cell genomics (Introduction)
by David Turell 
, Tuesday, March 26, 2024, 20:02 (44 days ago)
cell genomics: the cytoplasmic genome in action
by David Turell , Tuesday, March 26, 2024, 21:57 (44 days ago) @ David Turell
I've offered a website which is copy protected, but I found a solution:
https://aeon.co/essays/biology-is-not-as-hierarchical-as-most-textbooks-paint-it?utm_so...
"We now know that several other kinds of hereditary information are spread all over the cell.
For instance, developmental biologists, who study how an embryo develops from a single cell, have shown that the spatial arrangement of various molecules in the cytoplasm of the egg cell helps to determine where the head and the tail of the growing organism will be, how the front side will develop differently from the back side, and so on.
***
"We are told that the genes contain blueprints to make proteins. However, genes do not contain all the information needed to make proteins. They only specify a one imensional protein chain; the three-dimensional structure that the proteins take, which is vital for their function, is determined by the cellular environment as well. Further, the way proteins behave also varies with where they are in the cytoplasm. The genetic ‘information’, on its own, is nowhere near enough for the cell to function. (my bold)
***
"The nuanced interaction between cellular organelles, in fact, stands as a direct challenge to the coercive, top-down notion of order that a centralised factory suggests. The ‘departments’ in the ‘factory’ seem to be communicating with each other and giving each other orders without keeping the ‘head office’ in the loop.
***
"One alternative metaphor for the cell nucleus, I tentatively suggest, could be a ‘collaborative notebook’. The cell keeps this notebook, and all the cell’s components use it to keep track of their activities and help maintain the cell. The cell ‘writes’ in the notebook, writes in the ‘margins’ and ‘refers’ to its own notes. Cellular organelles sense each other’s needs and take ‘care’ of each other. While the ‘factory’ metaphor attributes control and information to the nucleus, the ‘nucleus as a collaborative notebook’ shows agency on the part of the cell. While the factory metaphor makes the cell seem obsessed with ‘production’, alternative metaphors can highlight the mutual aid among the cellular
components and the labour of maintaining the cell.
"Why do we find a lack of such metaphors in scientific discourse? Why does it seem like too much anthropomorphism to talk about organelles taking ‘care’ of each other but not when we talk about genes ‘instructing’ their underlings? Could this selectiven anthropomorphism reinforce the ideology of centralised control through the accepted scientific nmetaphors? If that is so, we will fail to capture how the cell works until we check our assumptions. If we
want to comprehend the unruly structure that is the cell, we need to change the lenses through which we view the world.
***
"The reason we find centralised functioning everywhere is not necessarily because it is
everywhere. It just appears to be everywhere because of the lens through which we view the world. When scientific narratives, using all the authority of science, project the social hierarchy onto nature, they can reinforce the same hierarchy as ‘natural’. The centralised model from cells to animal social groups suggests that everything in nature is centralised, and that centralisation works. The ‘truth’ about nature is influenced by our values, and this ‘truth’ can then play a role in doubling down and reinforcing the same social values in the world.
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"Scientists are supposed to leave their values and beliefs outside their labs. However, research in feminist science studies suggests otherwise. One does not necessarily need to be free of values to do good science, but denying their influence undermines the quality of scientific work. Instead of denial, reflecting on values and biases would help researchers steer clear of the pitfalls. Self-reflection can help scientists identify how their values are shaping their science, and think of better experimental designs that could ‘catch’ their
assumptions before they compromise results. (my bold)
***
"If we are unable to conceive of the cell, the basic unit of organisms like ours, without coercive hierarchies, we will never fully appreciate the complexity of nature. If we fail to imagine society without a centralised authority, we will find it difficult to understand or empower the oppressed. Unless we reflect on our assumptions, our science will be loaded with so many landmines it may never unravel all the mysteries of life."
Comment: a very important essay, the first part of it tells us the real complexity of the cellular genome, introducing the role of genomics in the cytoplasm with instructive discourse at every level of actions taken. Thus, the nucleus is part guide, part scorekeeper. The second part brings out a discussion of the role of personal bias. This is a major point for me. The Darwinist literature never mentions the aspects that intelligent design reports. They infer design is present is a tangential way, so as to avoid any mention of a deity. Darwinism is its own religion in its non-deist belief system.
cell genomics: human engineering of genes
by David Turell , Wednesday, May 01, 2024, 18:10 (8 days ago) @ David Turell
Using bacterial mechanisms to edit:
https://www.the-scientist.com/mega-crispr-engineering-better-immunotherapies-with-rna-e...
"Many foundational research technologies have transformed cellular therapies, moving treatments from concept to clinic. In the past decade, chimeric antigen receptors (CAR) and genome editing are two standouts that led to breakthrough CAR T cell therapies for leukemia and lymphoma. Scientists engineer these treatments with virus-mediated gene insertion ex vivo, which instructs T cells to express synthetic receptors that detect tumor-specific antigens and guide cancer cell eradication after transplantation. Researchers investigate clustered regularly interspaced short palindromic repeats (CRISPR) editing to improve CAR T cell therapies and expand their applicability to more cancer types. However, CRISPR-associated nuclease 9 (Cas9)-based genome cutting tools face unique safety and efficacy limitations due to the permanent nature of DNA editing.
"To circumvent these limitations, bioengineer Lei (Stanley) Qi and physician immunologist Crystal Mackall at Stanford University developed an RNA editing tool called multiplexed effector guide arrays (MEGA). In a study published in Cell, the team used Cas9’s cousin, Cas13, and a pooled array of guide RNAs to simultaneously edit multiple gene transcripts in primary human T cells without targeting or cutting genomic DNA. This multi-targeting method addresses an unmet need in cell therapy optimization by allowing the researchers to dynamically regulate several pathways per T cell, rather than add or ablate individual genes completely, one at a time. The researchers screened for genes that synergistically affect T cell function and knocked down redundant transcripts that drive T cell exhaustion in culture and in mice.
“'Our years of experience on gene editing at the DNA level makes us realize that this technology, while very powerful, still has some intrinsic challenges, which possibly could only be addressed if we find methods to engineer RNA,” said Qi. Among these difficulties are off-target cuts and accumulation of genomic instability through multiple DNA edits. “RNA is completely different. If we target RNA, we do not touch the DNA all, and RNA editing is reversible,” Qi explained. Another advantage is Cas13’s ability to process several unique guide RNAs from a single array, which allowed the researchers to target multiple RNA transcripts at once in the same cell.
"The research team first put MEGA through its paces in cell culture. To validate the tool, they targeted three previously established inhibitors of T cell function at once, which effectively suppressed T cell exhaustion. The research team also performed a large-scale, combinatorial screen with multiple guide arrays, uncovered new genetic regulators of T cell function, and created a drug-inducible form of MEGA for dose-responsive CAR activation. They then used MEGA to enhance CAR T cell fitness and anti-tumor activity in cancer cell co-cultures and in a mouse model of leukemia by disrupting multiple metabolic pathway components in T cells before transplantation.
“'This is a beautiful paper. It adds another dimension to what we have already been able to do with DNA-targeting CRISPR by taking advantage of this excellent RNA-targeting CRISPR platform,” said Neville Sanjana, a bioengineer at New York University who was not involved in this study. “We need a broad genome engineering toolbox. They're great tools, Cas9 and Cas13, but being able to turn genes on and off, and to do this in multiplexed ways, that's the future that we really want.'”
Comment: Suddenly humans are at a God-the-designer level of actions with the genome. The current focus is on cancer defenses, but the ethical considerations will come into play if editing is at a level which affects personality for example.