell University and the University of Michigan have come up with another, this one called CRISPR-Cas3, which is capable of efficiently editing long stretches of DNA from a targeted site in the human genome. They published their research in the journal Molecular Cell.

“My lab spent the past ten years figuring out how CRISPR-Cas3 works,” stated Ailong Ke, professor of molecular biology and genetics and corresponding author of the study. “I am thrilled that my colleagues and I finally demonstrated its genome editing activity in human cells. Our tools can be made to target these viruses very specifically and then erase them very efficiently. In theory, it could provide a cure for these viral diseases.”

They believe it might be able to “erase” ectopic viruses such as herpes simplex, Epstein-Barr, and hepatitis B. The CRISPR-Cas3 can scan the genome and detect non-coding genetic elements, which make up about 98% of the genome. These elements are often regulators that control the expression of proteins in coding genes.

CRISPR-Cas9 uses a bacterial RNA as a guide and allows the system to recognize a DNA sequence. The guide RNA directs CRISPR-associated (Cas) proteins to the precise site, and the Cas9 protein cuts the target DNA at the right place. CRISPR-Cas3 is similar, but instead of cutting the DNA in half, its nuclease erases DNA continuously for up to 100 kilobases.

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A Deeper Understanding of ALS

Researchers with the Centre for Regenerative Therapies Dresden (CRTD) at Technical University of Dresden (TUD), working with researchers from Germany, Italy, the Netherlands, and the U.S., have identified new mechanisms involved in amyotrophic lateral sclerosis (ALS). ALS is an incurable disease of the central nervous system. Most of the time, the disease is fatal within a short period after diagnosis. But some patients live with it for decades. For example, late astrophysicist Steven Hawking. The team published their research in the journal Acta Neuropathologica.

During the course of the disease, specialized brain cells called motor neurons die. As the disease progresses, patients suffer from increasing muscle weakness and paralysis, eventually causes paralysis and problems with speech, movement and swallowing. The team’s research focused on an RNA-binding protein called Fused in Sarcoma (FUS), which plays an important role in regulating genetic messengers and the interaction of different proteins. FUS mutations caused FUS to accumulate in the cytoplasm, which causes one the most aggressive types of ALS. Their work found that these proteins are even more critical than thought.

“Mislocalized FUS overwhelms the protein degradation machinery, causing FUS to accumulate within the cytoplasm,” stated Lara Marrone, lead author of the study and a PhD student at the CRTD. “This triggers a vicious cycle that further hampers the cellular protein quality control systems responsible for the maintenance of protein homeostasis.”

3D-Printed Human Heart

Researchers at Tel Aviv University successfully printed the first 3D human heart. The research team used the patient’s own cells and various biological materials such as collagen and glycoprotein. Their work was published in the journal Advanced Science.

“This heart is made from human cells and patient-specific biological materials,” stated Tal Dvir, lead researcher. “In our process these materials serve as the bioinks, substances made of sugars and proteins that can be used for 3D printing of complex tissue models. People have managed to 3D-print the structure of a heart in the past, but not with cells or with blood vessels. Our results demonstrate the potential of our approach for engineering personalized tissue and organ replacement in the future.”

Dvir and his team began by taking biopsies of fatty tissues from the omentum, a fold of visceral peritoneum that hangs from the stomach, in the abdomen of humans and pigs. They then separated the cellular materials from extraneous materials and reprogrammed the cellular materials to become pluripotent stem cells. From there, they were able to develop all three body layers that had the potential to produce any cell or tissue in the body.

They then built an extracellular matrix from collagen and glycoproteins into a hydrogel using the bioprinter. They mixed the cells with the hydrogel, which were then differentiated into cardiac or endothelial cells. This created what they’re calling “patient-specific, immune-compatible cardiac patches complete with blood vessels.”

From that point, they then created an entire—but small—bioengineered and bioprinted human heart.

The scientists admit the technology isn’t ready for human transplantation. “At this stage, our 3D heart is small, the size of a rabbit’s heart,” Dvir stated. “But larger human hearts require the same technology.”

New Mechanism Found for How Colon Cancer Cells Hide From the Immune System

Researchers with The Institute of Cancer Research (ICR), London, and the Royal Marsden NHS Foundation Trust published research that showed another mechanism for how colon cancer cells hide from the immune system. They published their work in the Journal of ImmunoTherapy of Cancer.

“Cancer is very good at hiding from the body’s immune system,” stated Marco Gerlinger, Team Leader in Translational Oncogenomics at The Institute of Cancer Research, London. “The latest successful immunotherapies work by acting as a matchmaker to bring the immune system together with cancer, so that it can see it and attack it.”

Gerlinger added, “Our study has found that bowel cancers have a way of dodging even the newest of immunotherapies—changing their spots by altering the levels of a key molecule on the surface of cells, so that they become harder to recognize.”

The team took biopsies from eight bowel cancer patients. They then used a new technique to grow the organoids of the tumors. They identified three groups of cells, some with high levels of CEA on the cancer cells’ surface, some with low levels, and some with a mixture.

They found that treatment with cibisatamab reduced growth by 96% in cancer cells with high CEA levels, but only by 20% in the cancer cells with low CEA. In the cancer cells with mixed levels of CEA, the drug decreased growth by 53%.

The researchers then isolated the individual cells with high or low CEA and regrew them into organoids. What they found was that the CEA levels changed in the regrown tumors. This suggests that the cancer cells can quickly shift to a different state and they use this to “hide” from immunotherapy.

New Mutation Identified That Causes an Inherited Metabolic Disorder

Scientists from BC Children’s Hospital, the University of British Columbia and an international team, identified a new gene mutation that causes an undiagnosed, degenerative metabolic disease. They published their work in the New England Journal of Medicine.

The research was into the cause of three children’s undiagnosed disorder. The children presented with early-onset delay in overall development, progressive ataxia, and elevated glutamine levels. One patient also showed cerebellar atrophy.

The researchers narrowed the cause to specific areas of the genome and conducted additional exome sequencing and whole genome sequencing. Even then, they couldn’t identify the cause. Using bioinformatics tools and manual analysis, co-authors Britt Drogemoller and Phillip Richmond identified that the gene that caused the disorder was intact, but a repeat expansion error stopped it from functioning. The gene codes for an enzyme that turns glutamine into glutamate. Although not yet completely clear why this error causes the disease, they believe that either an accumulation of glutamine or a lack of glutamate cause the developmental delays and disabilities. Working with the international consortium, they confirmed that this particular repeat expansion was found in only 1 in 8,000 people.

“In our search, we focused on variations that would have been hard to discover through exome sequencing,” stated Drogemoller. “After months of experimenting with various different analyses, we finally uncovered this novel genetic variant by using new targeted approaches and identifying DNA repeat expansions.”

Genetic Variants of Asthma

Although the environment has a major influence on asthma, there are genetic risk factors as well. Researchers with the Harvard Pilgrim Health Care Institute conducted a large, multi-ethnic genome-wide association study (GWAS) to identify genetic factors related to asthma. They published their research in the Journal of Allergy and Clinical Immunology.

“Identifying the genetic variants associated with asthma through GWAS is crucial for determining the genetic basis of asthma,” stated Joanne Sordillo, research scientist at Harvard Pilgrim and co-first author of the study. “It’s also necessary to understand how genetic heterogeneity underlying asthma risk may be influenced by ethnic background, using large, multi-racial patient populations.”

The researchers utilized the Kaiser Permanente Northern California Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, utilizing a total of 68,623 asthma and non-asthmatic controls. They identified a possible novel mechanism for asthma susceptibility related to the IL1RL1 gene, which might create asthma susceptibility via introduction of a new binding site for micro RNA, a small non-coding RNA molecule that regulates expression of the locus. It also confirmed 16 novel associations in the non-Hispanic white populations, all linked to either HLA-DQA1, a major histocompatibility complex gene, or IL18R1/IL1RL1. They also didn’t find any overlap in genome-wide associations across the ethnic groups, which suggests the biological pathways that contribute to asthma susceptibility are unique to the different ethnicities.

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