Tag: phenotype

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 Blogs

Hard lessons: learning from the Charlie Gard case

by Dominic Wilkinson and Julian Savulescu

 

On the 24th July 2017, the long-running, deeply tragic and emotionally fraught case of Charlie Gard reached its sad conclusion (Box 1). Following further medical assessment of the infant, Charlie’s parents and doctors finally reached agreement that continuing medical treatment was not in Charlie’s best interests. It is expected that life support will be withdrawn in the days ahead.

Over the course of multiple hearings at different levels of the court in both London and Strasbourg, the Charlie Gard case has raised a number of vexed ethical questions (Box 2). The important role of practical ethics in cases like this is to help clarify the key concepts, identify central ethical questions, separate them from questions of scientific fact and subject arguments to critical scrutiny. We have disagreed about the right course of action for Charlie Gard,1 2 but we agree on the key ethical principles as well as the role of ethical analysis and the importance of robust and informed debate. Ethics is not about personal opinion – but about argument, reasons, and rational reflection. While the lasting ramifications of the case for medical treatment decisions in children are yet to become apparent, we here outline some of the potential lessons.

1. Parents’ role in decision-making for children: We need to clarify harm

Much of the media attention to the Gard case has focussed on the rights of parents in decision-making for children, and whether the intervention of the courts in this case means that doctors frequently overrule parents in the UK.

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 biological status of the early human embryo. When does human life begins?

“Those who argue that that embryo can be destroyed with impunity will have to prove that this newly created life is not human. And no-one, to the best of our knowledge, has yet been able to do so.”

Introduction

In order to determine the nature of the human embryo, we need to know its biological, anthropological, philosophical, and even its legal reality. In our opinion, however, the anthropological, philosophical and legal reality of the embryo — the basis of its human rights — must be built upon its biological reality (see also HERE).

Consequently, one of the most widely debated topics in the field of bioethics is to determine when human life begins, and particularly to define the biological status of the human embryo, particularly the early embryo, i.e. from impregnation of the egg by the sperm until its implantation in the maternal endometrium.

Irrespective of this, though, this need to define when human life begins is also due to the fact that during the early stages of human life — approximately during its first 14 days — this young embryo is subject to extensive and diverse threats that, in many cases, lead to its destruction (see HERE).

These threats affect embryos created naturally, mainly through the use of drugs or technical procedures used in the control of human fertility that act via an anti-implantation mechanism, especially intrauterine devices (as DIU); this is also the case of drugs used in emergency contraception, such as levonorgestrel or ulipristal-based drugs (see HERE), because both act via an anti-implantation mechanism in 50% of cases.

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 biological status of the early human embryo. When does human life begins?

“Those who argue that that embryo can be destroyed with impunity will have to prove that this newly created life is not human. And no-one, to the best of our knowledge, has yet been able to do so.”

Introduction

In order to determine the nature of the human embryo, we need to know its biological, anthropological, philosophical, and even its legal reality. In our opinion, however, the anthropological, philosophical and legal reality of the embryo — the basis of its human rights — must be built upon its biological reality (see also HERE).

Consequently, one of the most widely debated topics in the field of bioethics is to determine when human life begins, and particularly to define the biological status of the human embryo, particularly the early embryo, i.e. from impregnation of the egg by the sperm until its implantation in the maternal endometrium.

Irrespective of this, though, this need to define when human life begins (see our article  is also due to the fact that during the early stages of human life — approximately during its first 14 days — this young embryo is subject to extensive and diverse threats that, in many cases, lead to its destruction (see HERE).

These threats affect embryos created naturally, mainly through the use of drugs or technical procedures used in the control of human fertility that act via an anti-implantation mechanism, especially intrauterine devices (as DIU); this is also the case of drugs used in emergency contraception, such as levonorgestrel or ulipristal-based drugs (see HERE), because both act via an anti-implantation mechanism in most of the time.

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

Dueling BRCA Databases: What About the Patient?

The news release Monday morning grabbed my attention:

“Study finds wide gap in quality of BRCA1/2 variant
classification between Myriad Genetics and a common public database.”

Myriad Genetics had been exclusively providing tests, for
$3000+ a pop for full BRCA gene sequencing, for 17 years before the Supreme
Court invalidated key gene patents back in 2013. Since the ruling a dozen or so
competitors have been offering tests for much lower prices. Meanwhile, Myriad
has amassed a far deeper database than anyone else, having been in the business
so much longer. And it’s proprietary.

CLASSIFYING GENE VARIANTS

(NHGRI)

Public databases of variants of health-related genes have
been around for years too. The best known, ClinVar, collects and curates data
from the biomedical literature, expert panels, reports at meetings, testing
laboratories, and individual researchers, without access to Myriad’s database.
ClinVar uses several standard technical criteria to classify variants as
“pathogenic,” “benign,” or “of uncertain significance.” (“Likely pathogenic”
and “likely benign” were used more in the past.)

ClinVar lists 5400 variants just for BRCA1. The criteria
come from population statistics, how a particular mutation alters the encoded
protein, effects on the phenotype (symptoms), and other information.
Bioinformatics meets biochemistry to predict susceptibility. The BRCA1 protein
acts as a hub of sorts where many other proteins that control DNA repair
gather. DNA Science discussed the genes behind breast and ovarian cancers here.

As gene sequences accumulate in the databases and troops of
geneticists and genetic counselors annotate them, the proportion of pathogenic
and benign entries will increase as that of the unsettling “variants of
uncertain significance” — VUS — will decrease.

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

Dueling BRCA Databases: What About the Patient?

The news release Monday morning grabbed my attention:

“Study finds wide gap in quality of BRCA1/2 variant
classification between Myriad Genetics and a common public database.”

Myriad Genetics had been exclusively providing tests, for
$3000+ a pop for full BRCA gene sequencing, for 17 years before the Supreme
Court invalidated key gene patents back in 2013. Since the ruling a dozen or so
competitors have been offering tests for much lower prices. Meanwhile, Myriad
has amassed a far deeper database than anyone else, having been in the business
so much longer. And it’s proprietary.

CLASSIFYING GENE VARIANTS

(NHGRI)

Public databases of variants of health-related genes have
been around for years too. The best known, ClinVar, collects and curates data
from the biomedical literature, expert panels, reports at meetings, testing
laboratories, and individual researchers, without access to Myriad’s database.
ClinVar uses several standard technical criteria to classify variants as
“pathogenic,” “benign,” or “of uncertain significance.” (“Likely pathogenic”
and “likely benign” were used more in the past.)

ClinVar lists 5400 variants just for BRCA1. The criteria
come from population statistics, how a particular mutation alters the encoded
protein, effects on the phenotype (symptoms), and other information.
Bioinformatics meets biochemistry to predict susceptibility. The BRCA1 protein
acts as a hub of sorts where many other proteins that control DNA repair
gather. DNA Science discussed the genes behind breast and ovarian cancers here.

As gene sequences accumulate in the databases and troops of
geneticists and genetic counselors annotate them, the proportion of pathogenic
and benign entries will increase as that of the unsettling “variants of
uncertain significance” — VUS — will decrease.

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

Creative Minds: The Worm Tissue-ome Teaches Developmental Biology for Us All

Caption: An adult Caenorhabditis elegans, 5 days
Credit: Coleen Murphy, Princeton University, Princeton, NJ

In the nearly 40 years since Nobel Prize-winning scientist Sydney Brenner proposed using a tiny, transparent soil worm called Caenorhabditis elegans as a model organism for biomedical research, C. elegans has become one of the most-studied organisms on the planet. Researchers have determined that C. elegans has exactly 959 cells, 302 of which are neurons. They have sequenced and annotated its genome, developed an impressive array of tools to study its DNA, and characterized the development of many of its tissues.

But what researchers still don’t know is exactly how all of these parts work together to coordinate this little worm’s response to changes in nutrition, environment, health status, and even the aging process. To learn more, 2015 NIH Director’s Pioneer Award winner Coleen Murphy of Princeton University, Princeton, NJ, has set out to analyze which genes are active, or transcribed, in each of the major tissues of adult C. elegans, building the framework for what’s been dubbed the C. elegans “tissue-ome.”

Although C. elegans and humans diverged from a common ancestor more than 300 million years ago, they share about 40 percent of their protein-coding DNA in common. These genetic similarities, along with the ease of manipulating the C. elegans genome and its relatively short life span, has made it a great system for unraveling the molecular mechanisms that underlie development, behavior, and aging in a multi-cellular organism.

However, researchers have run into difficulties when they’ve attempted to conduct cell-specific analyses of gene transcription in various types of C.

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

Of Mice and Men: Study Pinpoints Genes Essential for Life

Many people probably think of mice as unwanted household pests. But over more than a century, mice have proven to be incredibly valuable in medical research. One of many examples is how studies in mice are now helping researchers understand how mammalian genomes work, including the human genome. Scientists have spent decades inactivating, or “knocking out,” individual genes in laboratory mice to learn which tissues or organs are affected when a specific gene is out of order, providing valuable clues about its function.

More than a decade ago, NIH initiated a project called KOMP—the Knockout Mouse Project [1]. The goal was to use homologous recombination (exchange of similar or identical DNA) in embryonic stem cells from a standard mouse strain to knock out all of the mouse protein-coding genes. That work has led to wide availability of such cell lines to investigators with interest in specific genes, saving time and money. But it’s one thing to have a cell line with the gene knocked out, it’s even more interesting (and challenging) to determine the phenotype, or observable characteristics, of each knockout. To speed up that process in a scientifically rigorous and systematic manner, NIH and other research funding agencies teamed to launch an international research consortium to turn those embryonic stem cells into mice, and ultimately to catalogue the functions of the roughly 20,000 genes that mice and humans share. The consortium has just released an analysis of the phenotypes of the first 1,751 new lines of unique “knockout mice” with much more to come in the months ahead.

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

The social framing of diagnoses and empathetic listening by Aaron J. Jackson

The account that follows depicts a visit with my neurologist. The visit was one of many within a five-month period of navigating various medical spaces to get to the bottom of the illness that was ailing me. It speaks to the systemic and cultural dimensions of illness that threaten to undermine medical understandings, diagnosis and treatment, alongside personal narratives of suffering.

I need a body to live and my current one is harbouring a ghost. To medical professionals, its idiopathic guise makes it seemingly innocuous. But it’s not. How do I know? Because it’s already stripped me of valuable time with my children. Because I’m the one embodying these curious ailments. My muscles twitch. My hands ache. There’s an old guy sitting to my right in the waiting room, plaid shirt and jeans, who’s called in for his appointment. He has more bounce in his step than I do. I feel like I’m living an 80’s body swap comedy. But my body hasn’t been swapped. It’s the same white body I’ve always had. It just feels different. I’m envious of his seventy-five-year-old vitality.

Finally, Professor Mead – let’s call him that for purposes of anonymity – calls my name. The office atmosphere feels stiff and lifeless. He tells me to lie down on the bed. My shorts and t-shirt provide unencumbered access to my body’s flesh. A needle electrode is inserted into my muscles to record the electrical activity at rest. The monitor declares the electrodes findings through a series of wavy and spiky lines.

Small fasciculations are recorded in my left foot.

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

Hacking CRISPR: Patents, Gene Therapy & Embryos

Bruiseless bananas, vegan cats, pig-to-human transplants, and super-muscular dogs: can you tell the real CRISPR projects from fake ones? It’s getting harder these days, as the latest generation of “gene editing” tools are not only (relatively) quicker, cheaper, and easier than any previous genetic engineering method, but have become “probably the fastest-spreading technology in the history of biology.” As it spreads, researchers the world over are discovering new hacks, complexities, and limitations for CRISPR. Here’s a round-up of recent developments in this booming arena.  

Trending globally: gene editing experiments with human embryos

On April 8, news broke that the second paper documenting CRISPR experiments in human embryos had been published. Researchers at Guangzhou Medical University sought to enhance nonviable embryos leftover from IVF with a naturally occurring mutation that confers HIV resistance: CCR5Δ32.


(Image via Wikimedia: Guangzhou Circle)

The experiments were largely unsuccessful: only 4 of 26 embryos wound up with a copy of the desired mutation, and none had the two copies that would be needed to resist the virus. Mosaicism was also a problem. A year prior in April 2015, the first research using CRISPR in tripronuclear human zygotes was reported by a team at Sun Yat-sen University in the obscure journal Protein & Cell, after Nature and Science turned it down. This second paper was reported in “an obscure reproductive journal” published by the American Society of Reproductive Medicine (the same body that releases non-enforceable guidelines into the void of any regulation over assisted reproductive technologies in the United States).

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.