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Genetic Linkage

How Targeted Cancer Drugs Disrupt the Cell Cycle

"If you're an adult with newly diagnosed non-small cell lung cancer that's spread and tests positive for PDL1 without an abnormal EGFR your first option could be …" announces a TV ad for a pair of targeted cancer drugs, flying by so fast that I doubt many patients can grasp anything.


According to the FDA, the wording of the ads comes from a "research team of social psychologists." Science journalists might better communicate drug mechanisms to consumers.


Another way to fathom the info in cancer drug ads is to go back to high school biology and consider the cell cycle – the molecular choreography that tells a cell whether, when, and how often to divide. The cycle has offshoots, called checkpoints, which enable a cell to die by apoptosis (aka programmed cell death) or pause for a time-out. Many targeted cancer drugs interrogate cell cycle enzymes and proteins that oversee checkpoints, stopping runaway cell division.


To continue reading, go to DNA Science, where this post first appeared.

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How (and Why) the Octopus Edits its RNA

What I love most about science in general, and genetics in particular, is when new findings upend everything we thought we knew about something. That was so in 1977, when "intervening DNA sequences" – aka "introns" – were discovered to interrupt protein-encoding genes.


Sometimes, we discover new ways that organisms do things. Changing gene expression – the set of genes that are transcribed into mRNA and then translated into proteins under a particular circumstance – is how organisms rapidly respond to a challenge. For an octopus, that might be a sudden plunge in water temperature, which slows enzyme activity.


But some species control genetic responses another way – via RNA editing. Changes in one of the four types of nitrogenous bases of an mRNA alter the encoded protein in ways that alter the protein's function.


In a new report in Cell, Joshua Rosenthal of the Marine Biological Laboratory at Woods' Hole and Eli Eisenberg at Tel Aviv University describe how the cephalopods – octopi, squid, and cuttlefish – change mRNAs in ways that alter enzymes. Because the edits are in RNA, and not DNA, they are fleeting. "We're used to thinking all living things are preprogrammed from birth with a certain set of instructions. The idea the environment can influence that genetic information, as we've shown in cephalopods, is a new concept," said Rosenthal.


To continue reading, go to DNA Science, where this post first appeared.

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Topical Gene Therapy FDA-Approved for Severe Skin Disease, Dystrophic Epidermolysis Bullosa

The newest FDA-approved gene therapy treats the severe, skin-peeling condition dystrophic epidermolysis bullosa (DEB). The gene treatment has been a long time coming, but it differs from the handful of other approved gene therapies: it isn't a one-and-done.


My now decade-old book The Forever Fix: Gene Therapy and the Boy who Saved It, told the stories of children who had received one-time deliveries of working copies of genes, to compensate for their mutations. The initial gene therapies helped people with a form of inherited retinal blindness to see and children with profound immune deficiencies to survive. Today, several single-gene blood, brain, muscle, and metabolic disorders are responding to one-time infusions of a gene therapy.


The biology behind a single-gene condition suggests how a particular gene therapy would be delivered, targeted, and the effect maintained. Compared to slash-and-burn technologies like standard chemo and radiation that impact cells beyond the targeted ones, a gene therapy is both rational and tailored.


To continue reading, go to DNA Science, where this post first appeared.

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Experimental Myotonic Dystrophy Treatment Teams Monoclonal Antibody and siRNA

Myotonic dystrophy type 1 (DM1), an inherited disease affecting muscles, was one of the first described "expanding repeat" disorders. In these 50 or so conditions, symptoms may appear earlier and worsen from generation to generation, as the mutant gene grows, adding copies of a 3- or 4-base DNA sequence. For many expanding repeat disorders, forty copies seems to be a threshold, causing symptoms when crossed.


In a family with myotonic dystrophy type 1, a grandfather might experience mild weakness in his forearms, while his daughter may have more noticeable arm and leg weakness, slurred speech, and a flat facial expression. Her children have even weaker muscles that contract for too long, creating limitations like being unable to unclench a fist or release a grip.


In MD1, skeletal muscle fibers that contract for too long impair balance and coordination, called ataxia. The condition also causes cataracts, small gonads, frontal balding, fatigue, sleepiness, digestion problems, and cognitive and behavioral impairment. Life may be shortened. MD1 affects about one in 7,500 people, or more than 40,000 people in the US.


To continue reading. go to DNA Science, where this post first appeared.

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The Love Songs of W. E. B. Du Bois Celebrates Afro-Indigenous History with Genealogy – No DNA Needed

When a dear friend recommended The Love Songs of W. E. B. Du Bois, I thought the book was a tribute to the famous Black historian, sociologist, scholar, and civil rights activist. Although excerpts of his writings open chapters, the book is sweeping historical fiction – perhaps the best I've ever read.


The Love Songs of W. E. B. Du Bois, the first novel by award-winning poet Honoree Fanonne Jeffers, traces an American Black family back eight generations, through the eyes of Ailey Pearl Garfield, who untangles her own origins while doing research for a doctorate in American history. I expected something similar to Alex Haley's Roots: The Saga of an American Family from 1976, but the added dimension of a contemporary Black female perspective transcends even that classic.


To continue reading, go to DNA Science, where this post first appeared.

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Bioprospecting in Dental Tartar from Neanderthals for Novel Antibiotics and Revisiting the Discovery of Penicillin


Dense living communities of hundreds of bacterial species form biofilms on our teeth. Without careful brushing and flossing of this dental plaque, minerals seep in, hardening it into tartar. When proteins in saliva adhere tartar to tooth surfaces, a trip to the dentist is required to hack the stuff off.


Over time, the mineralized microbes of tooth tartar come to comprise a mouthful of tiny fossils, including snippets of degraded bacterial DNA. Because many antibiotic drugs come from or are based on modern bacteria, tooth tartar – aka dental calculus – from ancient people may hold genetic recipes for novel antibiotics from the past.


A team of researchers from the Leibniz Institute for Natural Product Research and Infection Biology, the Max Planck Institute for Evolutionary Anthropology, and Harvard University has reconstructed "paleogenomes" of previously unknown bacteria from the dental tartar of ancient and modern people. The work appears in Science.


To continue reading, go to DNA Science, where this post first appeared.

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Embracing Diversity, Equity, and Inclusion in Genetics Textbooks and Testing

I just finished revising the fourteenth edition of my college textbook, Human Genetics: Concepts and Applications. The first was published at the dawn of the human genome sequencing era, 1994. I'm accustomed to incorporating feedback from professors and updating content every 2 or 3 years, but this revision threw something new at me: the publisher asking all textbook authors to strive for DEI:


DIVERSITY: depicting various identities and differences
EQUITY: providing fair and equitable access and opportunity
INCLUSION: respecting and welcoming all individuals


Ironically, just as I finished the new edition, the American College of Medical Genetics and Genomics (ACMG) published a "points to consider" statement in Genetics in Medicine, "Clinical, technical, and environmental biases influencing equitable access to clinical genetics/genomics testing."


The subtext: Textbooks shouldn't use only or mostly photos of white people, and interpreting DNA test results shouldn't be based on research done mostly on white people.



To continue reading, go to DNA Science, where this post first appeared.

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Seventy Years Since Watson and Crick’s Paper Introduced DNA: A Brief History of the Molecule of Life

On April 25, 1953, "MOLECULAR STRUCTURE OF NUCLEIC ACIDS: A Structure for Deoxyribose Nucleic Acid" was published in Nature. J. D. Watson and F. H. C. Crick's work was a brilliant deduction based on the experimental findings of many others.


DNA is a sleek double helix, with "rungs" consisting of a purine base paired with a smaller pyrimidine base: adenine (A) with thymine (T) and guanine (G) with cytosine (C). Hydrogen bonds link the pairs, individually weak but in large numbers powerfully strong, like a zipper.


"It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material," Watson and Crick wrote near the end of the one-page article, planting the seeds for modern biotechnologies like recombinant DNA, transgenic organisms, gene silencing and therapy, and CRISPR gene editing.


The April 1953 paper was groundbreaking yet a bit of a tease, a "save-the-date" of sorts to announce the discovery and briefly describe the structure, for much confirming work needed to be done. Six months later, Francis Crick eloquently laid out the clues in "Structure of the Hereditary Material," in a Scientific American volume, "Genetics": "A genetic material must carry out two jobs: duplicate itself and control the development of the rest of the cell in a specific way." DNA encodes amino acid sequences comprising proteins, which impart traits.


On this anniversary of the famous paper, DNA Science revisits the discoveries that catalyzed Watson and Crick's deduction of how a molecule could carry and transmit genetic information.


To continue reading, go to DNA Science, where this post first appeared.

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