Tag: human genome

Uncategorized

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.

Uncategorized

Ten years since the discovery of iPS cells. The current state of their clinical application

Photo Neurons derived from human iPS cells Stem Cells Australia

Background

Few biomedical discoveries in recent decades have raised so many expectations as the achievement of adult reprogrammed cells or induced pluripotent stem (iPS) cells.1

Pluripotent cells are obtained from adult cells from various tissues that, after genetic reprogramming, can dedifferentiate to a pluripotency state similar to that of embryonic cells, which allows for subsequent differentiation into different cell strains.2,3

In our opinion, this discovery is relevant not only to biomedical issues but also to ethical ones, given that iPS cells could replace human embryonic stem cells (see HERE) – whose use raises numerous ethical problems – in biomedical experimentation and in clinical practice. However, after the last 10 years, the use of iPS cells has still not been clarified. A number of expectations have been met, but other mainly clinical expectations are still far from being achieved.

Current research limitations with iPS cells

There is a notable low efficacy in the techniques employed for obtaining a sufficient proportion of iPS cells, which represents a difficulty in its clinical application.4  Another limitation is the incomplete reprogramming, which depends on the type of cell employed,5 and the problems of mutagenesis resulting from inserting exogenous transcription-factor coding genes, which can cause tumors in the employed cells used.6 Recent studies aim to mitigate this effect.7 A clinical trial for treating macular degeneration with retinal pigment epithelium cells derived from autologously obtained iPS cells has recently been halted.8 After an initially successful experience with the first treated patient, the genetic sequencing of the iPS cells obtained from the second patient revealed mutations in 3 different genes, one of which was classified as oncogene in the Catalogue of Somatic Mutations in Cancer.

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.

Uncategorized

Creative Minds: Studying the Human Genome in 3D

Jesse Dixon

As a kid, Jesse Dixon often listened to his parents at the dinner table discussing how to run experiments and their own research laboratories. His father Jack is an internationally renowned biochemist and the former vice president and chief scientific officer of the Howard Hughes Medical Institute. His mother Claudia Kent Dixon, now retired, did groundbreaking work in the study of lipid molecules that serve as the building blocks of cell membranes.

So, when Jesse Dixon set out to pursue a career, he followed in his parents’ footsteps and chose science. But Dixon, a researcher at the Salk Institute, La Jolla, CA, has charted a different research path by studying genomics, with a focus on understanding chromosomal structure. Dixon has now received a 2016 NIH Director’s Early Independence Award to study the three-dimensional organization of the genome, and how changes in its structure might contribute to diseases such as cancer or even to physical differences among people.

The human body is made up of trillions of cells, each much too small to see without a microscope. And yet, if you could unwind and stretch the DNA contained within the nucleus of any one of those vanishingly small cells, you’d find it’s more than 6 feet long!

How is that possible? It takes a lot of careful folding and packaging. It also requires that the genome is arranged to ensure that the right genes are activated in the right place and at the right time. That’s because DNA is not a disorganized mass of spaghetti in the nucleus.

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.

Uncategorized

Gene Editing For A Long Life – A No Brainer?

Guest Post: Isabelle L Robertson
Paper: Student Essay- Designing Methuselah: an ethical argument against germline genetic modification to prolong human longevity

I am 16 years old. I am at the start of my life and looking towards my future, deciding on universities, career options and how I want my life to be. At the moment I can expect to perhaps live to 90 years of age. To me, this seems like a pretty good life. If I was offered more would I take it? I’m not sure; perhaps, if my health and independence can be guaranteed, then yes, I might.

Scientists have identified genes in mice that regulate lifespan. They have then edited these genes and have bred mice that have lived a full generation longer than their peers. These genes have their equivalents in the human genome too. Gene editing is becoming more refined by the day and it is predictable that it will one day be technically possible to edit the genome of human embryos to extend their lifespan. Again, extending from mice trials humans with these same genes altered could live to around 130 years old, the equivalent of a whole extra generation.

Gene editing technology brings with it many exciting opportunities such as the possibility of ridding some individuals of disease causing genetic variants. The possibilities extend beyond this though. It is not an unlikely prospect that in my lifetime I will be faced with the choice of deciding if I want my children to have any genetic alterations. These alterations might not just be limited to lifespan extension either; it is foreseeable that enhancements to traits as varied as intelligence, appearance and athletic capability may be potentially on offer.

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.

Uncategorized

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.

Uncategorized

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.

Uncategorized

Missing Genes Point to Possible Drug Targets

Every person’s genetic blueprint, or genome, is unique because of variations that occasionally occur in our DNA sequences. Most of those are passed on to us from our parents. But not all variations are inherited—each of us carries 60 to 100 “new mutations” that happened for the first time in us. Some of those variations can knock out the function of a gene in ways that lead to disease or other serious health problems, particularly in people unlucky enough to have two malfunctioning copies of the same gene. Recently, scientists have begun to identify rare individuals who have loss-of-function variations that actually seem to improve their health—extraordinary discoveries that may help us understand how genes work as well as yield promising new drug targets that may benefit everyone.

In a study published in the journal Nature, a team partially funded by NIH sequenced all 18,000 protein-coding genes in more than 10,500 adults living in Pakistan [1]. After finding that more than 17 percent of the participants had at least one gene completely “knocked out,” researchers could set about analyzing what consequences—good, bad, or neutral—those loss-of-function variations had on their health and well-being.

Gene knockouts are expected to occur more frequently in certain countries, such as Pakistan, where people sometimes marry and have children with their first cousins. That makes it much more likely that a person carrying a loss-of-function gene variation will have inherited that same variation from both of their parents.

In the latest study, a team led by Sekar Kathiresan at the Broad Institute of Harvard and MIT, Boston, turned to the Pakistan Rise of Myocardial Infarction Study (PROMIS) in hopes of finding more gene knockouts.

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.

Uncategorized

Creative Minds: A New Mechanism for Epigenetics?

Keith Maggert

To learn more about how DNA and inheritance works, Keith Maggert has spent much of his nearly 30 years as a researcher studying what takes place not just within the DNA genome but also the subtle modifications of it. That’s where a stable of enzymes add chemical marks to DNA, turning individual genes on or off without changing their underlying sequence. What’s really intrigued Maggert is these “epigenetic” modifications are maintained through cell division and can even get passed down from parent to child over many generations. Like many researchers, he wants to know how it happens.

Maggert thinks there’s more to the story than scientists have realized. Now an associate professor at the University of Arizona College of Medicine, Tucson, he suspects that a prominent subcellular structure in the nucleus called the nucleolus also exerts powerful epigenetic effects. What’s different about the nucleolus, Maggert proposes, is it doesn’t affect genes one by one, a focal point of current epigenetic research. He thinks under some circumstances its epigenetic effects can activate many previously silenced, or “off” genes at once, sending cells and individuals on a different path toward health or disease.

Maggert has received a 2016 NIH Director’s Transformative Research Award to pursue this potentially new paradigm. If correct, it would transform current thinking in the field and provide an exciting new perspective to track epigenetics and its contributions to a wide range of human diseases, including cancer, cardiovascular disease, and neurodegenerative disorders.

The cells of all eukaryotic organisms, whether a fruit fly or human, must continuously produce lots of small subcellular structures called ribosomes, which build the proteins that are essential to life.

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.

Uncategorized

The Semantics of Therapy, Part II

A previous blog post of “The Semantics of Therapy” posed three questions about the human genome being a “patient” to be treated. One reader found the post “provocative and disturbing” and called for further explanation and discussion of the questions posed. That will take some time and several postings.

The first of the questions to be considered is this: If the “patient” is a genome, to whom does the researcher answer?   An answer from recent history may shed some light on this important issue.

33 infertile couples underwent a novel procedure at New Jersey’s Saint Barnabas Medical Center during the years 1996-2001. Embryologist Jacques Cohen used cytoplasmic transfer–ooplasm from the oocytes of fertile women was transferred into the eggs of infertile women–in the hope of establishing pregnancies in the latter. The outcome was 13 pregnancies and 17 babies from the Saint Barnabas experience (see accounts here and here).

According to a 2014 BBC article, one resulting pregnancy, which ended in miscarriage, revealed a missing X chromosome in the fetus. The same anomaly was noted in another child: one of a set of twins from a different pregnancy. Later, one child showed evidence of developmental delay. In 2014, Cohen estimated that the worldwide experience of cytoplasmic transfer between oocytes had resulted in the births of 30-50 babies, although the FDA had effectively stopped the procedure in the U.S. in 2002.

What had the follow-up on the babies born through cytoplasmic transfer been in 2014?

Due to a lack of funding, Cohen says, it hasn’t been possible to find out about how any of the children like Alana who were born from cytoplasmic transfer are doing.

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.

Uncategorized

Three-parent babies green-lighted in the UK

A genetically engineered baby could be born in the UK before Christmas. The UK government has given a licence to Newcastle University to create three-parent embryos to combat mitochondrial diseases.

The UK’s fertility authority, the Human Fertilisation and Embryology Authority(HFEA), had already announced in December that licences for the controversial procedure were to be granted on a case-by-case basis. It appears that a number of couples have applied for the procedure, so the University will have no trouble in enrolling patients.

Sally Cheshire, chair of the UK’s fertility authority, said: “I can confirm today that the HFEA has approved the first application by Newcastle Fertility at Life for the use of mitochondrial donation to treat patients. This significant decision represents the culmination of many years hard work by researchers, clinical experts, and regulators, who collectively paved the way for Parliament to change the law in  2015 to permit the use of such techniques.

“Patients will now be able to apply individually to the HFEA to undergo mitochondrial donation treatment at Newcastle, which will be life-changing for them, as they seek to avoid passing on serious genetic diseases to future generations.”

Critics described the move as “ethically reckless”. Mark Bhagwandin, of the pro-life charity Life, told the Daily Telegraph:

“We had hoped that the HFEA would have listened to the thousands of people who have expressed concern about three parent embryos. Instead it has ignored the alarm bells and approved a procedure which will alter the human genome. It is at the very least reckless and irresponsible given that we have absolutely no idea what the long term consequences are to us interfering with the human genome.

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.