Highlights
British biotech startup Bit Bio, owned by Cambridge University and formerly called Elpis Biomed, has raised $103 million in Series B funding.
Bit’s goal is to commercialize its proprietary Opti-OX technology platform to produce stable and scalable batches of absolutely any human cell. The industry’s need for the latter is extremely high and still unmet: they are needed for scientific research, new drug development, and the creation of cell therapies. The widespread availability of human cells opens up prospects for the accelerated emergence of highly effective drugs against cancer, autoimmune and neurodegenerative diseases.
In simplified words, the Opti-OX platform embeds the desired genetic code directly into the DNA of human stem cells, activating transcription factors that reprogram the cells for a specific function, telling them what to do. What makes Opti-OX unique is that the approach is consistent: each time the code is injected into the cells, the reprogramming is activated in the same way. This means that Opti-OX is a scalable solution, unlike other reprogramming technologies.
According to Bit, life is the final frontier of mathematics, as living organisms exhibit extraordinary brevity and elegance that are the hallmarks of mathematical structure. The human genome is only 3 gigabytes of data. Viruses occupying 7 kilobytes can call the right subroutines from the genome, similar to the way modular software works. If the proper nuances of the “operating system of life” are revealed, the creation of human cells will become as uncomplicated as the creation of software. The paradigm of biomedical sciences will change from observational to predictive.
Mass production of all kinds of human cells is a real breakthrough, and Bit is sure that the day when science fiction will become reality is not far off: new organs — liver, kidneys, lungs, and heart — can be printed on a biological printer.
The cumulative investment in Bit has already totaled $145 million.
Details
Continuing biotechnological progress has advanced medicine incredibly seriously, launching new and highly effective medicines. From low-molecular-weight compounds, the treatment of diseases has moved to powerful biological approaches, addressing modalities such as monoclonal and bispecific antibodies, gene therapy, gene editing, and cell therapy, for example.
Yes, testing scientific ideas on animal cell lines and models can be successful, but subsequent clinical trials in humans often fail because human biology is different from that of rodents and primates. Much would change if it were possible to study experimental drugs on human cells, but pharmaceutical companies still face a distinct shortage of them due to the lack of a scalable source that is readily available and renewable.
- What are human cells for? For decades, the pharma industry has relied on animal models to determine measures such as toxicity and efficacy of experimental drugs and to validate their targets. However, not only are animal models expensive and time-consuming, but, most importantly, they are far from being relevant to human biology. This is because animal models of disease are often completely contrived.
- Take Alzheimer’s disease, for example. Toxic accumulations of amyloid beta, which forms from the amyloid precursor protein (APP), are thought to be to blame for its development. Mouse models expressing high levels of APP in the brain show the classic phenotype of Alzheimer’s. However, it does not develop naturally in mice as it does in humans. This is why such animal models do not reflect the true biology of the disease. Thus, the translational reliability and prognostic value of the mouse model for developing treatments for Alzheimer’s is not particularly impressive.
- It turns out that preclinical work is being done on imperfect models, and it is not at all surprising how many candidate drugs fail in human clinical trials. A new model is needed.
Human cells are difficult to obtain: not only is it difficult to obtain enough cells from an individual human, but often some types of cells are not available at all. An alternative method that involves creating the right types of cells from stem cells is fraught with instability, duration, and complexity of the relevant protocols, which are all the more difficult to reproduce and scale. By the way, these same problems prevent the use of cells for initiatives such as biological meat production and laboratory-grown skin.
The help comes in the form of cellular reprogramming, which is understood as the activation of a new cell type program by bypassing the usual intermediate stages of cell development. The approach makes it possible to obtain real stem cells from a blood or skin sample of any person. Shin’ya Yamanaka and John Gurdon won the Nobel Prize in Medicine and Physiology in 2012 for this discovery. Their development closed the ethical issues associated with the use of human embryonic stem cells. Subsequent reprogramming of the stem cells transforms them into any desired type, be it brain, liver, or blood cells. That would be all right, but generating the right type of cells from stem cells is tied to the inefficiency of the process itself, where the harvest of cells is too small relative to the cost.
Bit has developed a proprietary genetically engineered technology platform, OPTi-OX (optimized inducible over-expression), which allows the precise reprogramming of whole stem cell cultures into any other somatic cell type, doing so with high precision and high throughput.
Bit has modified the algorithm for direct transformation of human induced pluripotent stem cells (hiPSCs), implemented by forced expression of transcription factors. The OPTi-OX technology systematically optimized the expression of inducible genes in hiPSCs through a strategy of dual genomic targeting of genes at their “safe loci”, paving the way for robust and deterministic direct reprogramming of hiPSCs into cells including neurons, oligodendrocytes, and functional skeletal myocytes.
Traditional methods of hiPSCs direct programming turn to lentiviruses to insert a transgene encoding a transcription factor into the cellular genome. The problem is that the lentiviral method works like a scattergun, scattering (inserting) transgene randomly throughout the genome.
Additionally, stem cells strongly resist being remade and therefore activate a mechanism to fight the unauthorized genomic material — trigger the process of gene silencing by compacting chromatin with blocking the transcription machine’s access to the transgene. The desired gene expression turns out to be variable or absent altogether.
What if we directly place the transgene in a “safe” place and in a configuration where it is almost invisible? OPTi-OX does this by so-called genomic safe harbors (GSHs), regions of the genome where genes are easily expressed and the risk of silencing is minimized. The most commonly used GSH is adeno-associated virus integration site 1 (AAVS1) on chromosome 19. The use of GSHs means that there is no risk of disruption of any important endogenous processes that could induce oncogenes.
It is appropriate to think of GSH as a kind of USB port: the transgenic construct is a program that plugs into the genomic “hard drive”. If all goes well, the program is started and the transcription factors begin to reprograming the stem cells.
The OPTi-OX technology platform overcomes the limitations of direct programming based on virus-mediated transgene delivery and minimizes genomic off-target effects, and is characterized by a number of positive properties:
- Contains an on/off switch to control the expression of transcription factors during the reprogramming process with further deactivation after achieving complete cell transformation.
- Endows reprogramming factors with resistance to endogenous silencing mechanisms.
- Provides very high levels of transgene expression necessary for a successful cellular transformation process.
- Ensures that all successfully reprogrammed cells are genetically identical and do not contain genomic alterations that could potentially disrupt target cell function.
- Does not depend on the optimization of protocols for production and titration of lentiviral vectors and subsequent transduction of hiPSCs, which are a traditionally difficult cell type to transduce.
- Enables complete predictability and reproducibility of the resulting direct programming protocol among different laboratories and users.