Hey, very well written blog. I agree that the majority of increase in diabetes prevelence can be attributed to contacentrated sugar drink (along with our lifestyle). Nonetheless there are two things to be noted. Type 2 diabetes majory begins with insulin resistance. That is to say your body is making insulin fine but is unable to use it. In later stages of Type 2 diabetes you get UPR in Beta Islets , followed by inflammation and everything goes down the drain after that. So if you manage your diet well and follow your doctor's advice type 2 is pretty much cobtralable in early stage.
Second point being that the nature study you mentioned. The mice did not get cured because of caffeine. They had synthetic genetic modification responsive to caffeine. They made modified
transcription factor and made HEK293T cells express them. They then encapsulated these cells and implanted them in a type 2 diabetes mouse model. Then when they fed them caffeine the cells made and secreted glucagon peptide in mice, which improves blood sugar homeostasis.
So I am not sure about caffeine but it might be possible to treat patients with encapsued cells that secrete these hormones.
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Biological transcription factors or actual specialised gland cells??? Great point by the way!!
Well technically all transcription factors will be biological. Tramscription factors are what binds to DNA and promote binding of RNA polymerase in that region, which causes gene expression. Now it is not like the gene switches - where you modify a transcription factor such that you control when and where it binds and expresses a gene, haven't been made before. There have been ones that can be controlled by tetracycline. There are others controlled by light. The selling point of this paper is there system requires a cheap, non toxic and a non antibiotic molecule aka caffeine to control genes.
So all they did was to first design a a caffine binding protein, technically an antibody.Lets call it aCaff This molecule will dimerize (bond together) with another molecule if aCaff if both of them has caffine bound to them. Now a gene switch system for Tetracycline already exists. It has a transcription factor with DNA binding domain and a tramsactivation domain. The transption factor causes expression of genes it is bound to only when both domains come together. So they fused this transcription factor to caffine binding protein instead of tetracycline binding protein. Now you express these fusion proteins in the cells, along with the gene you want to express and there it is. See this figure
https://www.nature.com/articles/s41467-018-04744-1/figures/1
To answer your next question no they did not use glandular cells. They used human embryonic kidney 283T cells. Which is a cell line once made and now commercially available to any researcher. They use this because it is extremely easy to put any DNA in these cells as compared to your actual glandular primary cells or any other cell line for that matter. So they put DNA for their fusion protein in these cells so it express it. Then they use a promoter(A DNA sequence specific to transcription factors ) specific toTetR and fuse it with gene for glucagon peptide (a protein which is already favourite biological for treating type 2 diabetes). Now you also insert this gene in HEK cells that you inserted your fusion proteins in. Now these cells will express gene for glucagon of and only if you treat them with caffine.
The rest of the story is pretty simple. You just add these cells with all your synthetic genes in a microcapsule and implant it intraperitoneal in the mice. If the implamted mice is model for type 2 diabetes(the leptin knockout mice), then serving them coffee improves their glucose homeostasis.
Let me know if you have more questions on this.
Sunny Kataria, AMRSB
I absolutely love the fact that you explained this fully that all makes sense and especially in non-laymans terms! I think the fact that they didn't use actual glandular cells makes sense but my last question is was that because the process for mRNA rewriting is quicker or is it just ease of getting those specific cells?? Great experiment they're doing too gene controlling is something I'm seriously interested in and I will follow for your future posts mate!
Glad I was able to. Well the speed of making mRNA can be attributed to two major factors. One being the promoter and transcription factor of course. The second being the sequence if gene itself. The former decides the binding and availability of RNA pol to the gene and later decides speed at which RNA pol moves on the gene. Since RNA pol is available at sufficient amount in all cells. I doubt if cell type used will affect speed of mRNA synthesis. It can however effect processing if mRNA and its translation. But then this is what I know of , I am not aware of any study done to test how any other factor in nuclei of different cell type effects speed of RNA pol. Any I guess I digressed a bit. But yes for this paper they used HEK because they are smooth to work with then it comes to availability, culture and even in terms of inserting DNA for different genes.
I don't know if you saw my last blog, but I have a picture of HEK cells I inserted DNA inside to produces viruses containing GFP gene (along with some shRNA, but I will keep that secret for now).
Anyway , I don't think that HEK are best cells as far as using this method in humans is concerned. For starters they are transformed immortalized cells. They can grow even if you spit on them (I even tell that to students that come to me for training in the lab) . Moreover they produce all kind of crap that you may not want in your body. So if I was to treat humans with this method, HEK won't be my cells of choice.
Thanks for the hugely informative posts, they're far better explanations than I could hope to write. I think that even with the current rapid advances in medicine, hoping for a straight up caffeinated cure is certainly wishful, but this avenue of research could lead to an inexpensive method of regulating the illness.
This is indeed exciting. Though this is just one avenue. There are many people are working on. I was myself working on inflammatory aspect of Type 2 diabetes where injecting t regulatory cells improved the glucose homeostasis. I moved to continue with another project in the meantime. But will try to list the different approaches in some soon.
Hey thanks. i'm also a firm believer that diet and exercises are the best response to type 2 diabetes, especially in the early stages. Unfortunately I have the willpower of a slug and completely fail to stick to healthy diets for any length of time.
Re the nature study, yeah while it isn't a straight-up cure, I welcome any research that helps to regulate the levels of blood sugar, especially with rising levels of both obesity and diabetes worldwide.
I agree. Another good tip is probably to incline ones bed http://www.inclinedbedtherapy.com