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Glenn Nichols, surrounded by his hospice team. The author is in yellow.

Genetic Linkage

When a Bad Animal Model is Good: Cystic Fibrosis

January 29, 2016

Tags: cystic fibrosis, animal models, Kalydeco

(NHGRI)
A “good” animal model is one that has the same symptoms of a disease that we do, right?

Not always. Sometimes we can actually learn more when an animal is not a perfect model; their good health can reveal new points of intervention. That’s the case for cystic fibrosis, according to findings published in Science. Mice with cystic fibrosis (CF) that do not develop airway infections hold a chemical clue to how people with CF might do the same. (more…)

When Mutation Counters Infection: From Sickle Cell to Ebola

November 19, 2014

Tags: balanced polymorphism, Ebola, sickle cell, cystic fibrosis, natural selection, Niemann-Pick C1, PKU, genetic disease, prions, mad cow disease

Balanced polymorphism retains mutant genes in populations when they protect against other conditions.
While pharmaceutical companies focus on drug discovery for Ebola virus disease, a powerful clue is coming from a rare “Jewish genetic disease” that destroys the brain. People with Niemann-Pick C1 disease can’t get Ebola, adding to the list of disease pairs that arise from a fascinating form of natural selection.

Balanced polymorphism, aka heterozygote advantage, is a terrific illustration of ongoing evolution. And it pits the human body against all sorts of invaders – prions, viruses, bacteria, protozoa, and fungi. (more…)

Medical Success Stories: From Cystic Fibrosis to Diabetes

September 4, 2014

Tags: cystic fibrosis, type 2 diabetes, gastric bypass, Leber congenital amaurosis, gene therapy, A1C, natural history study, adenosine deaminase deficiency, SCID-X1

The many guises of CF.
A skinny little boy, with mocha skin and curly black hair, lived in the apartment building next door when I was growing up in Brooklyn in the 1960s. He didn’t live long enough to go to kindergarten. He had cystic fibrosis.

Today’s tots with CF face a far brighter future. A recent report in the Annals of Internal Medicine applied trends in survival from 2000 to 2010 to project life expectancy for children diagnosed in 2010: 37 years for girls and 40 years for boys. (The difference may reflect hormones or the extra creatinine in the more muscular male of the species.) Factoring in the current rate of treatment improvements gives a soaring median survival of 54 years for women and 58 years for men when those kids grow up! (more…)

DNA Day: 20 Years of Writing a Human Genetics Textbook

April 19, 2013

Tags: human genome, DNA, genetics, Gregor Mendel, cystic fibrosis, textbook

10 editions of my textbook chronicle the evolution of genomics
This month we celebrate the DNA anniversaries: unveiling of DNA’s structure in 1953, and the human genome sequence in 2003.

From now until DNA Day, April 25, bloggers will be worshipping the human genome. Nature will offer podcasts (“PastCasts”) and last week, Eric Green, director of the National Human Genome Research Institute, spoke to reporters, summarizing the “quantitative advances since the human genome project.”

It’s also the 20th anniversary of my non-science majors textbook, Human Genetics: Concepts and Applications. Writing the 10 editions has given me a panoramic view of the birth of genomics different from those of researchers, physicians, and journalists. Here are a few observations on the evolution of genetics to genomics, as I begin the next edition. (more…)

Hidden Meanings in Our Genomes – And What To Do With Mendel

August 20, 2012

Tags: human genome, exome, linkage, mutation, American Journal of Human Genetics, Human Genetics: Concepts and Applications, DNA, Huntington disease, cystic fibrosis, osteogenesis imperfecta, ALS, essential tremor, Gregor Mendel, Ricki Lewis

Gregor Mendel: should he stay or should he go (in textbooks)? (National Library of Medicine)
Summer reading for most people means magazines, novels, and similar escapist fare, but for me, it’s the American Journal of Human Genetics (AJHG). Perusing the table of contents of the current issue tells me what’s dominating this post-genomic era: information beyond the obvious, like a subtext hidden within the sequences of A, (more…)

Gene Therapy and the 10,000-Hour Rule

January 4, 2012

Tags: Gene therapy, The Forever Fix: Gene Therapy and the Boy Who Saved It, Malcolm Gladwell, 10, 000-hour rule, Ashi DeSilva, Biology Digest, William French Anderson, Donald Kohn, ADA deficiency, Leber congenital amaurosis, Kalydeco, ivacaftor, Vertex Pharmaceuticals, cystic fibrosis, severe combined immune deficiency, Ricki Lewis, Corey Haas, Jesse Gelsinger

“Breakthroughs” in biomedicine are rarely that – they typically rest on a decade or more of experiments. Consider gene therapy.

I just unearthed an article from the December 1990 issue of Biology Digest, "Gene Therapy." I wrote it a mere two months after the very first gene therapy experiment, the much-publicized case of 4-year-old Ashi DeSilva, (more…)

Genetic Sense and Nonsense

June 20, 2011

Tags: RNA modification, nonsense mutation, Cystic Fibrosis Foundation, World Federation of Hemophilia, Muscular Dystrophy Association, International Rett Syndrome Foundation, misfolded protein, Ricki Lewis, University of Rochester, targeted pseudouridylation, hemophilia, cystic fibrosis, Duchenne muscular dystrophy, Rett syndrome, genetic code, nonsense read-through, gentamicin, aminoglycoside antibiotics, progressive supranuclear palsy, PSP, Perelman School of Medicine, University of Pennsylvania, Nature, Gerard Schellenberg, Yi-Tao Yu

Genetic Linkage connects new research findings, based on the wiring of my brain after years of writing a human genetics textbook and lots of articles. Here, the linking of sense and nonsense.

The excitement of genetic research these days is when genome sweeps of people sharing a disease reveal possible responsible genes. That’s what happened when researchers at the Perelman School of Medicine at the University of Pennsylvania looked at genomic landmarks among 1,114 brains from people who had died of progressive supranuclear palsy (PSP), a form of dementia that affects movement.

PSP is a “tauopathy,” in which the dark gummy protein tau, of Alzheimer’s fame, smothers the brain. Compared to unaffected brains, the PSP brains differ in three genome neighborhoods, harboring three new
candidate genes that make sense: one impairs brain cells’ abilities to untangle misfolded proteins, another boots misfolded proteins out of cells, and a third may help wrap brain cells in insulating myelin. New drug targets!

In genetics nonsense is important too. A nonsense mutation inserts a “stop” right smack in the middle of a gene, like a period in the middle of a sentence. It shortens the encoded protein, causing some 1800 diseases. Ignoring a nonsense mutation can restore function, like saving a sentence truncated by an errant period with a stroke of white-out. The idea isn’t new – researchers discovered that bacteria can read-through nonsense mutations in the 1960s, and that certain common antibiotics, such as gentamicin, enable cells to read-through nonsense. Those drugs may provide old-fashioned (cheap) treatments for genetic diseases such as Rett syndrome. Alas, early attempts at treating cystic fibrosis, hemophilia, and Duchenne muscular dystrophy by suppressing nonsense mutations didn’t work because the antibiotic doses necessary would be toxic.

Now Yi-Tao Yu and co-workers at the University of Rochester report in Nature that they have invented a way to mimic antibiotic-mediated nonsense suppression. They’ve used a synthetic RNA to chemically tweak nonsense codons so that they are instead read as bona fide amino acids, in essence altering the genetic code. So far this approach, dubbed RNA modification, works in a test tube. But carefully-directed nonsense suppression holds enormous promise for correcting many genetic diseases. Stay tuned!

instruction
Project to engage students in helping families with rare genetic diseases
Book Club Reader's Guide
Many challenging questions to stimulate thought and discussion.
Instructor's Guide
38 discussion questions to get students thinking and talking about gene therapy, including the science, ethical issues, and the drug approval process.
Narrative science
The Forever Fix is the uplifting true story of 8-year-old Corey Haas, who was cured of hereditary blindness just 4 days after gene therapy.
College Textbooks
A spectacularly-illustrated, clearly written human anatomy and physiology textbook, used in pre-health profession programs throughout the U.S.
A highly engaging, clearly written, beautifully illustrated introduction to the science of human genetics for the non-scientist. Now in its 11th edition, 12th to be published in September 2018.
Nonfiction
An ideal starting point for anyone who wants to know more about genes, DNA, genomes, and the genetic ties that bind us all.

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