The Research Roundup - February 2022

Updated: Jun 15

The following is my third high-level overview of medical papers and news articles. Please comment and let me know what has been helpful to you, or email ideas for topics you'd like covered to: Research@cmpnrf.ca.


This list of papers is not in any sequence (but all published recently, this month of February 2022) and I make only the smallest of comments. This review includes an eclectic gathering of 13 topics (click on any topic in this list to jump to that summary):

  1. Hereditary hematologic malignancy assessment

  2. Spatial organization of transcribed eukaryotic genes

  3. Nanoparticle-based drug delivery system

  4. Data Compression and Machine Learning

  5. Next Generation CAR-T

  6. Spatial Biology

  7. Super Selective PCR Primers to support personalized diagnosis and treatments

  8. Catalog of Gene Activators

  9. R-Loops and DNA Damage

  10. HSC Differentiation influenced by key Histone

- Russ Hardy


[Note: Russ' comments are offset in gray, and research article exerpts are included in "quotes".]


 

I was very interested in this webinar, particularly due to my monozygotic relationship to my brother (who passed away in June from an aggressive MPN). I had experienced very strong representations from medical caregivers that MPN was definitely not influenced by heredity; yet here in this webinar there is recent information even to the point of encouraging including germline genetic testing in clinical practices for specifically screened patients.

Webinar: Hereditary hematologic malignancy assessment: Making it (germline predisposition testing for HHM’s) mainstream, genetics@insights.invitae.com, by Sarah Bannon, MS, CGC Genome Medical

Sarah is a leader in the genetic counseling field on inherited predispositions to hematologic malignancies. And . . .


Dr. Lucy Godley, M.D., Ph.D. Hospira Foundation Professor in Oncology Departments of Medicine and Human Genetics, The University of Chicago


Recognition also to Invitae Genetics: Invitae’s mission is to bring comprehensive genetic information into mainstream medicine to improve healthcare for billions of people.


“Presented in partnership with the RUNX1 Research Program, this webinar is intended for genetic counselors, hematologic oncologists, hematologists, oncologists, and related healthcare providers. This webinar includes the following learning objectives:

  • List three clinical indications for hereditary hematologic malignancy assessment

  • Compare and contrast the clinical and familial presentations among RUNX1, CEBPA, and DDX41

  • Identify the ideal specimen source for hereditary hematologic malignancy susceptibility testing, given an individual’s clinical presentation

  • Describe potential management implications when identifying an individual with an active hereditary hematologic malignancy”


Germline Predisposition Testing is NOT Somatic Testing.


 



This article describes interesting observations regarding the mechanisms of transcription during the processes of making proteins. . . another example of the complexities beyond just the genes within DNA.

Spatial organization of transcribed eukaryotic genes

by Ludwig Maximilian University of Munich, February 21, 2022


Susanne Leidescher et al, Spatial organization of transcribed eukaryotic genes, Nature Cell Biology (2022). DOI: 10.1038/s41556-022-00847-6

Journal information: Nature Cell Biology


“Despite a huge progress in our understanding of the molecular mechanisms of transcription, so far very little is known about the spatial organization of individual expressed genes or the behavior of transcribed genes. This raises the question as to what moves and what remains stationary. It so happens that, in eukaryotes, frequently expressed genes are often very short—too short for the available imaging resolution—whereas large genes are generally not highly expressed and are therefore unsuitable for transcription studies. The results of the study show," says Heinrich Leonhardt, head of the laboratory Human Biology and BioImaging, "that even in our time dominated by molecular biology, microscopy remains an important and powerful tool to study basic biological questions.”

 
This article describes a third alternative approach to the use of nanoparticles in cancer therapies that may be more cost effective and better for mass production. . . corn.

Researchers develop a nanoparticle-based drug delivery system based on corn to target cancer cells February 15, 2022

by Tokyo University of Science, Daisuke Sasaki et al, Development of nanoparticles derived from corn as mass producible bionanoparticles with anticancer activity, Scientific Reports (2021). DOI: 10.1038/s41598-021-02241-y

Journal information: Scientific Reports


“Nanomaterials have revolutionized the world of cancer therapy, and plant-derived nanoparticles have the added advantage of being cost-effective and easy to mass produce. Researchers from Tokyo University of Science have recently developed novel corn-derived bionanoparticles for targeting cancer cells directly, via an immune mechanism. However, conventional, synthetic nanoparticles are complicated and expensive to produce. Extracellular vesicles (EVs), which have emerged as an alternative option to synthetic nanoparticles, show challenges for mass production. A third option is that of plant-derived nanoparticles (NPs), which can be easily produced in high levels at relatively lower costs. The strong TNFα response (tumour necrosis factor) was encouraging and indicated the role of cNPs in treating various types of cancer.”


 
This article once again highlights the importance of data analytics and Information Technologies (in this case Machine Learning and data compression).

Compressing gene libraries to expand accessibility, research opportunities February 14, 2022

by Gabrielle Stewart, Pennsylvania State University

Boyang Zhao et al, A pan-CRISPR analysis of mammalian cell specificity identifies ultra-compact sgRNA subsets for genome-scale experiments, Nature Communications (2022). DOI: 10.1038/s41467-022-28045-w

Journal information: Nature Communications


“In image compression, a large file that could be cumbersome to store or share loses a small amount of visual information. This "lossiness" largely preserves the image while vastly reducing its file size—and serves as the inspiration for a new research direction in genomics, according to Justin Pritchard, assistant professor of biomedical engineering. This idea of compression dramatically reduces the scale of the experiments, opening up possibilities for new experiments. This can unlock biological mysteries, such as why different genes and drugs work differently together, and it allows us to unravel very complicated biology using simpler experiments. Using machine learning, we compressed the scale of the experiment from 18,000 genes to as few as 200 genes; Despite the loss of some data in the compression, we found that a subset of 200 genes could provide surprisingly good information on the full 18,000 genes."


 

Current CAR-T therapies are still incredibly costly, carry risks and have not been safe or effective outside of leukemias or myelomas. This article outlines some potential future improvements on the horizon.

Scientists are making CAR-T cells more clever. Here’s what the next generation could look like. By Angus Chen Jan. 14, 2022


  • Controllable CAR “Currently, armed with a CAR, T cells become pros at killing cancer cells that have their target, but they’ll also kill normal cells that happen to carry the protein, too. Once a CAR-T cell is in the body, there isn’t much a clinician can do to rein it in if it starts causing a lot of toxicity. So, researchers are also trying to create CAR-T cells that they can manually activate or deactivate.

  • Logic Gated CAR “Other researchers are working on developing new CARs that can function like a biomolecular computer, able to make simple logical decisions to target cancer cells. But, a drawback of logic-gating is that by increasing the complexity of the system, you might also be increasing the chance something goes wrong.”

  • The Armoured CAR “So, researchers are working on “armoring” the CAR T-cell against the hostile signals in the microenvironment. Also, Other scientists are working to keep CAR-T cells — which can lose power over time — functional for longer.”

  • New cell types “Some future approaches might see T cells abandoned altogether. Scientists are slapping synthetic receptors on new or different cell types, such as natural killer cells. Another approach - instead of taking a cell from a patient, but rather build a completely defined, minimal synthetic cell that can do what we want and nothing else. It cannot evolve. Cannot mutate. Then, self-destruct when you don’t want it there”


 
This article explores the emerging fields of Spatial Biology combined within the context of epigenetics. "This is the first time we can look at which histone modifications control genome-wide gene expression directly in the tissue, and how they do it.”

Mapping how cell types and tissues develop by Yale University February 11, 2022


Yanxiang Deng et al, Spatial-CUT&Tag: Spatially resolved chromatin modification profiling at the cellular level, Science (2022). DOI: 10.1126/science.abg7216

Journal information: Science


“Researchers have developed a technique that allows them to look simultaneously at a spatial level and at a genome-wide level at epigenetic mechanisms underlying tissue development, a breakthrough with multiple scientific and medical applications. This is a critical obstacle, since there's a strong connection between how cells are organized in tissue and how they function. Each cell has the same genome, but the difference lies in which genes have been activated or repressed. Specifically, the researchers looked at modifications to chromatin, the material that enwraps the DNA of every cell and controls access to it. Epigenetic drugs are something that's emerging now, so potentially we can develop drugs to target those epigenetic mechanisms," Fan said. "Having the tools to understand the epigenetic origin of different disease states could open up a whole new avenue of therapeutics.”

 

This article discusses some advances in the field of peripheral blood samples of DNA fragments and the potential uses for personalized diagnosis and treatments.

New assay shows promise for advancing personalized cancer treatment by Elsevier, February 11, 2022


Diana Y. Vargas et al, Multiplex SuperSelective PCR Assays for the Detection and Quantitation of Rare Somatic Mutations in Liquid Biopsies, The Journal of Molecular Diagnostics (2021). DOI: 10.1016/j.jmoldx.2021.11.006

Journal information: Journal of Molecular Diagnostics


“Using a routine blood sample, investigators have developed an extremely sensitive assay to detect and quantify DNA fragments containing rare genetic mutations in a patient's cancer cells. This assay uses "SuperSelective" PCR primers that virtually ignore abundant closely related non-mutant DNA fragments derived from patients' normal cells. This new assay is faster and considerably cheaper than current methods and can be performed on widely available instruments. Current techniques for analyzing liquid biopsies involve either next-generation sequence analysis, which is expensive, lengthy, and has limited sensitivity; or use a PCR technique in which both the mutant DNA fragments and the closely related wild-type DNA fragments are amplified, also limiting sensitivity.”


 
This article highlights the results from the University of Toronto to catalog “Transcription Activators” and Co-Activators (enzymes). . . very interesting.

Researchers reveal largest catalog of gene activators by University of Toronto, February 9, 2022


Nader Alerasool et al, Identification and functional characterization of transcriptional activators in human cells, Molecular Cell (2022). DOI: 10.1016/j.molcel.2021.12.008

Journal information: Molecular Cell


“University of Toronto researchers have created a first-in-class functional catalog of proteins that activate gene expression, with implications for tailored therapy for cancer and other diseases that occur when wrong genes are switched on. The research was led by Mikko Taipale, an associate professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research at the Temerty Faculty of Medicine, in collaboration with Anne-Claude Gingras, a senior investigator at the Lunenfeld-Tanenbaum Research Institute, Sinai Health System and professor of molecular genetics at U of T. In the article, the researchers describe the first unbiased proteome scale study that has expanded the number of known transcriptional activators from a handful to around 250. They have also established how these proteins combine with other cellular machineries to turn genes on, and how protein misregulation can lead to cancer. They also used AlphaFold, a revolutionary bioinformatic tool developed for the prediction of protein structures, to find the interaction interfaces between the TFs and their activators.”


 

This article describes links between certain kinds of DNA damage called R-Loops and blood cancers. NB. Really interesting to read this and the above webinar #1 which mentions the same mutant variant of protein DDX41, albeit the Germline type.

Link between excessive R-loop levels and DNA damage to be a potential cause of disease

by Universitaet Mainz,February 9, 2022


Thorsten Mosler et al, R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability, Nature Communications (2021). DOI: 10.1038/s41467-021-27530-y

Journal information: Nature Communications


“There are many ways in which the genetic material DNA can be damaged, resulting in the development of diseases such as cancer. Certain forms of DNA damage are associated with so-called R-loops. These are three-stranded structures consisting of two DNA strands and one RNA strand, whereby one of the DNA strands forms the loop. The level of R-loops needs to be strictly regulated to avoid genomic instability and consequent damage. They discovered that a tumor suppressor protein called DDX41 is responsible for preventing R-loops from building up in cells and that this is an important mechanism for preventing genomic instability and subsequent disease. We propose that R-loop accumulation and genomic instability-associated inflammatory response may contribute to the development of familial AML with mutated DDX41.”


 
This article explores how Hematopoietic Stem Cells perform self renewal and differentiation, particularly vis a vis an important role of a particular Histone. Blood HSC’s are probably the most studied stem cells, but it is important to further understand the influence of the cellular environment on the differentiation and mutations that play a role in hematological malignancies.

Researchers identify key regulator of blood stem cell development

by Weill Cornell Medical College, January 31, 2022

Peipei Guo et al, Histone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability, Nature Cell Biology (2021). DOI: 10.1038/s41556-021-00795-7

Journal information: Nature Cell Biology


“A protein that masterminds the way DNA is wrapped within chromosomes has a major role in the healthy functioning of blood stem cells, which produce all blood cells in the body, according to a new study from researchers at Weill Cornell Medicine. The protein, known as histone H3.3, organizes the spool-like structures around which DNA is wrapped in plants, animals, and most other organisms. Histones enable DNA to be tightly compacted and serve as platforms for small chemical modifications—known as epigenetic modifications—that can loosen or tighten the wrapped DNA to control local gene activity. The study found that H3.3 is crucial for both processes (self renewal and differentiation); deleting the protein from HSCs led to reduced HSC survival, an imbalance in the types of blood cell produced by the HSCs and other abnormalities."

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