Tag: mutation

Bioethics News

The Scariest Part of Genetic Testing?

July 31, 2017

Be the first to like.
Share

AnneMarie Ciccarella, a fast-talking 57-year-old brunette with a more than a hint of a New York accent, thought she knew a lot about breast cancer. Her mother was diagnosed with the disease in 1987, and several other female relatives also developed it. When doctors found a suspicious lump in one of her breasts that turned out to be cancer, she immediately sought out testing to look for mutations in the two BRCA genes, which between them account for around 20 per cent of families with a strong history of breast cancer.

Ciccarella assumed her results would be positive. They weren’t. Instead, they identified only what’s known as a variant of unknown or uncertain significance (VUS) in both BRCA1 and BRCA2. Unlike pathogenic mutations that are known to cause disease or benign ones that don’t, these genetic variations just aren’t understood enough to know if they are involved or not.

“I thought you could have a mutated gene or not, and with all the cancer in my family, I believed I would carry a mutation. I didn’t know there was this huge third category,” she says. “I got no information – it felt like a huge waste of blood to get a giant question mark.”

Thousands of people have had their BRCA genes tested for increased genetic susceptibility to breast, ovarian, prostate and other cancers. About 5% have learned that they carry a VUS. That number is even higher for other genes: in one study, almost 20% of genetic tests returned a VUS result.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Snapshots of Life: Muscling in on Development

Credit: Gabrielle Kardon, University of Utah, Salt Lake City

Twice a week, I do an hour of weight training to maintain muscle strength and tone. Millions of Americans do the same, and there’s always a lot of attention paid to those upper arm muscles—the biceps and triceps. Less appreciated is another arm muscle that pumps right along during workouts: the brachialis. This muscle—located under the biceps—helps your elbow flex when you are doing all kinds of things, whether curling a 50-pound barbell or just grabbing a bag of groceries or your luggage out of the car.

Now, scientific studies of the triceps and brachialis are providing important clues about how the body’s 40 different types of limb muscles assume their distinct identities during development [1]. In these images from the NIH-supported lab of Gabrielle Kardon at the University of Utah, Salt Lake City, you see the developing forelimb of a healthy mouse strain (top) compared to that of a mutant mouse strain with a stiff, abnormal gait (bottom).

In each strain, you see the lateral triceps and brachialis muscles (purple), other types of muscle (red) and tendons (green). However, in the healthy mouse, the lateral triceps and brachialis muscles are distinct, which gives the forelimb its flexibility; while in the mutant mouse, the two muscles are fused and indistinct, limiting the forelimb’s function.

The mice with the abnormal lateral triceps and brachialis have a mutation in a gene called Tbx3, which codes for a transcription factor that switches other genes off and on. If you follow this blog, you know that a lot of exciting research is currently focused on transcription factors, including how precise combinations of transcription factors can turn skin cells into blood stem cells or be used to make neurons.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics News

Genetically Engineering Nature Will Be Way More Complicated Than We Thought

July 20, 2017

Be the first to like.
Share

For more than half a century, scientists have dreamed of harnessing an odd quirk of nature— “selfish genes,” which bypass the normal 50/50 laws of inheritance and force their way into offspring—to engineer entire species. A few years ago, the advent of the CRISPR-Cas9 gene editing technology turned this science fictional concept into a dazzling potential reality, called a gene drive. But after all the hype, and fear of the technology’s misuse, scientists are now questioning whether gene drives will work at all.

Gene drive is a molecular technology that forces an edited gene to be passed along into all of an organism’s offspring, overriding nature’s 50/50 inheritance mix. The first human-engineered gene drive was only demonstrated in fruit flies in 2015, but scientists were soon talking about using gene drives to exterminate invasive pests or kill off throngs of malarial mosquitoes.

But soon after, other researchers demonstrated that as an infertility mutation in female mosquitoes was successfully passed on to offspring over many generations, resistance emerged, allowing some mosquitoes to avoid inheriting the mutation. Just as bacteria can develop resistance to antibiotics, wild populations can develop resistance to modifications aimed at destroying them. Gene drive, dead.

… Read More

Image: By DBCLS 統合TV, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=55175302

Be the first to like.
Share

Gizmodo

Tags: , , , , ,

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Another Milestone in the Cystic Fibrosis Journey

Caption: Two-year-old Avalyn is among the cystic fibrosis patients who may be helped by targeted drugs.
Credit: Brittany Mahoney

As NIH Director, I often hear stories of how people with serious diseases—from arthritis to Zika infection—are benefitting from the transformational power of NIH’s investments in basic science. Today, I’d like to share one such advance that I find particularly exciting: news that a combination of three molecularly targeted drugs may finally make it possible to treat the vast majority of patients with cystic fibrosis (CF), our nation’s most common genetic disease.

First, a bit of history! The first genetic mutation that causes CF was discovered by a collaborative effort between my own research lab at the University of Michigan, Ann Arbor, and colleagues at the Hospital for Sick Children in Toronto—more than 25 years ago [1]. Years of hard work, supported by the National Institutes of Health and the Cystic Fibrosis Foundation, painstakingly worked out the normal function of the protein that is altered in CF, called the cystic fibrosis transmembrane regulator (CFTR). Very recently new technologies, such as cryo-EM, have given researchers the ability to map the exact structure of the protein involved in CF.

Among the tens of thousands of CF patients who stand to benefit from the next generation of targeted drugs is little Avalyn Mahoney of Cardiff by the Sea, CA. Just a few decades ago, a kid like Avalyn—who just turned 2 last month—probably wouldn’t have made it beyond her teens. But today the outlook is far brighter for her and so many others, thanks to recent advances that build upon NIH-supported basic research.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics News

The Uncertain Future of Genetic Testing

July 18, 2017

Be the first to like.
Share

AnneMarie Ciccarella, a fast-talking 57-year-old brunette with a more than a hint of a New York accent, thought she knew a lot about breast cancer. Her mother was diagnosed with the disease in 1987, and several other female relatives also developed it. When doctors found a suspicious lump in one of her breasts that turned out to be cancer, she immediately sought out testing to look for mutations in the two BRCA genes, which between them account for around 20 per cent of families with a strong history of breast cancer.

Ciccarella assumed her results would be positive. They weren’t. Instead, they identified only what’s known as a variant of unknown or uncertain significance (VUS) in both BRCA1 and BRCA2. Unlike pathogenic mutations that are known to cause disease or benign ones that don’t, these genetic variations just aren’t understood enough to know if they are involved or not.

“I thought you could have a mutated gene or not, and with all the cancer in my family, I believed I would carry a mutation. I didn’t know there was this huge third category,” she says. “I got no information – it felt like a huge waste of blood to get a giant question mark.”

… Read More

Image: © Catherine Losing

Be the first to like.
Share

Mosaic

Tags: , , , , , ,

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics News

Charlie Gard: Judge Allows Parents of Terminally Ill Infant to Consult American Doctor

A London High Court judge has ruled that terminally ill infant Charlie Gard can be examined by a doctor from the United States, amidst his parents’ battle to pursue experimental therapy abroad instead of the terminated life support prescribed by his British doctors. The 11-month-old infant was born with mitochondrial DNA depletion syndrome, a rare genetic condition that causes muscular degeneration, respiratory failure and motor skill decline. Most children with the disease fail to live past early childhood; Charlie’s doctors have stated that it will eventually cause his death.

In Britain, courts rather than parents dictate children’s best interests in the face of opposing medical advice. Though Charlie’s doctors at Great Ormond Street Hospital were granted court permission in April to remove the infant from life support, Charlie’s parents’ lawyers have since been advocating for the right to maintain life support and pursue alternative therapy despite his doctors’ insistence on the low likelihood of the proposed therapy’s effectiveness, and the high likelihood of lifelong pain with the disease.

The high-profile case has attracted the attention of President Trump, Pope Francis, and anti-abortion groups, all of whom have vocalized their support for Charlie’s parents interests. Several notable medical authorities and colleges have expressed their support for the hospital’s consensus or condemned the politicization of the case. 

Following the judge’s novel permission, a New York-Presbyterian Hospital/Columbia University Medical Center neurologist will evaluate the potential effectiveness of a nucleoside therapy that has successfully prolonged the lifespan of similarly ill patients, though such patients’ conditions have owed to a mutation distinct from Charlie’s.

The case pivots on several bioethical questions that are particularly acute in the context of terminal illness. Where should the law draw the line between parental authority and medical authority? Whose preferences speak for a voiceless patient?

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Medical Decision-Making In the Tragic Life of Charlie Gard

by Craig Klugman, Ph.D.

On Friday, Charlie Gard is scheduled to have his life support discontinued. Charlie Gard is an 11-month-old baby born with RRM2B encephalomyopathic mitochondrial DNA depletion syndrome—a rare genetic disorder with no cure. Those with the mutation live at most into early childhood with a multitude of life threatening conditions (lactic acidosis, ammonia build up, heart abnormalities). Charlie suffers from seizures, cannot independently breathe. He is also blind and deaf. Great Ormond Street Hospital (London) and Charlie’s doctors believe there is nothing more medically that can be done to benefit him and requested to remove his life sustaining treatment. Connie Yates and Chris Gard, his parents, believe that there is a chance of a miraculous cure in an experimental nucleoside treatment in the United States, even though the technique has never been tried for this condition. In the words of the unnamed U.S. specialist, nucleoside treatment would provide a “small hope” for helping

The case has gone through the British courts and the European Court of Human Rights, all of which agreed with the hospital. They declared that prolonging Charlie’s life would be “inhumane and unreasonable.” The courts believed that the experimental treatment in the US would be futile and could cause Charlie much suffering. The European Court ruled on July 4 that life support can be removed on Friday.

Under British law, when parents and physicians disagree on treatment, the courts normally intervene and are the final decision-makers. Unlike in the US, the highest value is the best interest (benefit) to the child rather than parental rights to make decisions for their child.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Huntington’s Disease: Gene Editing Shows Promise in Mouse Studies

My father was a folk song collector, and I grew up listening to the music of Woody Guthrie. On July 14th, folk music enthusiasts will be celebrating the 105th anniversary of Guthrie’s birth in his hometown of Okemah, OK. Besides being renowned for writing “This Land is Your Land” and other folk classics, Guthrie has another more tragic claim to fame: he provided the world with a glimpse at the devastation caused by a rare, inherited neurological disorder called Huntington’s disease.

When Guthrie died from complications of Huntington’s a half-century ago, the disease was untreatable. Sadly, it still is. But years of basic science advances, combined with the promise of innovative gene editing systems such as CRISPR/Cas9, are providing renewed hope that we will someday be able to treat or even cure Huntington’s disease, along with many other inherited disorders.

My own lab was part of a collaboration of seven groups that identified the Huntington’s disease gene back in 1993. Huntington’s disease occurs when a person inherits from one parent a mutant copy of the huntingtin (HTT) gene that contains extra repetitions, or a “stutter,” of three letters (CAG) in DNA’s four-letter code. This stutter leads to production of a misfolded protein that is toxic to the brain’s neurons, triggering a degenerative process that, over time, leads to mood swings, slurred speech, uncontrolled movements, and, eventually, death. In a new study involving a mouse model of Huntington’s disease, researchers were able to stop the production of the abnormal protein by using CRISPR tools to cut the stutter out of the mutant gene.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Skin Health: New Insights from a Rare Disease

Courtesy of Keith Choate, Yale University School of Medicine, New Haven, CT

Skin is the largest organ in the human body, yet we often take for granted all of the wonderful things that it does to keep us healthy. That’s not the case for people who suffer from a group of rare, scale-forming skin disorders known as ichthyoses, which are named after “ichthys,” the Greek word for fish.

Each year, more than 16,000 babies around the world are born with ichthyoses [1], and researchers have identified so far more than 50 gene mutations responsible for various types and subtypes of the disease. Now, an NIH-funded research team has found yet another genetic cause—and this one has important implications for treatment. The new discovery implicates misspellings in a gene that codes for an enzyme playing a critical role in building ceramide—fatty molecules that help keep the skin moist. Without healthy ceramide, the skin develops dry, scale-like plaques that can leave people vulnerable to infections and other health problems.

Two patients with this newly characterized form of ichthyosis were treated with isotretinoin (Accutane), a common prescription acne medication, and found that their symptoms resolved almost entirely. Together, the findings suggest that isotretinoin works not only by encouraging the rapid turnover of skin cells but also by spurring patients’ skin to boost ceramide production, albeit through a different biological pathway.

Keith Choate at Yale University School of Medicine, New Haven, CT, has dedicated his career to studying ichthyoses. That includes working with his team to recruit more than 800 affected families into the National Registry for Ichthyosis and Related Skin Disorders, now housed at Yale.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics News

CRISPR used in viable human embryos and germline genetic modification. An ethical apprach

From an ethical point of view, the use and destruction of human embryos, members of our species and worthy of full dignity is completely unacceptable and, it should be noted,  these experiments involve genetic modification of the germline, the safety of which is still far from being guaranteed

On 9th March this year, New Scientist reported the first results obtained by a team of scientists in China who had applied the CRISPR gene editing technique in normal human embryos.

This technique has already been applied in China on two occasions in non-viable human embryos, which have a limited capacity for development and so would be unable to result in the birth of a child, even if implanted in a woman. The efficacy of the technique was very low in both studies, giving rise to numerous off-target mutations (in parts of the genome where nothing should have happened).

In England, gene editing in embryos has already been approved, which in theory will use embryos left over from in-vitro fertilisation treatments. However, the results of this research have yet to be published.

Details of technique applied

In the aforementioned study published in New Scientist, the technique was applied to six embryos with some mutation in their DNA (they had been created purposely to have these mutations, fertilising eggs with sperm from men who had a hereditary disease). The genome was correctly repaired in only one of these embryos, but in another two, the repair occurred only in some cells. In a fourth embryo, CRISPR introduced an undesired mutation, while in another two, the technique did not work.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.