Bit Bio: You can now order neurons online!
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Yea me, and the friends that I messaged about this thought that was crazy too.
I did have an idea of ordering a couple neurons and putting them into a pendant with magnifying lense.., however there is a slightly better use for these neurons.
Let's start with some background stats:
Bringing a drug to market costs about $1.78 billion and takes about 13 years, with a 3.5% success rate. With so many new ideas emerging in the biotech industry, this is a large barrier to the commercialization of any of these innovations.
A partial reason for this is that pre-clinical R&D currently relies on laboratory animals, immortalized cell lines (comparable to cancel cells) or human-derived primary cells (cells taken from real human tissue).
Animals
Although there are animals that we share over 95% of our DNA with, it is quite rare that a treatment that works and is non-toxic for an animal will behave the same way in humans.
Take Alzheimer's as an example. Almost every type of cell in the mouse brain is present in the human brain, which may give off the impression that testing Alzheimer's treatments on mice is effective. Unfortunately, 2/3 of all our shared genes with mice are expressed differently in the same cell types.
Even more specifically, there is a specific gene that makes serotonin receptors turn on in mice, but off in humans. One of the functions of these receptors is to send messages between neurons, which is something that the neurons of an Alzheimer’s patient aren’t very good at. If a drug was made to target these receptors in mice, it would not even be close to working in humans.
Another example is a drug called Fialuridine, which was developed in 1993 and worked really well in animals. When it was tested on humans, it ended up killing 5 and cause 7 to have liver failure. The reason that this happened was because of a protein in our mitochondria that transports the drug from a random space in the cell into the mitochondria. The mitochondria are then poisoned, which means the energy to the liver is cut off. In retrospect, there were only 3 minor differences between DNA and mice that caused this!
For neuronal research, fewer than 10% of findings derived from animal models are applicable to research in humans.
Human Cell lines & primary cells
Immortalized cell lines are comprised of cells that have been mutated to undergo never-ending division. They are therefore, very scalable and are well adapted for research. However, because these cells have gone through years of mutation, the DNA differs significantly from the orinal tissue they belonged to. what isn’t toxic to them can be extremely toxic to humans. Again, the DNA is quite different so cell lines aren’t the most efficient at identifying the effectiveness of a drug on humans.
Human primary cells are usually gathered from donor tissue but are very unpredictable and difficult to scale due to a very limited supply.
Lack consistency, scalability, maturity and purity.
Both of these methods are highly variable: two-thirds of labs that attempt to reproduce someone else's data fail, and more than 1/2 of researchers fail at reproducing their own data.
Pluripotent stem cells — an unlimited source of all cell types
Scientists have been researching this topic for a long time, but have been quite unsuccessful. 10 years ago, it took researchers over half a year to differentiate human pluripotent stem cells (HPSCs) into neural cells. At this rate, using this method was obviously not at all scalable.
Up until recently, the method that scientists have been using to forward program (go from HPSCs to differentiated cells) involved lentiviral transduction. This process includes randomly insert transgenes (artificially introduced genes) into the genome of a cell using a viral vector (a vehicle that can carry DNA), such as one from the HIV virus.
However, since the genetic material is introduced randomly into the cell, there is a high risk of interference with the endogenous transcriptional program (regular protein synthesis in the cell).
If your goal was to teach a monkey how to recite Shakespeare while on a pedestal. Would you start by building the pedestal or training the monkey?
This famous principle that is used by Google X (and other moonshots) applies to this situation quite nicely.
Dr. Mark Kotter, the CEO of bit bio created a goal for his lab: to figure out a way to forward program HPSCs into mature + pure neurons in a scalable way. This was the ‘training the monkey to recite Shakespeare’ part of solving the problem, so he spent years at his lab, with his reputation at stake trying to figure out a method.
Bit bio can now forward programmed HPSCs into neurons in 10 days
About 10 years ago, Shinya Yamanaka, a Japanese researcher discovered a way to reprogram human skin cells into HPSCs, that like embryonic stem cells, are able to become any cell in the human body. When ECSs, Oct4, Sox2, Klf4, and Myc genes (named the Yamanaka factors) are introduced and overexpressed into a cell, the cell will start to backward program into its pluripotent state.
So what this means is that we now have an endless supply of stem cells.
As I mentioned earlier, researchers would previously randomly insert the genes that activate differentiation into these stem cells. Months later they would have an unpure, not fully mature neural cell.
Instead, bit bio has taken a slightly different approach. Genomes have these small sections inside of them called Genomic safe harbours (GSHs). When genomic data is inserted into this site, it ensures that 1, the data will function properly and 2, won’t cause alterations of the host’s genome/create any sort of risk.
The system being used is called the Tet-ON system.
“Tet” stands for tetracycline, and when introduced to the system, the promoter (activator of the next step) is turned on💡. The system also responds to doxycycline (dox) which is synthetically derived from tetracycline.
Dox then activates the release of rtTA (reverse tetracycline transactivator). RtTA then regulates another promotor, which is the one to actually drive the expression of the transgene.
So to summarize, we have Dox (an antibiotic) which activates rtTA, which can then regulate the expression of the transgene we are trying to introduce.
Bit bio didn’t reinvent the wheel on this one, since we had already been using this method to introduce new genes into cells. The part that they did change is that they split this system into two parts. Whereas previously, this was all one large group of steps in one GSH, bit bio has split it into two different GSHs.
Now how this works, is they start by using a vector to introduce the DOX-activated system into one genome safe harbour, and the rtTA activated system into another one. First, they add the Doxyxicline antibiotic to the cell, and then after about 4 days start adding the desired gene. This method creates the highest purity and homogeneity of downregulation (stem cells into differentiated cells).
And that’s it — you’ve just made functioning neurons.
Bit bio has successfully manufactured glutamatergic neurons (90% of the neurons in our brain), as well as skeletal myocytes (muscle cells). They have partnered with Charles River Laboratories, which helps biotech companies through the preclinical/clinical phase.
As of right now, bit bio is focused on figuring out how to manufacture as many different types of cells as possible, however, also are looking into their own cell therapies.
All of this being said, with bit bio’s technology, we can increase the success rate of clinical trials by an order of magnitude, which can bring us several hundreds of steps closer to developing cures to some of the most complicated diseases out there.
My sources for this article:
Hi there😌 — thanks for reading!! My name is Elizabeth, I’m a 15 y/o trying to figure out my way through biology. Currently looking into field of bioinformatics, computational biology and other applications of AI x biotech. If you’d like to chat, or are curious about my progress my LinkedIn and twitter.
