General Biosystems, Inc

02/14/2022

Heart-disease risk soars after COVID

Massive study shows a long-term, substantial rise in risk of cardiovascular disease, including heart attack and stroke, after a SARS-CoV-2 infection.

Even a mild case of COVID-19 can increase a person’s risk of cardiovascular problems for at least a year after diagnosis, a new study1 shows. Researchers found that rates of many conditions, such as heart failure and stroke, were substantially higher in people who had recovered from COVID-19 than in similar people who hadn’t had the disease.

What’s more, the risk was elevated even for those who were under 65 years of age and lacked risk factors, such as obesity or diabetes.

People who had recovered from COVID-19 showed stark increases in 20 cardiovascular problems over the year after infection. For example, they were 52% more likely to have had a stroke than the contemporary control group, meaning that, out of every 1,000 people studied, there were around 4 more people in the COVID-19 group than in the control group who experienced stroke.

The risk of heart failure increased by 72%, or around 12 more people in the COVID-19 group per 1,000 studied. Hospitalization increased the likelihood of future cardiovascular complications, but even people who avoided hospitalization were at higher risk for many conditions.

01/26/2022

Immune cells still recognize Omicron variant

Omicron’s genome is loaded with mutations — more than 30 in the region that codes for the spike protein, used in COVID-19 vaccines — meaning that the efficacy of antibodies raised against previous variants could be compromised.

When it comes to coronavirus immunity, antibodies have stolen the limelight. Researchers are monitoring people’s levels of antibodies — particularly ‘neutralizing antibodies’ that directly prevent the virus from replicating — with bated breath. A drop in neutralizing-antibody levels correlates with an increased risk of symptomatic infection. Antibodies are also easier to study than T cells, making it easier to analyse them in large, international vaccine trials.

But the rise of coronavirus variants has shown how fragile antibody-based immunity can be in the face of a changing virus. Neutralizing antibodies bind to a handful of regions on the SARS-CoV-2 spike protein, used as a template for many COVID-19 vaccines. Mutate those sites, and antibody protection fades.

T cells, however, are more resilient. These cells perform a variety of immune functions, including acting as ‘killer’ cells that destroy virus-infected cells. By killing infected cells, T cells can limit the spread of infection — and potentially reduce the chance of serious illness.

Omicron overpowers key COVID antibody treatments in early tests

T-cell levels do not tend to fade as quickly as antibodies after an infection or vaccination. And because T cells can recognize many more sites along the spike protein than can antibodies, they are better able to recognize mutated variants. “What sounds like a lot of mutations doesn’t dent the T-cell response,” says Burgers.

So far, computer and lab analyses suggest that this is the case for Omicron. Several research groups have cross-referenced the mutations in Omicron with sites in the SARS-CoV-2 genome that are known targets of T cells. They have found that the majority of sites that T cells recognize are present in Omicron.

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01/24/2022

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01/21/2022

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12/05/2016

Researchers led by scientists at Dana-Farber Cancer Institute identified unique genomic changes that may be integral to testicular cancer development and explain why the great majority are highly curable with chemotherapy -- unlike most solid tumors. The findings, which may shed light on factors in other cancers that influence their sensitivity to chemotherapy, was featured on the cover of last week’s Nature.

Germ cell tumors are growths that arise from reproductive cells (germ cells produce s***m and eggs), most commonly in the te**es. Approximately 8,720 new cases are expected in the U.S. in 2016 with about 380 deaths. Although rare, primary testicular germ cell tumors are the most common solid cancers in young men. Tumors are generally highly sensitive to chemotherapy, and 80 percent of patients with germ cell tumors can be cured with standard chemotherapy, even when the cancer has metastasized. However, a significant number become chemotherapy-resistant, and about 10 percent of patients with metastatic germ cell tumors die as a result.

Previous studies of the genomes of testicular tumors revealed mutations and chromosome damage, but haven't pinpointed specific alterations or events linked to chemosensitivity or resistance. Scientists led by Eliezer Van Allen, MD, of Dana-Farber and the Broad Institute of MIT and Harvard, and Christopher Sweeney, MBBS, of Dana-Farber decided to conduct a comprehensive search for the critical genomic and molecular features of these cancers. The team analyzed samples of 59 tumors from 49 patients treated between 1997 and 2014 at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC). The samples were sequenced for the whole-exome DNA and RNA transcriptome, with the findings correlated to clinical outcomes data. Although mutated genes are the main drivers of many cancers, no single gene was discovered that really explains the formation of testicular cancers.

The more surprising insights came when they analyzed the sequence data for copy number variation, looking for extra or missing pieces of DNA in the tumor genome. One feature of the tumors that had been previously reported was a gain of extra DNA copies on one arm of chromosome 12, in a segment labeled 12p. The new study revealed widespread genetic rearrangement in the cancer cells with many having multiple parts of the genome having gain of one parental allele while simultaneously losing a copy of the other parental allele -- a type of chromosomal damage called reciprocal loss of heterozygosity (RLOH). This abnormality maybe linked to the development of germ cell tumors and cause them to be sensitive to chemotherapy, but exactly how it does so remains to be discovered.

The analysis revealed another feature of the chemosensitive germ cell tumors possessed intact copies of the p53 tumor suppressor gene, which is often inactivated or lost in cancer cells. Moreover, the researchers discovered that in contrast to most types of cancer, which have evolved strategies for blocking the cell's orders to self-destruct, testicular tumor cells are already highly "primed” for self-destruction by apoptosis. This be account for the high susceptibleness to chemotherapy by most testicular tumors, although the mechanism remains undetermined.

By studying drug-resistant germ tumor cells across the entire treatment course, the scientists found that as the cancers progressed, they showed increases in chromosomal abnormalities seen in all the tumors. The cells of the germ cell tumors also became more "differentiated" -- a trait that's usually associated with less-aggressive cancers; this observation remains a puzzle, the authors said, but may explain the resistance of these tumors to chemotherapy. An important next step in this research will be understanding what drives the RLOH events, and exploring whether therapeutics can block that factor or reverse the path to drug resistance.

Read more: Taylor-Weiner A, et al. Genomic evolution and chemoresistance in germ-cell tumours. Nature 2016 DOI: 10.1038/nature20596

Tumors are generally highly sensitive to chemotherapy, and 80 percent of patients with germ cell tumors can be cured with standard chemotherapy, even when the cancer has metastasized. However, a significant number become chemotherapy-resistant

12/05/2016

Led by investigators at Massachusetts General Hospital (MGH) and the Broad Institute of MIT and Harvard, an international research team has developed the largest database of protein-to-protein interaction networks, a resource that can illuminate how numerous disease-associated genes contribute to disease development and progression. The team reported the development of the network called InWeb_InBioMap (InWeb_IM) on Nov. 28th in Nature Methods.

It has been widely recognized that mapping large-scale interaction networks is important in understanding genomic data and the underlying mechanisms of gene groups and pathways that contribute to diseases. Recent experimental efforts have identified approximately 30,000 direct protein-protein interactions, albeit representing well under a quarter of the most conservative estimates of the total number of interactions. Lage's team, in collaboration with researchers in Denmark and the U.K., developed a computational framework to integrate data from more than 43,000 published articles, including data from eight established protein-protein interaction databases. They applied stringent quality control in creating InWeb_IM, which consisted of almost 586,000 interactions when the paper was submitted in February 2015 and now includes more than 625,500 interactions.

"Modern genetic technologies allow us to routinely sequence the genomes of people with, for example, cancer or psychiatric diseases, but understanding the cellular systems that are affected by disease-causing genetic variations remains a major challenge," says Kasper Lage, MGH Department of Surgery, project leader and co-corresponding author of the Nature Methods report. "Having more complete maps of the physical interactions of human proteins will enable us to start exploring cellular processes affected in disease at a higher resolution than is currently possible."

Lage adds, "The rapidly declining cost of genome sequencing has far outpaced our ability to interpret the gene variants we identify in patients with undiagnosed diseases. By exploring interaction networks at the level of proteins and of the genes that may be causing a disease, clinicians may begin to see patterns of genetic data that would otherwise be difficult to discern, which we illustrate in the article for cancers and autism. For example, around 30 genes appear to be involved in cardiomyopathies, but many individuals with the condition do not have mutations in any of those genes. By looking at interaction partners at the protein level of the 30 cardiomyopathy genes, we can start to identify new candidate genes based on the 'cardiomyopathy network,' potentially leading to new molecular insights into the disease. It is our hope that InWeb_IM can be a resource that contributes to interpreting clinical exome sequencing data and play a part in enabling clinical action in patients with an unknown cause of disease."

The team is continuing to develop ways of using InWeb_IM to explain large-scale genomic datasets and improve understanding of complex biological systems in a tissue-specific manner by integrating proteomic, transcriptomic and genomic data. In collaboration with several groups at MGH, the information will be applied to the understanding of cardiovascular diseases, birth defects, cancers, reproductive disorders and psychiatric disease. InWeb_IM will be maintained and updated quarterly and is fully accessible to academic users at http://www.lagelab.org/resources/ or http://www.intomics.com/inbiomap.

Read more: Taibo Li, et al. A scored human protein–protein interaction network to catalyze genomic interpretation. Nature Methods, 2016; DOI:10.1038/nmeth.4083

Modern genetic technologies allow us to routinely sequence the genomes of people with, e.g. cancer or psychiatric diseases, but understanding the cellular systems that are affected by disease-causing genetic variations remains a major challenge

11/23/2016

A team made up of researchers spanning five countries has used gene-replacement therapy to partially restore vision in genetically blind rats. The new practice is the first successful gene editing tool that can replace damaged genes with fully functioning versions of DNA in adult cells, according to the Salk Institute study, which was published in Nature journal on Wednesday.

To repair the rats’ genetic defect, the team, which included researchers from Saudi Arabia’s King Abdullah University of Science and Technology (KAUST), developed a new method which allowed them to introduce DNA at a targeted location in the non-dividing cells which make up most adult tissues and organs, such as neurons and muscles. The new approach builds on the genome-editing technique CRISPR-Cas9, which co-opts an immune mechanism from bacteria to enable scientists to direct a payload to a specified target location in the genome. In tandem with native DNA repair mechanisms, this has brought precise genome-editing within scientists’ reach.

So far these technologies have primarily been used to knock out genes rather than insert DNA at a specific location. For example, in a study published this year, CRISPR-Cas9 was used to disable one of the malfunctioning genes in rats with the inherited degenerative eye disease, retinitis pigmentosa, preventing degradation of the rats’ retinas.

A major shortcoming has been the restriction of these techniques to dividing cells. To overcome these limitations, the team developed a strategy called homology-independent targeted integration (HITI) which combines a customized nucleic acid cocktail with CRISPR-Cas9 to take advantage of a DNA repair mechanism that is active even in nondividing cells. The new technique was tested by using it to introduce DNA encoding a green fluorescent protein (GFP) downstream of a specific gene in cultured human neurons.

“To our excitement, a couple of days later, we found many neurons with GFP! That was the first indication that HITI could work in non-dividing cells,” says Juan Carlos Izpisua Belmonte of the Salk Institute in California, the lead scientist of the project. “We immediately designed a series of experiments and applied HITI directly in vivo using rodent models.”

The team then used different techniques to deliver the HITI cocktail into muscle, kidney and brain cells in live mice, including local and systemic injections of a viral vector called AAV carrying the HITI components. All of the experiments worked to some extent, though the efficiency varied depending on the tissue and delivery mode. “The development of more efficient gene delivery methods, which is a bottleneck for in vivo genome editing in general, will improve HITI efficiency in the near future” says Izpisua Belmonte.

As a final test, the researchers used HITI to repair the defective Mertk gene in the eyes of three-week-old rats with retinitis pigmentosa, which causes blindness. They introduced a functional copy of the gene at the right genome location, thereby repairing the disease-causing mutation. The rats were able to detect light five weeks following the injection, and showed significant recovery of their visual functions.

The ability to correct loss-of-function mutations in adult tissues holds tremendous therapeutic appeal, and HITI also has the potential to advance basic and translational research. However, other scientists have noted that the technique still needs refinement and its safety needs to be studied. Further research would need to be conducted before scientists can test HITI on humans, Salk Institute scientists said. But they were confident clinical trials would be underway after more extensive studies were conducted.

Read more: Suzuki, K. et al. In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. Nature http://dx.doi.org/10.1038/nature20565 (2016)

http://www.generalbiosystems.com/index.php?c=content&a=show&id=28681

A new way to edit DNA that can fix broken genes, alter the effects of aging, cure diseases and possibly lead to longer life has been discovered.