Tag: cells

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

Creative Minds: Rapid Testing for Antibiotic Resistance

Ahmad (Mo) Khalil

The term “freeze-dried” may bring to mind those handy MREs (Meals Ready to Eat) consumed by legions of soldiers, astronauts, and outdoor adventurers. But if one young innovator has his way, a test that features freeze-dried biosensors may soon be a key ally in our nation’s ongoing campaign against the very serious threat of antibiotic-resistant bacterial infections.

Each year, antibiotic-resistant infections account for more than 23,000 deaths in the United States. To help tackle this challenge, Ahmad (Mo) Khalil, a researcher at Boston University, recently received an NIH Director’s New Innovator Award to develop a system that can more quickly determine whether a patient’s bacterial infection will respond best to antibiotic X or antibiotic Y—or, if the infection is actually viral rather than bacterial, no antibiotics are needed at all.

To build the foundation for his new diagnostic approach, Khalil is sequencing the transcriptomes of a variety of bacterial strains to analyze their genomic response to various antibiotics. He then uses that information to produce a panel of RNA sensors specific to each particular bacterial strain, and freeze-dries those sensors onto strips of testing paper, creating what he thinks will be a highly specific diagnostic test with a very long shelf life.

As Khalil envisions it, the clinical use of his test would involve obtaining a sample of infected material from a patient and exposing the sample to a certain antibiotic. After about 20 minutes, the sample’s cells would be lysed and the resulting solution placed on the test strip. That liquid would serve to reconstitute the freeze-dried RNA sensor reactions embedded on the paper, and those sensors would light up if the sample contains a bacterium that is a good candidate for the antibiotic.

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

Scientists produce functional intestine. Tissue, nerves and muscles from a single line of human stem cells

When it comes to growing intestines, the first inch is the hardest -, especially in a Petri dish. Scientists at Cincinnati Children’s Hospital Medical Center have met that benchmark: they recently reported in Nature Medicine that they had grown a piece of gut—nerves, muscles and all—from a single line of human stem cells. In the future, such tissue could be used for studying disease and more.

In 2011 researchers at the same center announced that they had grown intestinal tissue—but it was missing nerve cells and so was unable to contract in the undulating motion that pushes food along a colon. This time around, the scientists grew neurons separately and then combined them with another batch of stem cells that had been induced to become muscle and intestinal lining. Voilà: an inch-long piece of gut formed. “Just like in developing human bodies, the nerve cells knew where to go,” says Michael Helmrath, surgical director of the Intestinal Rehabilitation Program at Cincinnati Children’s.

Intestine tissue production

The scientists then transplanted the tissue onto a living mouse’s intestine so it could mature. After harvesting it for testing, they stimulated the bespoke chunk with a shock of electricity. It contracted and continued to do so on its own. “The function was remarkable,” Helmrath says. Intestines now join kidneys, brain matter and a few other kinds of tissue that can be grown in the lab.

Helmrath and his colleague Jim Wells would like to coax longer pieces of intestine by working with pigs. Eventually, the researchers hope to treat people with gastrointestinal problems by making copies of a patient’s gut to observe how a disease manifests—or even to transplant the tissue.

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

Precision Oncology: Gene Changes Predict Immunotherapy Response

Caption: Adapted from scanning electron micrograph of cytotoxic T cells (red) attacking a cancer cell (white).
Credits: Rita Elena Serda, Baylor College of Medicine; Jill George, NIH

There’s been tremendous excitement in the cancer community recently about the life-saving potential of immunotherapy. In this treatment strategy, a patient’s own immune system is enlisted to control and, in some cases, even cure the cancer. But despite many dramatic stories of response, immunotherapy doesn’t work for everyone. A major challenge has been figuring out how to identify with greater precision which patients are most likely to benefit from this new approach, and how to use that information to develop strategies to expand immunotherapy’s potential.

A couple of years ago, I wrote about early progress on this front, highlighting a small study in which NIH-funded researchers were able to predict which people with colorectal and other types of cancer would benefit from an immunotherapy drug called pembrolizumab (Keytruda®). The key seemed to be that tumors with defects affecting the “mismatch repair” pathway were more likely to benefit. Mismatch repair is involved in fixing small glitches that occur when DNA is copied during cell division. If a tumor is deficient in mismatch repair, it contains many more DNA mutations than other tumors—and, as it turns out, immunotherapy appears to be most effective against tumors with many mutations.

Now, I’m pleased to report more promising news from that clinical trial of pembrolizumab, which was expanded to include 86 adults with 12 different types of mismatch repair-deficient cancers that had been previously treated with at least one type of standard therapy [1].

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: A Van Gogh Moment for Pancreatic Cancer

Credit: Nathan Krah, University of Utah

Last year, Nathan Krah sat down at his microscope to view a thin section of pre-cancerous pancreatic tissue from mice. Krah, an MD/PhD student in the NIH-supported lab of Charles Murtaugh at the University of Utah, Salt Lake City, had stained the tissue with three dyes, each labelling a different target of interest. As Krah leaned forward to look through the viewfinder, he fully expected to see the usual scattershot of color. Instead, he saw enchanting swirls reminiscent of the famous van Gogh painting, The Starry Night.

In this eye-catching image featured in the University of Utah’s 2016 Research as Art exhibition, red indicates a keratin protein found in the cytoskeleton of precancerous cells; green, a cell adhesion protein called E-cadherin; and yellow, areas where both proteins are present. Finally, blue marks the cell nuclei of the abundant immune cells and fibroblasts that have expanded and infiltrated the organ as a tumor is forming. Together, they paint a fascinating new portrait of pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer.

Pancreatic acinar cells, which produce and secrete digestive enzymes, are organized like a cluster of grapes, with a narrow stalk-like tube connected to them that is lined with duct cells. PDAC had long been described as arising in the duct cells. But recent studies show that acinar cells also can form PDAC tumors, inspiring several groups to try and figure out how that’s possible.

Krah and his colleagues in the Murtaugh lab think they might have the answer.

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

Guest Post: Crispr Craze and Crispr Cares

Written by Robert Ranisch, Institute for Ethics and History of Medicine, University of Tuebingen

@RobRanisch

Newly discovered tools for the targeted editing of the genome have been generating talk of a revolution in gene technology for the last five years. The CRISPR/Cas9-method draws most of the attention by enabling a more simple and precise, cheaper and quicker modification of genes in a hitherto unknown measure. Since these so-called molecular scissors can be set to work in just about all organisms, hardly a week goes by without headlines regarding the latest scientific research: Genome editing could keep vegetables looking fresh, eliminate malaria from disease-carrying mosquitoes, replace antibiotics or bring mammoths back to life.

Naturally, the greatest hopes are put into its potential for various medical applications. Despite the media hype, there are no ready-to-use CRISPR gene therapies. However, the first clinical studies are under way in China and have been approved in the USA. Future therapy methods might allow eradicating hereditary illnesses, conquering cancer, or even cure HIV/AIDS. Just this May, results from experiments on mice gave reason to hope for this. In a similar vein, germline intervention is being reconsidered as a realistic option now, although it had long been considered taboo because of how its (side)effects are passed down the generations.

The developmental history of genome editing reveals itself as a recalibration of ethical standards in research. Two years ago, the first-time use of these new tools on (non-viable) embryos in China led to a solid scandal; in retrospect, it is not clear anymore whether the outrage was triggered by ethical concerns or by the circumstance that this (perceived) taboo was broken by China of all countries.

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 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 Blogs

No Pain, All Gain: The Case for Farming Organs in Brainless Humans

Guest post by Ruth Stirton, University of Sussex (@RuthStirton) and David Lawrence, Newcastle University (@Biojammer)

It is widely acknowledged that there is a nationwide shortage of organs for transplantation purposes.  In 2016, 400 people died whilst on the organ waiting list.  Asking for donors is not working fast enough.  We should explore all avenues to alleviate this problem, which must include considering options that appear distasteful.  As the world gets safer, and fewer young people die in circumstances conducive to the donation of their organs, there is only so much that increased efficiency in collection (through improved procedures and storage) can do to increase the number of human organs available for transplantation. Xenotransplantation – the transplantation of animal organs into humans – gives us the possibility of saving lives that we would certainly lose otherwise.

There are major scientific hurdles in the way of transplanting whole animal organs into humans, including significant potential problems with incompatibility and consequent rejection.  There is, however, useful similarity between human and pig cells, which means that using pigs as the source of organs is the most likely to be viable.  Assuming, for the moment, that we can solve the scientific challenges with doing so, the bigger issue is the question of whether we should engage in xenotransplantation.

A significant challenge to this practice is that it is probably unethical to use an animal in this way for the benefit of humans. Pigs in particular have a relatively high level of sentience and consciousness, which should not be dismissed lightly.  Some would argue that animals with certain levels of sentience and consciousness – perhaps those capable of understanding what is happening to them – have moral worth and are entitled to respect and protection, and to be treated with dignity.  It is inappropriate to simply use them for the benefit of humanity.  Arguably, the level of protection ought to correlate to the level of understanding (or personhood), and thus the pig deserves a greater level of protection than the sea cucumber.  The problem here is that the sea cucumber is not sufficiently similar to the human to be of use to us when we’re thinking about organs for transplantation purposes.  The useful animals are those closest to us, which are by definition those animals with more complex brains and neural networks, and which consequently attract higher moral value.

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: A Transcriptional “Periodic Table” of Human Neurons

Caption: Mouse fibroblasts converted into induced neuronal cells, showing neuronal appendages (red), nuclei (blue) and the neural protein tau (yellow).
Credit: Kristin Baldwin, Scripps Research Institute, La Jolla, CA

Writers have The Elements of Style, chemists have the periodic table, and biomedical researchers could soon have a comprehensive reference on how to make neurons in a dish. Kristin Baldwin of the Scripps Research Institute, La Jolla, CA, has received a 2016 NIH Director’s Pioneer Award to begin drafting an online resource that will provide other researchers the information they need to reprogram mature human skin cells reproducibly into a variety of neurons that closely resemble those found in the brain and nervous system.

These lab-grown neurons could be used to improve our understanding of basic human biology and to develop better models for studying Alzheimer’s disease, autism, and a wide range of other neurological conditions. Such questions have been extremely difficult to explore in mice and other animal models because they have shorter lifespans and different brain structures than humans.

Kristin Baldwin

Kristin Baldwin

The focus of Baldwin’s work will be the thousands of proteins, called transcription factors, that switch genes on and off in our cells and play key roles in determining cell fate. Groundbreaking research several years ago in the lab of Marius Wernig at Stanford University, Palo Alto, CA, established that forcing the activation of three preselected transcription factors in mature skin cells, or fibroblasts, could convert them into neurons [1]. Baldwin wondered whether greatly expanding the list of transcription factors might produce a diverse array of neuronal subtypes.

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.