hi @orthogs - Many practical factors including a current expertise, past work, ability and interest to build on findings with a focus on uncovering the pathomechanism rather than completing one study, technologies and data processing pipelines at the centres (critical), and a working relationship. Crucially, the scientists’ appreciation of what is happening to patients based on literature, our data and experience with the more peculiar aspects. As an additional benefit, the cost would be significantly higher - I would expect double - if we were paying for personnel and work. We are only being charged the cost of sequencing.
Regarding the aims of this study: To find alterations that provide a basis for cell/animal modelling of the pathology. Obviously Baylor’s report, unlike the findings and hypotheses in other prior investigations, tie directly to the entire network of PFS symptoms - physical, sexual, and neurocognitive. As many of these are relevant to the symptoms in other tissues affected (brain, bone, skin, liver, etc), it strongly suggests that a cross-tissue mechanism is occurring in androgen target tissue. There isn’t another explanation for how one pill cases, or cases triggered suddenly after potentially years, have such an onslaught of multisystem symptoms occurring together, which include very peculiar and specific symptoms not seen in other conditions. I can say from experience, it’s very unlikely a doctor will believe you when your penis is eroding progressively and your semen has turned to water after a brief exposure to finasteride, and you cannot safely cross a road anymore due to complete cognitive incapacity. A lot of what happens in PFS is remarkable and novel, especially at the hard end, and as one of Irwig’s papers states “the symptoms reported go far beyond what is formally assessed by the ASEX”.
In terms of the “best” option, this is the option that made the most sense to us at this time. I would certainly prefer the investigate to use tissue from the brain and prostate, the sites of highest AR activity, but as you can easily imagine there are no reasonable paths to obtaining that. As the tissue used in Baylor is now validated twice in studies (Di Loreto also) as affected and is a tissue used in prior research by the scientists in Kiel, it’s sensible and justifiable to proceed with it.
In terms of mechanism: To mechanistically explain the changes in quantifiable RNA it is necessary to identify underlying changes that can explain this dysregulation. Investigation of this sort was suggested in the conclusions of the report at Baylor and we are in contact with them about it. Methylation and induced structural and quantitative rearrangement of chromatin can cause permanent changes in gene expression tissue-specifically, and AR overexpression is demonstrated to be able to induce genome wide level. This investigation is of course genome wide, so it will be a broad and neutral data based investigation.
We had also seriously considered projects with centres including CIBIO in Italy, which I visited, and Mt Sinai in New York, but they are not feasible at the moment. We had received a number of other proposals but the scientists involved were not convincing as a sensible option or well experienced, not familiar with the issue, had concerning and mistaken beliefs about the condition, provided poor study plans that were underpowered/conflicted with better advice received, etc etc. We are still working to find a way to a sensible genetic study with Mt Sinai/Norway if possible in the future, but it is not as simple as patients may assume to do something that could be of practical value. Power is limited by rarity, particularly of severe cases. After long consultations and conversations, including with a really good professor (not involved in this) published well in both Nature and Cell herself - and who has identified genetic predispositions to diseases before - neither they or I were confident at this time we had yet a solid way of proceeding. There are modern ways and means we were hoping to utilise, so the conversations aren’t closed. The key issue is that that sort of study may not show anything clearly, and could easily end up needing repeating if it’s done inappropriately. We’re not rushing anything and don’t have anything more to share.
It is going to be extremely hard to assess scientific proposals as a patient, but the expertise and prior work there is quite demonstrable and should speak for itself. In terms of a better understanding of epigenetics, I would recommend, presuming a textbook isn’t going to be on the cards, the paperback book the epigenetics revolution. It’s only about 400 pages and does include a broad overview of the determinant role of chromatin structure in gene expression. The best short “layman” but workable description of the gene to protein translation and transcription processes I can recall reading was in a book called Gene Machine Venki Ramakrishnan, who won the Nobel prize for his work determining the structure of the ribosome (the book is about that so probably not worth buying if you’re not interested beyond that). Both are paperbacks that are likely easy to find. Hope that answers your questions.
) of progress towards beating this!
