November 22, 2013
UK’s first gene therapy trial for patients with chronic heart failure begins at GJNH
The UK’s first gene therapy trial for advanced heart failure, CUPID 2, has officially begun at the Golden Jubilee National Hospital (GJNH); with the first candidate recently being administered with a dose of the MYDICAR treatment. Studies have shown that there is a clear connection between depletion of the SERCA2a gene in the heart and the progression of end-stage heart failure. (News-Medical)
Genetic tests do not appear to improve control of blood thinner
Contrary to what has been suggested, it appears genetic tests do not help to predict optimal doses of the blood thinner warfarin for patients. This was the finding of a late-breaking clinical trial whose results were presented at the American Heart Association’s Scientific Sessions 2013 in Dallas, TX, recently. (Medical News Today)
November 21, 2013
FDA allows marketing of four “next generation” gene sequencing devices
Today the U.S. Food and Drug Administration allowed marketing of four diagnostic devices that can be used for high throughput gene sequencing, often referred to as “next generation sequencing” (NGS). These instruments, reagents, and test systems allow labs to sequence a patient’s DNA (deoxyribonucleic acid). The new technology also gives physicians the ability to take a broader look at their patients’ genetic makeup and can help in diagnosing disease or identifying the cause of symptoms. (FDA)
HPV: Sex, cancer and a virus
The medical community is struggling to come to grips with the implications. There is currently no good screening method for HPV-caused cancer in the head and neck, and commercially available HPV vaccines are still prescribed only to people under the age of 26, despite evidence that they could prevent head and neck cancer in all adults. Plus, if HPV can get into the mucous membranes of the mouth and throat, where does it stop? There are hints that HPV is a risk factor for other, even more common, types of cancer, including lung cancer. (Nature)
Gene test in dogs boost hopes for haemophilia
Scientists on Tuesday said they had treated haemophilia in dogs by fixing a flawed gene, marking a step forward towards treating the condition in humans, too. Haemophilia A, the most widespread form of the inherited bleeding disease, occurs in around one in 10,000 men. It occurs through a malfunctioning gene, passed on through the maternal line, that causes a deficiency in a blood-clotting protein called Factor VIII. (Associated Press)
November 20, 2013
Double Nobel Prize winning biochemist Fred Sanger dies at 95
Fred Sanger, a double Nobel Prize-winning British biochemist who pioneered research into the human genome, has died at the age of 95, the University of Cambridge said on Wednesday. Sanger, who once described himself as “just a chap who messed about in his lab”, worked with colleagues to develop a rapid method of DNA sequencing – a way to “read DNA” – which became the forerunner for the work on mapping the human genome. (Reuters)
New cell therapy leading way to faster tissue repair
Past efforts to improve wound healing and tissue repair have mostly failed, but altering metabolism is a new strategy that could prove successful, Daley said. The researchers determined that the Lin28a protein could play a role because it regulates growth and development in juveniles, though its levels decline with age. (Fox News)
Many pediatricians uncomfortable providing care to kids with genetic conditions
Many primary care pediatricians say they feel uncomfortable providing health care to patients with genetic disorders. Also, many do not consistently discuss all risks and benefits of genetic tests with patients, according to research published today in the American Journal of Medical Genetics. (Medical Xpress)
November 19, 2013
The fabric of disease
Identifying the links between slight genetic aberrations and complex diseases is one of modern biology’s great challenges. A team of scientists from UC San Francisco and Kaiser Permanente Northern California is now four years into an ambitious effort to trace the genetic and environmental roots of a range of disorders, from diabetes to cancer. They are doing so by tapping into one of the world’s largest and most thorough collections of patient health records. (Medical Xpress)
New effort launched to personalize heart treatment
Cardiologists are taking aim at treating and preventing heart disease, the world’s No. 1 killer, with a more personalized approach under a new research collaboration that will marry data with the evolving understanding of genetics. The effort, being billed as Heart Studies v2.0 and which was announced on Sunday, will be a collaboration of the American Heart Association (AHA) along with Boston University and the University of Mississippi, which oversee ongoing landmark population studies, the Framingham Heart Study and the Jackson Heart Study, respectively. (NBC News)
November 18, 2013
Mighty mitochondria and reproductive technology
Mitochondria have made the news recently. Moves toward three-parent IVF have been motivated by mitochondrial issues, and new IVF embryo screening methods assess the health of the embryos’ mitochondria to select the embryo that is more likely to implant. Both of these news items raise important bioethics issues, but unless you have had a recent refresher on cellular biology, what mitochondria actually do might be a little hazy. Let’s review the inner workings of the mitochondria and how it relates to assisted reproductive technology.
What are mitochondria?
In high school biology we learn that mitochondria are the “power plant of the cell.” Cells are like factories, and their organelles are like different sections of the factory that perform specific tasks. Mitochondria’s task is oxidative metabolism, which provides the cell with the energy it needs to conduct its tasks. Mitochondria take carbohydrates, fats, and amino acids and break them down into simple molecules, like CO2 and H2O. This process releases energy for the cell to use to survive.
An important fact about mitochondria for understanding bioethics issues is that it contains DNA. Most of the cell’s DNA is found in the nucleus, but a very small portion is found in the mitochondria. Mitochondrial DNA codes for the proteins needed to perform oxidative metabolism, as well as other functions associated with the mitochondria. It has some unique features compared to nuclear DNA: 1) It is more susceptible to mutations, 2) it is circular in shape, and 3) it is passed down only from the mother. Some diseases occur as a result of mutations within the mitochondrial DNA. These mutations can be passed down from the mother, or – less commonly – they may be due to environmental factors. See here for a link to the United Mitochondrial Disease Foundation and here for a Nature SciTable article on mitochondrial disease. Both provide excellent information on the various forms of mitochondrial disease.
Assisted Reproductive Technology
Mitochondrial disease is typically passed down from the mother. The mitochondrial DNA that will be passed to the child comes from the egg, while the sperm cell’s mitochondria are destroyed in the fertilization process. Both the egg cell and the sperm cell contribute to the embryo’s nuclear DNA.
This is where “three-parent” IVF comes in. If the intended mother happens to have a known mitochondrial mutation and does not want to pass this down to her child, it is possible to remove the nucleus of her egg (oocyte) and place it in another woman’s enucleated oocyte. The newly formed oocyte would have nuclear DNA from the intended mother and mitochondrial DNA from the female egg donor, and would then be fertilized by a sperm cell. This means there would be three genetic contributors to a single embryo, although more than 99% of the DNA would be from the original mother and father, and only a small fraction from the egg donor. Britain has approved the use of three-parent IVF, and the U.S. is currently discussing whether to approve it or not.
Another option is to screen an already-created embryo’s mitochondrial DNA to ensure that it did not inherit a particular mutation or genetic marker for mitochondrial disease. If a couple creates several embryos through in vitro fertilization, doctors can select the embryo that has the “healthiest” mitochondria.
Recently, scientists reported that mitochondria might be helpful for selecting healthy embryos in any IVF situation. A new study showed some indications that embryos with lower numbers of mitochondria tended to implant more successfully than other embryos. Even embryos that appeared healthy under a microscope were less likely to implant if their mitochondrial count was above a certain threshold. Scientists speculate that a high mitochondrial count might be related to “stress” signals in the embryo.
A number of scientists and ethicists have voiced concern over the safety of three-parent IVF. While scientists saw success in monkey models, human reproduction is typically more complicated than trials involving animal models. Moreover, mitochondrial DNA codes for some of the proteins that will be used in the mitochondria, but not all of them. Some nuclear DNA codes for proteins that are transported to the mitochondria, which raises questions about compatibility and long-term effects. If the couple has a daughter and something goes wrong as a result of the technique, that daughter will pass the defective mitochondria to her offspring.
A child with three genetic contributors also raises some legal concerns. There will be three “biological parents,” although the vast majority of genetic contribution comes from the egg nucleus and sperm. To put numbers to it: in a cell the nuclear DNA has 3.3 billion DNA base pairs, while mitochondrial DNA only has 16,569 DNA base pairs. (Note: Although there are several mitochondria in a cell, they will all have the same DNA sequence.) In states where the biological parents are required to sign the birth certificate, will laws have to be amended to indicate that “biological parents” include only the primary genetic contributors? Will we have to set genetic boundaries for who counts as a biological parent?
Three-parent embryos bring up unique social concerns. Ancestral lines are often determined through mitochondrial DNA. Because mitochondrial DNA is preserved through the maternal line, many ancestral studies use mitochondria to trace family lineage. If scientists create embryos in which the mitochondria have been changed from the primary maternal genetic contributor, then ancestral studies can no longer be done for this individual.
Additionally, this technique of replacing the nucleus of one oocyte with another may fall into the category of “germ-line intervention” under UNESCO’s Universal Declaration on the Human Genome and Human Rights. Many members of the Council of Europe signed a petition saying that this type of intervention is contrary to human dignity and should not be allowed in Britain.
Mitochondrial screening, while not as potentially dicey as mitochondrial transplants, has issues of its own. According to Dr. Dagan Wells, co-author of the mitochondrial screening study cited above, “The mitochondrial screen could potentially be a free add-on on top of chromosomal screening … Once you’ve got those cells, you might as well do as much as you can with them.” This is the pervasive attitude towards screening: More information is better. But this assumes that we are reliably able to interpret the information correctly. Mitochondrial screening of embryos brings, along with its prospective benefits, the prospective risk of wrongly rejecting certain embryos based on preconceived notions or theories of what is “normal” or “healthy.” As with many forms of embryonic screening, there is a need for caution against subtly eugenic attitudes in which a person’s or society’s definition of “normal” excludes certain other persons.
As mentioned in a prior bioethics.com post, one of the problems with genetic screening is how to interpret the information. Having a genetic marker for a disease usually does not mean that the child will definitely develop the disease. In many cases, the mere presence of a gene is not enough. It also must be activated. Whether or not a gene is activated depends on many factors, including environment, lifestyle, and epigenetics.
Finally, we need to consider the potential for the destruction of embryos. While the technology used for mitochondrial screening does not destroy the embryo, the purpose behind screening is to accept healthy embryos and reject unhealthy ones. The unhealthy embryos are discarded based on an assumption about the correlation between the amount of mitochondria in a cell and the health of an embryo.
Additionally, the technique for creating a three-parent embryo does not necessarily result in the destruction of an embryo. However, current IVF technology typically results in a 30% success rate, and usually involves screening for healthy embryos. In regards to the fate of certain embryos, the three-parent IVF technique involves many of the same concerns as traditional IVF, particularly those that include third-party donors.
Mitochondrial disease can be devastating, and finding cures to diseases caused by mutations in mitochondrial DNA is certainly a worthy pursuit. Wanting to cure mitochondrial disease is not ethically problematic. But we must be careful to distinguish between curing people with a disease and curing the disease by getting rid of (or preventing the existence of) people who have it, as in the case of mitochondrial screening.
Additionally, we must consider the means by which we cure diseases – including those that afflict us at the genetic level. Three-parent IVF may have unforeseen consequences that would affect the child and may be passed down to later generations through the maternal line. We do not know the long-term effects three-parent IVF will have on the embryo, and must balance the cost of potentially getting mitochondrial disease with the cost of harm or defects due to the three-parent IVF technique. The gamble is that mitochondrial disease causes more harm than three-parent IVF, but we do not know this for certain unless an embryo is grown to term, which constitutes a dicey case of human experimentation.
New hope for asthma sufferers as scientists find gene that triggers condition
Scientists have found a gene that causes asthma in children, giving millions hope of new treatments or even a cure. A faulty version of the gene can weaken the lining of the airways, leaving people vulnerable to the respiratory disease, they found. (Daily Mail)
Genetic engineering enables human immunity to take on cancer, revolutionary therapy
Developments in genetic engineering make it possible to ‘re-programme’ the human immune system so that T cells – white blood cells that normally fight viruses – recognize and kill cancer cells. This approach, which directly harnesses the potency of the immune system, holds the prospect of a powerful new weapon in the fight against cancer. (Science World Report)
Persistent gene therapy in muscle may not require immunosuppression
Successful gene therapy is based on the effective delivery and maintained expression of healthy copies of a gene into tissues of individuals with a disease-associated genetic mutation. Recombinant adeno-associated virus (rAAV) vectors have shown promise in early clinical trials as effective therapies for several genetic diseases, including Leber congenital amaurosis, Parkinson disease, and hemophilia. Unfortunately, delivery of rAAV vectors to tissues other than the retina and CNS often results in development of an immune response against the viral capsid. The development of a neutralizing response against the rAAV vector prevents sustained expression of the healthy gene in the absence of immunosuppression. (Eurekalert)
Researchers use new approach to parse roles of key mutated protein that causes familial AD
Researchers at the University of California, San Diego School of Medicine have used genetic engineering of human induced pluripotent stem cells to specifically and precisely parse the roles of a key mutated protein in causing familial Alzheimer’s disease (AD), discovering that simple loss-of-function does not contribute to the inherited form of the neurodegenerative disorder. (News-Medical)
November 15, 2013
Study discovers that senescence also plays a role in embryo development
One of the main mechanisms the body uses to protect itself against cancer is to switch off defective cells by making them senescent; these cells do not die but stop dividing: their life cycle stops. A team of researchers from the Spanish National Cancer Research Centre (CNIO) in Madrid and another one from the Centre for Genomic Regulation (CRG) in Barcelona have discovered, and are publishing in two articles in the journal Cell, that this switching-off mechanism also takes place in embryos, and not as a response to cell damage but as part the normal process of development. (Medical Xpress)
Root of birth defects grounded in early embryonic development
In developed countries, birth defects are now the leading cause of infant mortality. Some heart defects, such as holes in the heart or “blue baby” syndrome are caused by improper orientation of organs in the body. In previous work along with others, Martina Brueckner of Yale revealed tiny hair-like structures on cells called cilia could be the cause. (Medical Xpress)
Therapeutic potential of gene therapy shown in preclinical study of heart failure
Scientists at the Cardiovascular Research Center at the Icahn School of Medicine atMount Sinai report that they have successfully tested a gene therapy, delivered directly into the heart, to reverse heart failure in large animal models. The team’s findings (“SUMO-1 Gene Transfer Improves Cardiac Function in a Large-Animal Model of Heart Failure findings”), published in November 13 issue of Science Translational Medicine, is the final study phase before human clinical trials can begin testing SUMO-1 gene therapy, noted Roger J. Hajjar, M.D., director of the research center and the Arthur & Janet C. Ross Professor of Medicine, adding that SUMO-1 is a gene that is “missing in action” in heart failure patients. (Genetic Engineering and Biotechnology News)
November 14, 2013
Hiding in plain sight: Finding new targets for old drugs
The typical interval between discovery and clinical trials is three to six years, but NuMedii’s approach—repurposing drugs that have already been proven safe in humans—could propel compounds from hypothesis to human much faster. Which is good for NuMedii—and potentially good for patients too. (Wired)
Redesigned protein opens door for safer gene therapy
The researchers put one and two together to create a safer viral vector: “We developed a fused protein with the head of the protein that HIV uses and the tail of the protein that MLV uses,” Dr. Rik Gijsbers explains. Writing in Cell Reports (“The BET Family of Proteins Targets Moloney Murine Leukemia Virus Integration near Transcription Start Sites”), the researchers say their retrofitted retroviral vector works: “Our experiments with cell cultures show that in the presence of this protein, the viral vector always inscribes itself in a safe place, just as it does in the HIV virus,” says Dr. Gijsbers. (Nanowerk)
Stem cells can self-repair some gene damage
Artificial embryonic stem cells called induced pluripotent stem cells spontaneously correct certain genetic defects, according to scientists speaking at a discussion this week on new findings in stem cells. During creation of the IPS cells, a few of them manage to repair themselves, said Marina Bershteyn, a researcher in the lab of Arnold Kriegstein of UC San Francisco. These cells grow faster, so with each generation the proportion of these cells increase. (The San Diego Union-Tribune)