The CRISPR Revolution
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a recently discovered tool for genetic editing. It allows for very precise and directed gene editing, and its discoverers have won the 2020 Nobel Prize.
Source: Lab Associates
The initial CRISPR system discovered was CRISPR-Cas9, and many modified CRISPR systems have been discovered or created since. You can read more about the technical details of CRISPR in our article “What Is CRISPR-Cas12a2? & Why Does It Matter?”
CRISPR is at the forefront of the genomic revolution, with the first gene therapies using it now getting approved for blood diseases, something we explored in depth in “How CRISPR Companies Target Sickle Cell Anemia”.
Since its discovery, finding how to leverage CRISPR to modify a specific gene or DNA sequence has been a painstaking task, requiring a lot of expertise and manual work. But this might change, thanks to the quick development of AI tools.
AI + CRISPR
Researchers at the University of Berkeley have investigated using LLMs (Large Language Models) in combination with CRISPR technology and published their findings in the scientific paper “Design of highly functional genome editors by modeling the universe of CRISPR-Cas sequences.”
More precisely, they gathered a dataset of 1 million CRISPR operons from 26 terabases worth databases of genomes (26 trillion genetic bases).
Then, they used the AI to create millions of diverse CRISPR-like proteins that do not exist naturally, as well as “single-guide RNA sequences for Cas9-like effector proteins”.
Testing the real-life efficiency of these new CRISPR-like proteins and RNA sequences, they found that the generated gene editors show comparable or improved activity and specificity relative to SpCas9.
Why does it matter?
CRISPR-Cas9 was initially found in bacteria, which use it as a defense against viruses.
As a result, bringing CRISPR-Cas9 into a human cell can make gene editing less efficient than in a bacterial cell. This is because the naturally found CRISPR systems are all bacterial and not optimized for functioning in more complex cells.
This also means that it is likely that other CRISPR-like systems could be designed to achieve more efficient, more precise, or quicker results than the naturally occurring CRISPR-Cas9.
However, until now, the quest for such new CRISPR-like systems has been limited to finding new bacterial CRISPR like Cas12 (favored by Editas Medicine), and we hope they are more powerful than the first one discovered.
With an AI able to generate millions of new possible sequences, this opens the possibility of finding the “perfect” CRISPR system for gene therapies in humans. And could also allow for designing a CRISPR system optimized for specific human tissues, and animal or plant species as well.
It could also open the way for new types of gene editing not allowed by standard CRISPR-Cas9, like base, prime, or epigenome editing.
Gene Editing Open-AI
Having demonstrated the potential of an AI-generated gene editor, the researchers have decided to release it to the public.
This AI compatible with base editing has been named OpenCRISPR-1.
Open CRISPR-1 – Source: Profluent
This model was linked to Berkeley-based startup Profluent, the AI-first protein design company. Making OpenCRISPR-1 an open-source software was a decision shared between the Berkeley researchers and Profluent, in a push to democratize the technology.
You can find the files and documentation about OpenCRISPR-1 on GitHub. It is free to use, including for commercial uses, but requires a license agreement in order to monitor whether the tool is used in a safe and ethical way.
AI-Designed Custom Therapies
The potential of OpenCRISPR-1 is absolutely massive, and in the long run might open the way to having much more efficient gene therapies.
Instead, we could imagine that in combination with the now below $1,000 cost of individual genome sequencing, it could allow for customized gene editing. So the CRISPR system used to do gene editing in an individual patient could be tailored to his specific genome, instead of a general template used for everyone.
However, it will take time to do so, as demonstrated by the decade it took to go from discovering CRISPR to having the first therapies approved. Gene editing is never a risk-less endeavor, and the FDA will certainly be cautious and require a lot of data before authorizing the use of untested gene editing systems in humans.
CRISPR Companies
Profluent is not (yet?) a publicly traded company, but many other companies are very active in developing CRISPR technology into commercial products.
1. CRISPR Therapeutics
What sets CRISPR Therapeutics apart is the all-star team of founders, this includes Dr. Emmanuelle Charpentier whose seminal research unveiled the key mechanisms of the CRISPR-Cas9 technology, laying the foundation for the use of CRISPR-Cas9 as a versatile and precise gene-editing tool. Numerous awards have recognized her work, including the Breakthrough Prize in Life Science.
CRISPR Therapeutics is developing an efficient and versatile CRISPR/Cas9 gene-editing platform for therapies to treat hemoglobinopathies, cancer, diabetes, and other diseases.
The first therapy that they were advancing was targeting the blood diseases β-thalassemia and sickle cell disease.
They have now been approved under the commercial name of Casgevy and for both applications. The company’s first allogeneic CAR-T program targeting B-cell malignancies is also in clinical trials.
While sickle cell is a disease with an arguably small market, once the technology is mature they can advance to targeting other disease vectors.
The advances in CRISPR technology like OpenCRISPR-1 can be a great advantage for companies with approved products like CRISPR Therapeutics and its partner Vertex. With a new improved CRISPR system, they could in a few years upgrade the β-thalassemia and sickle cell disease therapies. It would also renew the associated IP and patents, allowing Casgevy to be a profitable product for longer.
2. Ginkgo Bioworks Holdings, Inc.
The company is producing on-demand organisms for specific applications. It has diversified its applications widely with many research programs and partnerships:
Many of these modifications rely on CRISPR or similar gene editing technologies, notably its CAR-T cancer cell therapies.
By providing a ready platform for cell engineering, Ginkgo is becoming a key service provider in the biotech industry, going beyond the pharmaceutical industry and into agriculture, biosecurity, and industrial chemical processes. It provides expertise and speed and can help reduce fixed costs and the quantity of capex needed for a research project.
This is demonstrated by the very diverse array of clients and partners the company has had over the last few years.
Source: Gingko Bioworks
It is an attractive stock for investors looking to bet on gene editing and cell engineering technologies, but not one application in particular. This is also typically more interesting for growth-focused investors.
The appearance of open-source, free tools like OpenCRISPR-1 could be a massive boost for companies like Gingko, which are more focused on developing tens or hundreds of custom organisms and cells than pushing for a specific version of CRISPR or one therapy in particular. This way, it could quickly access CRISPR specific to a plant species or more effective on cannabinoid genes, etc.