"“We have lent a huge amount of money to the U.S. Of course we are concerned about the safety of our assets. To be honest, I am definitely a little worried.” "

Chinese premier Wen Jiabao 12th March 2009

""We have a financial system that is run by private shareholders, managed by private institutions, and we'd like to do our best to preserve that system."

Timothy Geithner US Secretary of the Treasury, previously President of the Federal Reserve Bank of New York.1/3/2009

Friday, April 04, 2008

Mitochondria, the charlatans promoting the Embryology and Fertilisation Bill, and all that jazz.

"...all living things must be continuously fed with energy and I am convinced that an understanding of the process of energy production will eventually help us in solving some of the practical problems of medicine."
Hans Krebs 1953 on receiving the Nobel Prize

Whilst it would be absurd to elevate the current level of discussion about the UK's Human Embryology and Fertilisation Bill as a debate, it does expose the levels of ignorance that commentators anxious to air their views publicly can exhibit.

We all inherit from our mums the tiny and essential cellular organelles called mitochondria. These chemical factories, utilise a fascinating process of cellular respiration so wonderfully and beautifully elucidated by the German Jewish refugee Hans Krebs at Cambridge University just prior to the Second World War , as the "citric acid cycle" , now eponymously named the Krebs cycle after he shared the award of the Nobel Prize for Medicine in 1953.... and made such a typically self effacing remark that giants of science make who have uncovered one of the major secrets of Life. Lord Patel was immensely lucky to have been taught by his collaborator Hans Kornberg who edited the Sheffield University Rag magazine as a
student, and he is a member of the British Humanists Association the only characteristics he shares with Lord Patel... whose understanding of the citric acid cycle was finally re-inforced Professorily by his reducing the steps of the cycle as a strip cartoon - an unorthodox but highly effective method of conveying the essentials of the subject.

In the cells of aerobic organisms this universal process is a critical part of a metabolic pathway which converts carbohydrates, fats and proteins into carbon dioxide and water to generate a form of usable energy.

The number of mitochondria in vertebrate animals varies with ther energy requirements of the cell, muscle cells have many more than , say nerve cells. They can move, grow and more importantly replicate or reproduce.

Within the central core or matrix of mitochondria is a very specific form of DNA which (as found in bacteria) is circular in form (graphic image here) and reproduces independently of the cell in which it is found; an apparent case of endosymbiosis this is given the shorthand of mtDNA. This is the unique contribution your mum makes - your dad has no part in it.

The entire human mitochondrial DNA molecule was completely mapped [1][2] in 1981 and it contains 16,569 nucleotide pairs - whilst the genetic code is universal , mitochondrial DNA does show a few notable exceptions. The "stop codons" are “UAA”, “UAG”, and “UGA”. In vertebrate mitochondria “AGA” and “AGG” are also stop codons, but “UGA”, codes for tryptophan instead. “AUA” codes for isoleucine in most organisms but for methionine in vertebrate mitochondrial mRNA/tRNA.

So mitochondria also contain their own transcription, translation, and protein assembly machinery. As such, they are able to maintain genomic independence from the nucleus although most mitochondrial proteins are encoded by nuclear DNA (nDNA) and imported into mitochondria.

A mitochnodrion hosts about 3,000 such proteins but only 37 of them are coded on the mitochondrial DNA which relate specifically to Adenosine Tri Phosphate (ATP) production an essential component in the cell respiratory cycle.

Thus, oxidative phosphorylation , the unique biochemical process that producs our cellular energy is achieved by a well-coordinated effort of the protein products from two separate genomes (nuclear and mitochondrial) working in conjunction within the same cells. (This is a very important matter to understand - see later)

A new study of how cancers metastasise (grow and spread within the body) published this week in Science has shown that mitochondrial mutations can spur metasasising - which can , in mice be reversed by drug treatment.

Cancer researchers a decade ago discovered that mtDNA in tumor cells tends to be riddled with mutations - more than in normal healthy tissues. Some researchers think mtDNA may cause tumors whilst others say that such mutation is a result of cancer not a cause. For example , patients with mitochondrial diseases are not particularly cancer-prone, and cancer risk is not inherited maternally, as would be expected for a disease linked to mitochondria. For a full history and overview of such research this is an ideal introduction.[3]

To explore the role of mtDNA mutations in cancer, Jun-Ichi Hayashi's group at the University of Tsukuba in Japan and collaborators swapped the mtDNA of two types of mouse tumor cells: one that tends to metastasise and another that does not. When they injected these hybrid cells under the skin of mice, the cells grew into tumors that eventually spread to the lungs. Mice that received the mtDNA from metastasising cells had many more lung tumors than mice that had mtDNA from less metastasis-prone cells, suggesting that mtDNA was indeed the culprit.

However, mtDNA did not seem to be involved in primary tumor formation: When the group swapped mtDNA from metastatic cells into normal cells, it did not cause these to form tumors.

The metastatic mtDNA seems to owe it's matasasising trick to 2 identifiable mutations that caused the mitochondria to overproduce so-called reactive oxygen species, which are toxic, DNA-damaging molecules. When the researchers put a drug (an anti-oxidant) that soaks up these molecules into the drinking water of mice that had been given metastatic cells under the skin, they developed almost no lung tumors.

This has excited many researchers as the role of anti-oxidants in cancer has been a hot topic for many years ( and used by the unscrupulous to sell all sorts of crap - see pic) ... maybe this research will help to shed a litle more light on the purpose and function of these essential cellular components in the never ending search for a defence and solution to human cancers.

What it does demonstrate is that producing hybrid cells combining say, the maternal mtDNA from a cow with the nucleus of a human is highly unlikely (probably impossible) to provide the basis for accurate, carefully controlled , rational, reproduceable, physiological experiments until we can fully elucidate the role of mitochrondrial DNA and the nDNA / mtDNA roles and functions.

That is a level of argument that does not enter the public consciousness , and certainly not the debate - we hope this helps a little with your understanding of one of the many issues involved in the debate.

However Lord Patel's opposition to the Bill is more concerned with the ever increasing power of the Human Embryology and Fertilisation Authority which is virtually 100% owned by the IVF industry who are so anxious to maintain their monopoly and profits ... and please don't mention to them the advisability of maintaining the genotypes within the human population whom chance, disease, God, intelligent design have rendered infertile.

[1] Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG: Sequence and organization of the human mitochondrial genome. Nature 1981, 290:457-465.
[2] Grivell LA: Mitochondrial DNA. Sci Am 1983, 248:78-89.
[3] Jennifer S Carew and Peng Huang Mitochondrial defects in cancer Molecular Cancer 2002, 1:9doi:10.1186/1476-4598-1-9

They raise these questions to answer the role of mitochondria in cancer :

(1) What is the exact role of mtDNA in cancer initiation and progression?
(2) How do heteroplasmic mtDNA mutations arise and evolve to a homoplasmic state in cancer cells?
(3) Is there a mechanistic link between mtDNA mutations, changes in respiration and ROS generation, and alterations in apoptosis?
(4) What are the most important mtDNA mutations that confer drug resistance and growth/metastasis advantage in clinically relevant cancer cells?
(5) How can we effectively kill those cancer cells that carry mtDNA mutations and become resistant to conventional anticancer agents?

A lot to do before we start mucking about with hybrid animal / human cells.

This article in Nature Reviews Genetics, advance online publication, 27 March 2008 doi:10.1038/nrg2348
Coordination of gene expression between organellar and nuclear genomes - Jesse D. Woodson1 & Joanne Chory .... reviews a lot of current work in this area, "...we review recent advances in elucidating the intracellular signalling pathways that coordinate gene expression between organelles and the nucleus", although much of it relates to plants as there is a functional and anatomical similarity between chlorophyll containing plant chloroplasts and animal mitochondria.
Here is a website that (last updated 04 May 2005 ) that provides information / support / personal stories of the inheritance of the A3243G gene defect, (carried by 16.3 per 100,000 of the adult population) on the Mitochondrial DNA which 'causes' / is associated with several problems, including Tinnitus, Diabetes amongst others.

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