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Nuclei swap to stop disease?

A technique may one day prevent something that is currently unpreventable -- the transmission of mitochondrial diseases from mother to child, according to a proof-of-concept paper published online today (April 14) in Nature. Blastocyst on day 5 after fertilizationImage: Wikimedia commons, EkemThe authors swapped the nuclei from one fertilized human egg with the nuclei from another, creating an embryo with nuclear DNA from the donor egg, but mitochondrial DNA primarily from the recipient. They s

By | April 14, 2010

A technique may one day prevent something that is currently unpreventable -- the transmission of mitochondrial diseases from mother to child, according to a proof-of-concept paper published online today (April 14) in Nature.
Blastocyst on day 5 after fertilization
Image: Wikimedia commons, Ekem
The authors swapped the nuclei from one fertilized human egg with the nuclei from another, creating an embryo with nuclear DNA from the donor egg, but mitochondrial DNA primarily from the recipient. They suggest the technique could ultimately prevent the transmission of mitochondrial diseases if doctors moved nuclei from a fertilized egg carrying the disease to another egg with disease-free mitochondria. The results come with major caveats, however. The resulting embryo would carry DNA from three parents, and to prove the technique could work in the clinic, scientists would have to try the technique in healthy human embryos -- a task that would be "impossible" due to the associated ethical issues, linkurl:Jun-Ichi Hayashi;http://www.biol.tsukuba.ac.jp/~jih-kzt/ of the University of Tsukuba in Japan, who was not involved in the research, told The Scientist. Nonetheless, the results are "very promising," said neurogeneticist linkurl:Carolyn Sue;http://www.kolling.usyd.edu.au/research/neurogenetics-group/csue.php of the Kolling Institute of Medical Research at the University of Sydney in Australia, who was also not directly involved in the research. "It's moving towards [a] treatment to prevent transmission of mitochondrial disease." Mitochondria, the cell's energy-making organelles, carry their own set of DNA -- 13 genes that encode the construction and function of new mitochondria. Pathogenic mutations in mitochondrial DNA (mtDNA) are found in about 1 in 250 live births, and can cause a variety of neuromuscular ailments. Currently, there are no specific treatments for mitochondrial diseases. Because mitochondrial are maternally inherited, women carrying mtDNA mutations pass them on to their children. To prevent the transmission of disease, an embryo must receive a whole new set of mitochondria. To achieve this goal, clinical scientist linkurl:Doug Turnbull;http://www.cnmd.ac.uk/researchgroups/dougturnbull and his colleagues at Newcastle University in the UK transplanted the nuclei from one human oocyte (termed pronuclei) into an oocyte whose pronuclei had been removed. The resulting embryos, which contained predominately mtDNA from the recipient oocyte, were then raised in culture for about a week. About 20 percent showed continued development, some all the way to the blastocyst stage, demonstrating the viability of the manipulated embryos. "This is definitely showing a proof of concept" that this type of technique, which had previously been applied to primates and other animals, can be applied to human oocytes, Sue said. However, the embryos still contained some mtDNA from donor egg. The technique, which involves sucking the pronuclei from the donor oocyte with a micro-manipulated pipette, Turnbull explained, can result in the transfer of small amounts of donor cytoplasm containing donor mitochondria, as well. "It's really tricky to" get just the pronuclei, he said. Refining their technique, the researchers were able to limit the amount of mitochondrial transfer, creating manipulated embryos with less than 2 percent donor mitochondria, "which we felt was a significant breakthrough in this area," Turnbull said. But even 2 percent "is still not quite acceptable to be translated into clinical practice," Sue said, as "very low levels [of mutated mtDNA] can still result in mitochondrial disease." Additionally, the safety and efficacy of the treatment must be tested before the therapy can begin to make its way towards clinical development, Turnbull said. The oocytes used in the study were abnormally fertilized embryos generated during in vitro fertilization (IVF) treatments that would have otherwise been discarded, but, to be approved for clinical use, the technique would have be tested in healthy embryos, researchers say. Indeed, the manipulation itself could increase the risk of epigenetic abnormalities in the offspring, said developmental biologist Josef Fulka, Jr. of the linkurl:Institute of Animal Science;http://www.feedforhealth.org/default.asp?ZNT=S0T1O796 in the Czech Republic. "These risks can not be excluded without using human healthy embryos and testing whether they are healthy throughout their life," Hayashi said in an email, and "it's impossible to carry out these experiments." Turnbull said that he and his team are currently discussing the next steps with the linkurl:Human Fertility & Embryology Authority;http://www.hfea.gov.uk/ -- a UK regulatory authority -- but could not comment more specifically on any potential future experiments. Other issues may arise from the fact that the resulting offspring would have three genetic parents -- the mother and father who donated the nuclear material, and a second mother who donated the mitochondria. "The interaction between the nuclear genome and the mitochondrial genome is still unclear," Sue said. "Simply, nobody on the earth ever had three biological parents," Hayashi added. L. Craven et al., "Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease," Nature, published online April 14, 2010, doi:10.1038/nature08958.
**__Related stories:__***linkurl:Surprising mtDNA diversity;http://www.the-scientist.com/blog/display/57199/
[3rd March 2010]*linkurl:First fix for mitochondrial diseases;http://www.the-scientist.com/blog/display/55925/
[26th August 2009]*linkurl:Support for mtDNA aging theory;http://www.the-scientist.com/news/display/23324/
[10th April 2006]
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Comments

Avatar of: anonymous poster

anonymous poster

Posts: 5

April 14, 2010

The teaser for this article states "A technique may one day prevent the transmission of mitochondrial diseases from mother to child, but is it too controversial to pursue?"\n\nTechniques are not not done because they are controversial, they are not done because they are found to be unethical.\n\nI have a hard time seeing how this reasearch and the result could be ethical.\n\nThe good of the research would be that it would allow individual women to have their nucleic DNA passed on.\n\nThe bad among many other concerns (Destruction of one undesired embryo to replace the nucleus with more desireable genetic material, ethical source of donor eggs, etc) would be the likely creation of children with at this point unpredictable abnormalities due to the epigentics and residual mutated mitochondria genes.\n\nWith such a high cost, what are we getting? \nThe ability for a limited number of women with mitochondrial mutations, lots of money and more concern about passing on their genes than about the health of their child.\n\nI speak as a woman who will never be able to have biological children, how can we as a society condone such research just for the vanity of passing on our genes.
Avatar of: anonymous poster

anonymous poster

Posts: 2

April 14, 2010

I don't mean to cause offense, but surely you realise that currently ART (and indeed unassisted human reproduction) often result in loss (or 'waste' as you put it), of healthy viable eggs which have been ethically donated. \nIf the epigenetic effects were not a problem, and I had previously donated eggs to be used by other couples for IVF I would be happy for the nucleus to be extracted and replaced with the biological parents nucleus.
Avatar of: Sergio Stagnaro

Sergio Stagnaro

Posts: 59

April 15, 2010

I am delighted with Nature paramount paper as well as with THE SCIENTIST.com. Firstly, from the clinical view-point, for the first time I have demonstrated - more than 25 years ago - that at the base of most common and severe diseases, today's growing epidemics, there is a mitochondrial cytopathy, I've termed Congenital Acidosic Enzyme-Metabalolic Histangiopathy (1,2),and conditio sine qua non of an awful number of Quantum Biophysical Semeiotic Constitutions (3-5). \nSecondly, as regards both stem cell utilization and cloning, in my opinion (http://www.washingtonpost.com/ac2/wpdyn/comments/display?contentID=AR2007041101736&start=41) a large amount of money on studying stem cells, even in amnyotic fluid, accounts for the reason there is an overlooked bias in such as research articles! In fact, in performing staminal cell researches all around the world scientists overlook both an inherited mitochondrial cytopathy, mentioned above. Independent of different countries, in recent decades diabetes prevalence has increased rapidly over time among both developed and developing populations. Surely, genetic factors alone cannot explain these patterns. However, as allows me to state my clinical experience, an individual, without diabetic AND dyslipidemic biophysical-semeiotic constitutions, and diabetic inherited real risk can not be involved by type 2 diabetes, at all (1-7). Certainly, rapid changes in lifestyle and risk factors such as obesity, unhealthy diets, physical inactivity, tobacco smoking, a.s.o., acting on people with diabetic and dyslipidaemic constitution may cause, AT FIRST, Pre-Metabolic Syndrome, then, over years or decades, metabolic syndrome 2, 6, IGT, and finally type 2 diabetes. In a few words, all around the world, e.g., the war against diabetes mellitus and its well-known and harmful complications, as well as the war against all other serious and common human diseases, is nowadays possible, also utilizing possibly stem cells of whatever origin, exclusively by means of a primary prevention, which must be perform at the bed-side, i.e., clinically, on a very large scale, using the simple stethoscope. In addition, we must in the future utilize stem cell, even of amnyotic fluid, of individuals not involved by above-cited biophysical semeiotic constitutions! In other words, in both primary prevention and screening programme for whatever disease, including DM and its complications, and cancer, we need efficacious clinical tools to obtain the best results, avoiding, e.g., to use staminal cell with impaired mitochondria. Really, early diagnosis must certainly be established in asymptomatic patients, who, for example, are evolving slowly towards diabetes mellitus, i.e. long time before disease onset, in order to avoid the well known, severe complications. In fact, to prevent these diabetic complications, including diabetic retinopathy, on very large scale it is extremely necessary that doctors use a clinical tool reliable in diagnosing early diabetes mellitus stages, from initial stages, i.e., biophysical-semeiotic constitutions, and then the Pre-Metabolic Syndrome See URL: syndrome engl.oc (1-7), useful particularly in selecting appropriate stem cells to be utilized. \nThirdly, sunday April 11,2010, I have announced Manuel's Story (8): spread quickly, the same day, also by The Los Angeles Times: \nhttp://www.latimes.com/features/health/la-he-practical-matters-20100412,0,2670974.story \ndott.stagnarosergio at 10:49 AM April 11, 2010. I have informed on the first newborn NEGATIVE for Oncological Terrain (i.e., predisposition to cancer), in spite of he is son of father and mother both involved formerly by Oncological Terrain, who were advised, in 2008, to undergo Coniugated-Melatonin treatment, namely a lot of months before pregnancy begin (1-5). Technically speaking, Manuel?s parents became positive exclusively for the residual variant form of predisposition to malignancy, which is not dangerous at all, because mitochondrial respiratory chain is perfectly functioning, so that endocellular energy level in every biological system results high. Notwithstanding, physician can recognise with the aid of Quantum Biophysical Semeiotics, the former presence of Oncological Terrain, especially under stress tests (1, 3). \nSuch as Medicine paramount progress opens a new, original way in the war against cancer by means of Primary Prevention. Old proverb sounds that the best of all therapies is Primary Prevention. Surely, if an outstanding, well-known oncologist, rather than the simple Founder of Quantum Biophysical Semeiotics, retired GP since 2000 year, would announce such as Medicine progress, cancer prevalence will next lower significanty: since ever, individual's power is more important and influent than theory POWER! \nIn any case, according to Aulo Gello's statement, Veritas Filia Temporis ! \nAll Authors admit, CANCER continues to be a GROWING epidemics, in spite of the excellent progresses of chemotherapy! \n\nReferences. \n1) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. Gazz Med. It. ? Asch. Sci, Med. 144, 423, 1985 \n2) Caramel S., L?importanza dei mitocondri e del mit-DNA nell?oncogenesi. http://ilfattorec.altervista.org/, 14 aprile 2010, http://ilfattorec.altervista.org/mitDNAoncogenesi.pdf \n3) Stagnaro-Neri M., Stagnaro S. Introduzione alla Semeiotica Biofisica. Il Terreno Oncologico. Ed. Travel Factory, Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm \n4) Stagnaro S. Reale Rischio Semeiotico-Biofisico. Ruolo diagnostico e patogenetico dei Dispositivi Endoarteriolari di Blocco neoformati patologici tipo I, sottotipo a) oncologici e b). Ed Travel Factory, Roma, www.travelfactory.it, Luglio 2010. \n5) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico-Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient Based Medicine. Travel Factory, Roma, 2004. http://www.travelfactory.it/ \n6) Stagnaro S. Diet and Risk of Type 2 Diabetes. N Engl J Med. 2002 Jan 243464:297-298. [MEDLINE]. \n7)Stagnaro S.-Neri M..Stagnaro S., Sindrome di Reaven, classica e variante, in evoluzione diabetica. Il ruolo della Carnitina nella prevenzione del diabetemellito. Il Cuore. 6, 617, 1993, [MEDLINE].\n \n\n
Avatar of: anonymous poster

anonymous poster

Posts: 2

April 19, 2010

I think that the writer needs to be informed that an egg has only one nucleus.

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Mettler Toledo
BD Biosciences
BD Biosciences