Organ Manufacturing: Build Log 001
I recently received some funding to explore a tissue therapeutic idea of mine. I thought it would be a good idea to publicly document my research process, so that’s what this build log series aims to do. I have a few reasons for doing so, namely to:
Connect with other researchers in this space.
Document my thinking and learnings as I go along, including sharing what doesn’t work.
Share every detail of my approach so I can get feedback/questions earlier, and therefore make my work as reproducible as possible
It’s just nice to share what I am doing with people
What’s the general idea?
I want to see if it’s possible to halt, and potentially reverse early-stage kidney disease in patients via tissue transplants.
The thinking here is that in early-stage kidney patients (stage 2-3) the main loss of function is the kidney’s ability to filter the blood. When left untreated, this leads to further loss of other kidney functions (as I have mentioned in previous posts, the kidney is responsible for a lot of things). The hypothesis is that if I can figure out how to solve the filtration problem that occurs in stage 2 -3 CKD (chronic kidney disease), then this should be able to halt the progression of the CKD, and potentially reverse it.
The part of the kidney that is responsible for filtering the body’s blood is called a “nephron”, which is made up of things called the glomeruli, tubules etc (you can read more about how a kidney works in my posts here and here). When there is an issue with the kidney’s ability to filter blood, it is usually because these nephron units are damaged in some way, so this is the specific area I want to focus on solving.
What’s the specific approach?
As of now, I have two high-level ideas.
Replace the faulty nephron units
As mentioned earlier, my understanding is that faulty nephrons, left untreated, has a negative domino effect on the kidney, resulting in the loss of the kidney's other functions until it becomes full-blown kidney failure. So one idea is to simply replace some of these damaged nephron units with healthier ones, therefore restoring previous filtering ability and preventing further kidney damage.
Some potential challenges with this idea
Assumes damage to the nephrons is in a local area (and not spread out across all nephrons, or several nephrons in different places)
Assumes it’s surgically possible to remove nephrons
Add new nephron units (whilst keeping the faulty nephron units)
An alternative to the above idea is to simply add more nephron units (and leave the damaged nephrons untouched)
Some potential challenges with this idea:
Assumes there is space for more nephrons (when we are born, we have a fixed number of nephrons, so the kidney technically was not designed to take on extra nephrons)
Assumes keeping the damaged nephrons and simply adding more nephrons will increase the kidneys filtering abilities
Assumes keeping the faulty nephrons will have a reduced to near enough zero impact if the overall number of healthy nephrons increases
Both approaches also assume that:
It’s possible to create an artificial nephron unit
It's surgically possible to connect an artificial nephron unit to an already-formed kidney
How will I spend this year of research?
Basically testing out all those assumptions, more specifically, answering the following questions:
Is it possible to create a functional piece of nephron tissue?
Is it possible to integrate an artificial piece of nephron tissue (assuming this is possible) into an already-formed kidney?
Does the addition of artificial nephrons (assuming this is possible) greatly increase eGFR?
The goal is to do a bunch of experiments proving (or disproving) these assumptions and answering these questions.
How will you measure success?
We measure the nephron's ability to filter blood using eGFR. There are accepted ranges of eGFR for different stages of kidney failure. Success would be reversal by at least one stage e.g the eGFR of stage 3 CKD to the eGFR of stage 2 CKD.
What have you done so far?
Lots of background reading on how to kidney works, general reading of different types of kidney disease, tissue engineering concepts etc. You can read about some of my research in my previous posts (although it is more focused on organ manufacturing in general).
Some readings I have done on this specific approach and the above topics so far:
Glomeruli damage
Artificial nephron/glomeruli
Impact of increasing nephron units
Kidney organoids
I haven’t done any lab work yet, but that should be changing soon.
What are your next steps?
I need to first choose the specific type of kidney disease that I will focus on. For example, a condition such as polycystic kidney disease impacts all parts of the kidney from day one, so this would not be an ideal problem for me to focus on. It is also a genetic problem, so the solution may only last a short time before the issue arises again (however, this is an assumption of mine that may be false, so I will still look into this).
My initial hunch is to focus on glomeruli-focused kidney damage. There is no particularly good reason for my choosing glomeruli-focused kidney damage over tubule-focused kidney damage, other than the fact that there is more research done on this sort of kidney damage, so this particular starting point is also subject to change.
I also need to figure out how I will create an artificial nephron unit. I was deciding between decell-recell (a methodolgy I have written about here) and self-assembly (basically “growing” the nephron tissue in a dish). I have opted to start investigating the latter as one of the key definers of success for me will be the lack of immunosuppressants. So far there is more evidence to support that the latter won’t cause an immune response, hence no immunosuppressants, so I thought it best to start here.
Goal for this week?
Choose a specific type of kidney damage to start with
Create a short list of protocols for inducing this damage in kidney organoids
Create a shortlist of protocols for self-assembling nephron tissue
Create a shortlist of protocols for combining tissue with a larger piece of tissue/organ (not limited to the kidney)
Early draft of experiment design
Draft of equipment needed (along with costs)
Figure out my lab space plans, as it is still a little up in the air at the moment
Anything else I need to know?
My posts won’t provide as much background in the future. Most likely, the structure of the posts will simply be something like this:
“What I have done this week”
“What I have learned this week”
“How I will move forward next week”
“What are my blockers” etc.
It makes it easier for me to write, and therefore more likely for me to actually post something on a regular cadence.
It is worth mentioning that this is an experiment, so this may very well fail! But I am excited to see how this goes.
If you have gotten this far, thanks for reading - I appreciate it! If you have any questions, feedback, or just want to chat about what I am doing, you can reach out to me via email adaobiadibe23@gmail.com
Thank you for the log. You probably will need to understand what damaged your kidneys much better. It seems natural to focus on AOSD-related kidney diseases.
This letter mentions that "the current understanding of specific immune abnormalities associated with different kidney diseases is quite rudimentary":
https://academic.oup.com/ckj/article/15/2/366/6425749
How to understand better what caused your condition?
This is awesome :)