November 19, 2013
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)
November 13, 2013
Mice regrow fingertips, hair with help of mitochondria-boosting protein
Researchers at Boston Children’s Hospital’s Stem Cell Program and Harvard University’s Medical School (HMS) have made an exciting discovery, discovering two ways by which a special gene family found in mice and humans alike can trigger tissue regeneration. The study shows that the key repair protein produced from this gene family can not only inhibit aging/maturation proteins that slow down healing, but also directly kick-start mitochondria, a cell’s power plants. (Daily Tech)
November 12, 2013
Depression ‘makes us biologically older’
Depression can make us physically older by speeding up the ageing process in our cells, according to a study. Lab tests showed cells looked biologically older in people who were severely depressed or who had been in the past. These visible differences in a measure of cell ageing called telomere length couldn’t be explained by other factors, such as whether a person smoked. (BBC)
Health disparities in kidney disease – emerging data from the human genome
Racial disparity in end-stage renal disease in the United States is well documented; hypertensive kidney disease has long been considered to be a leading cause of this disorder among black patients. The overall incidence of end-stage renal disease is 3.5 to 5 times as high among black patients as among white patients. Overall, nondiabetic chronic kidney disease afflicts black patients disproportionately. In one study, the rate of nephropathy associated with human immunodeficiency virus infection among black patients was 50 times that among white patients. (New England Journal of Medicine)
For $99, eliminating the mystery of Pandora’s genetic box
IF DNA is destiny, then Anne Wojcicki is in the right business. She is the co-founder and chief executive of 23andMe, a Silicon Valley start-up that offers a $99 DNA test, as easy as spitting into a tube, that provides detailed genetic information from disease risk to family lineage. In a recent interview at 23andMe’s office in Mountain View, Calif., Ms. Wojcicki (pronounced wo-JIT-skee) discussed the Silicon Valley girls’ club, the ties connecting her marriage and her business and why she is convinced that personal genetics will change health care. (New York Times)
Fast-mutating DNA sequences shape early development
What does it mean to be human? According to scientists the key lies, ultimately, in the billions of lines of genetic code that comprise the human genome. The problem, however, has been deciphering that code. But now, researchers at the Gladstone Institutes have discovered how the activation of specific stretches of DNA control the development of uniquely human characteristics—and tell an intriguing story about the evolution of our species. (Phys.org)
Event: International Conference on Emerging Ethical Issues
Centre of Biomedical Ethics and Culture, SIUT
International Conference on Emerging Ethical Issues
Themes: Pharma Industry, Genetics, Deceased Organ Donation
December 6-7, 2013
See here for more information.
November 11, 2013
Scientists re-grow cartilage, hair, bone and tissue in mice
Scientists claim to have regrown hair and repaired cartilage, bone, skin and other soft tissues in a mouse model, by reactivating a dormant gene called Lin28a, which is active in embryonic stem cells. The study at Boston Children’s Hospital also found that Lin28a promotes tissue repair in part by enhancing metabolism in mitochondria, suggesting that a mundane cellular “housekeeping” function could open new avenues for developing regenerative treatments. (Business Standard)
Cause of genetic disorder found in ‘dark matter’ of DNA
For the first time, scientists have used new technology which analyses the whole genome to find the cause of a genetic disease in what was previously referred to as “junk DNA”. Pancreatic agenesis results in babies being born without a pancreas, leaving them with a lifetime of diabetes and problems digesting food. In a breakthrough for genetic research, teams led by the University of Exeter Medical School and Imperial College London found that the condition is most commonly caused by mutations in a newly identified gene regulatory element in a remote part of the genome, which can now be explored thanks to advances in genetic sequencing. (Medical Xpress)
Eugenics to medical genetics
Nathaniel Comfort’s whirlwind tour through twentieth-century human genetics is alternately thought-provoking, entertaining and exasperating. His goal is to demonstrate a eugenic impulse that runs continuously from the early 1900s to the present. I think he succeeds in this aim to some extent. (Nature, by subscription only)