John Hemming's Web Log

As I biohacker I do quite a bit of self-experimentation. There is an interesting ethical question about self-experimentation. Obviously people have the right to make their own decisions. Self Experimentation has a long history in Medicine and at least five Nobel Prize winners have won a prize following self experimentation. However, it is potentially dangerous and people have died. The ethical question is whether researchers should be penalised by being unwilling to self-experiment. To that extent some US ethics committee argue against the academic publishing system accepting the results of self-experimentation. I personally, unsurprisingly, think that is wrong. There should not be a condition of employment that people self-experiment, but it cannot be right to exclude the results. We also need to recognise that there are serious problems with animal experiments. Everything Wrong with Mouse Studies (Kinda) subtitled: Odors, magnetic fields, and even a mouse's siblin...

Professor Thomas Seyfried and the Question: Is Cancer Primarily Nuclear DNA or Mitochondrial DNA? Professor Thomas Seyfried argues that cancer is mainly mitochondrial rather than purely nuclear/genetic. Below are the key experiments supporting the view that cytoplasmic/mitochondrial factors, rather than nuclear mutations alone, drive the malignant phenotype. Nuclear Transfer Experiments (Cancer Nuclei → Normal Cytoplasm) McKinnell, R.G., Deggins, B.A., Labat, D.D. (1969) Transplantation of pluripotential nuclei from triploid frog tumors Science, 165(3891):394-6 Summary: Nuclei from frog renal tumor cells transplanted into enucleated eggs developed into normal swimming tadpoles, demonstrating that cancer nuclei retained developmental pluripotency when placed in normal cytoplasm. McKinnell, R.G. (1979) The pluripotential genome of the frog renal tumor cell as revealed by nuclear transplantation International Review of Cytology Supplemen...

Analysis: mRNA Splicing & Childhood Development This analysis evaluates the role of mRNA splicing in human childhood development, distinguishing between splicing as a primary driver of developmental milestones versus a secondary consequence or fine-tuning mechanism. Executive Summary The evidence indicates that mRNA splicing is a critical functional driver of specific developmental phases in childhood, particularly in brain maturation (synaptic plasticity) and musculoskeletal adaptation . While transcriptional changes (turning genes on/off) generally drive early fetal cell fate , alternative splicing takes over in the postnatal/childhood period to drive cellular maturation . Therefore, splicing is likely a primary driver of functional specialization . 1. The Case for Splicing as a Driver of Childhood Development In this context, "driving" means that the developmental change would not occur—or would occ...

Prompt: ""of the diseases of aging which are assocated with changes to RNA splicing" Diseases of Aging Associated with Changes to RNA Splicing Many major age-related diseases have documented links to altered RNA splicing—both via age-related drift in the spliceosome and via disease-specific mutations in splicing factors or cis-elements. Below are key examples by system (not exhaustive, but covering major, well-supported cases). 1. Neurodegenerative Diseases Alzheimer’s disease (AD) What’s altered? Alternative splicing of tau (MAPT) , shifting 3R/4R isoform balance. Splicing of APP , PSEN2 , and various synaptic genes. Mechanism: Mis-spliced tau isoforms are more aggregation-prone and disturb microtubules; age-related decline in spliceosome components (e.g. SRSF and hnRNP proteins) pushes splicing patterns in a pro-pathology direction. Frontotemporal dementia (FTD) and other tauopathies What’s altered? ...

I put a couple of prompts into Gemini and the following came out as answers: Impact of RNA Splicing on Endothelial Function in CVD User Query To what extent are protein changes as a result of RNA splicing changes that cause endothelial problems part of cardiovascular disease? AI Analysis Protein changes resulting from aberrant RNA splicing in endothelial cells are not merely bystanders but are increasingly recognized as active drivers of cardiovascular disease (CVD). To answer your question directly: these changes contribute to CVD to a significant extent by creating "molecular switches" that can flip a healthy endothelial cell into a diseased state without necessarily changing the total amount of the gene being expressed. This process often explains why a patient might have "normal" levels of a protein but impaired function. The following s...

The principal mitochondrial K+ uniport is associated with respiratory complex I is an interesting preprint that has been withdrawn "due to disagreement with UCSF over data rights. This withdrawal decision is not related to the validity of the data presented in this study, and these authors understand that this work cannot be cited as reference for the project until the disagreement is resolved." It remains, however, interesting. The reason I find it interesting is that there is clear evidence that there is a link between the delta pH between the mitochondrial matrix and Intermembrane Space and the mitochondrial membrane potential. This was evidenced in experiments which varied one and saw the proton motive force (which is the total of the two adjusted for the same units) remain essentially constant. Furthermore it seems that where Potassium Ion transport changes with age we can also see a reduction in the membrane potential, but an increase in delta pH. This is signif...

These are two lists of reviews looking at mainly acetyl-CoA, but also other acyl-CoAs. They were selected by a search using chatGPT for the first one and Claude for the second one. Some are behind a paywall. My plan is to read through these and draw out conclusions I will separate out the ones which are behind a paywall. Acetyl-CoA: a central metabolite and second messenger (Cell Metab, 2015) Acetyl-CoA and the regulation of metabolism (Trends Biochem Sci, 2015) Spatiotemporal control of acetyl-CoA metabolism in chromatin regulation (Trends Biochem Sci, 2018) Compartmentalised acyl-CoA metabolism and roles in chromatin regulation (Molecular Metabolism, 2020) Should we consider subcellular compartmentalization of metabolism? (Trends Cell Biol, 2019) The multiple facets of acetyl-CoA metabolism: Energetics, biosynthesis, regulation, acylation and inborn errors (Mol Genet Metab, 2023) Molecular targets and small molecules modulating acetyl-CoA metabolism (ACS Pharmacol Transl...

I recently read a paper Ribonucleotide incorporation into mitochondrial DNA drives inflammation which I found very interesting. The reason I found it interesting is perhaps summarised in the first paragraph of the discussion section which I will quote: We demonstrate that increased incorporation of rNTPs into mtDNA during replication leads to the release of mtDNA fragments from mitochondria and proinflammatory signalling. Our results therefore highlight the challenge that the high molar excess of rNTPs relative to dNTPs poses to cells. Although RNase H2 removes incorporated rNMPs from nuclear DNA as part of the ribonucleotide excision repair pathway, this repair mechanism is not present in mitochondria, which are therefore prone to accumulating rNMPs in their genome. Similar to the effect of rNMPs on nuclear DNA replication27,40, due to the inherent reactivity of the 2′-OH group of the ribose ring or collisions with the replication fork, misincorporated rNMPs may cause DNA strand br...

People who study NCD (Non Communicable Diseases) and particularly those that focus on the diseases of aging (which I think include many of the NCDs, but not all of them) have a concept of someone having a biological age as well as a chronological age. This guides things like how frail someone is, how well their cognition works, whether they are at the risk of cancer or diabetes or indeed how they look. Human beings are quite good at judging each other's general health by appearance. That is because the various NCDs tend to correlate with how well the body maintains the skin and when someone is frail it is quite easy to see this by how they move around. Regular readers of my blog will know that I think this is because the genome stops functioning properly as people get older. In essence cells stop producing the right proteins. I provide full details of this hypothesis on this web page https://citrate.science/2025poster/poster2025.html . Various approaches have been used to cal...

I tend to ask chatGPT for a summary of the transcript of videos so that I don't have to spend the time watching them. I have done this for the ALS Scientific Advisory Council from about a month ago which follows (the critique is of chatGPT - my critique is that they don't talk about mitochondria, the closest they come to epigenetics is DNA methylation): International Alliance of ALS/MND Associations Scientific Advisory Council Webinar – Transcript Summary Opening & Housekeeping Jessica Mabe (Programs Coordinator, International Alliance) welcomed attendees and introduced the webinar, noting caption availability (via Zoom chat or QR code) and thanking sponsor Mitsubishi Tanabe Pharma . The Scientific Advisory Council Chair & Moderator: Dr Nicholas Cole (Head of Research, MND Association, UK) Panelists: Dr Kuldip Dave – Vice President of Research, ALS Association (USA) Dr Nadia Sethi – Co‑chair, NE...

I think it is useful to try to identify: a) The most heavily energy using neurons b) The balance in those cells between OxPhos (which produces Reactive Oxygen Species - ROS) and Glycolysis I will be using various LLMs to search for information relating to this and will be spending time checking the responses for hallucinations, but I may not at the time of you reading this page finished validating everything. I will also be concentrating on validating the analysis for dopaminergic and motor neurons because those are the neurons which cause PD and ALS/MND. In principle the rank is not really valid. Although this table is produced using a ranking that is not going to be reliable, it is still useful. What I am trying to get from this is to identify the cells which would be vulnerable to rapid deterioration through ROS. The first step is those with a high energy usage. This, however, I would expect to vary from time to time and any actual accurate calculation for one human being ...

Regular readers of my blog will have seen that I think there is solid evidence that some neurodegenerative diseases such as ALS (MND) and Parkinsons are caused by a deterioration of mitochondrial DNA primarily because of damage by free radicals (Reactive Oxygen Species - ROS) in the cells. This gradually causes the cells to fail to produce the right proteins and the cells stop working. I think the reason this happens in ALS (MND) and Parkinson's disease is that the cells that suffer are ones which both have a high energy demand, but also make high use of Oxidative Phosphorylation (OxPhos). Hence the mitochondria generate damaging molecules at higher rate which damages the mitochondria at a higher rate than normal. Cells have systems to deal with this, but once it gets to a certain point the deterioration becomes more rapid. Cells in the Central Nervous System have a supply of melatonin via the CerebroSpinal Fluid (CSF) that helps to resist this, but if there is a shortage for...

Given the links between mtDNA damage, splicing, ALS (MND) and PD, an obvious thing to look at is Multiple Sclerosis. MS is a failure of the myelin sheaf. It has been thought to be as a result of an auto-immnue response, but an alternative perspective would be a failure of homeostasis. I thought I would ask chatGPT to look at both sides of the argument about splicing and this is the response: chatGPT O3 response to question: " what are the arguments for and against multiple sclerosis resulting from aberrant splicing in the production of myelin " The summary result from chatGPT is: Bottom line The case for aberrant splicing in myelin production as a contributor to MS is biologically plausible and experimentally supported, but the case against it being the primary cause remains strong. At present, the weight of population genetics and virology favours a model in which immune dysregulation (often EBV-driven) comes first, with myelin-splice errors acti...