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, a story we explored in “Investing in Nobel Prize Achievements – CRISPR For Precise Genetic Engineering.”
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 “Sickle Cell Disease Gene Therapies Approved by FDA Highlighting Potential of CRISPR/Cas9 Technologies”.
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.
CRISPR & AI
The first step in merging AI with CRISPR technology was taken a few months ago with “OpenCRISPR-1″, an open-source AI made to design a custom CRISPR system for specific situations (follow the link for our associated article).
Now, a new step is happening with CREME (Cis-Regulatory Element Model Explanations). CREME is able to browse through in-silico through thousands, or hundreds of thousands of possible mutations and assess their therapeutic potential.
This research was conducted at the Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, New York by Shushan Toneyan & Peter K. Koo, and published in Nature Genetics under the title “Interpreting cis-regulatory interactions from large-scale deep neural networks”.
Peter Koo – Source: CSHL
Scaling Up CRISPRi
What the CREME AI system does is a virtual version of CRISPi, or CRISPR interference. CRISPRi is a method to turn down specific genes on demand using CRISPR technology, by using it to create something similar to RNAi methods (RNA interference).
In theory, CRISPRi can provide very valuable insight into gene functions and their connection to cellular signaling, metabolic pathway, hormone & immune system responses, etc.
In practice, CRISPRi is money and time-consuming, limiting its real-life applications. So this is where the idea first to simulate CRISPRi through AI came from before deciding which ones are worth exploring.
CREME allows scientists to make similar changes in a virtual genome and predicts their effects on gene activity. In other words, it’s almost like an AI version of CRISPRi.
“In reality, CRISPRi is incredibly challenging to perform in the laboratory. And you’re limited by the number of perturbations and the scale.
But since we’re doing all our perturbations [virtually], we can push the boundaries. And the scale of experiments that we performed is unprecedented—hundreds of thousands of perturbation experiments.”
Peter Koo – Assistant Professor at Cold Spring Harbor Laboratory.
Understanding Genome At Scale
There are at least millions of mutations that can be of interest to research in genetics and genomics. So this is very much like looking at a needle in a haystack. And despite progress in genome sequencing, multiomics, and lab automation, testing potential ideas one by one is still too time-consuming.
CREME instead turns this process into thousands of virtual experiments with the click of a button. This can be used to begin identifying and understanding key regions of the genome.
AIs Synergy
A growing trend in using AI for fundamental research is to leverage several ultra-specialized AIs in one research project. This is because each AI is usually designed to do only one specific task. One AI’s output can become another AI’s input for further insight at ultra-high speed.
In this research, they combined CREME with another AI tool, Enformer, a Google AI able to predict how DNA sequence influences gene expression. The combination of the 2 AIs allowed Peter Koo’s team to uncover a series of genetic rules that Enformer learned while analyzing the genome.
This is an important discovery, as in practice, many AIs are somewhat a “black box” with no clear indication of how the deep learning neural network reaches its conclusions.
This also could help make RNAi and CRISPR techniques more precise:
“Understanding the rules of gene regulation gives you more options for tuning gene expression levels in precise and predictable ways,”
Peter Koo – Assistant Professor at Cold Spring Harbor Laboratory.
Overall, these new AI tools are likely to deliver new therapeutic targets and contribute to an overall better understanding of how the genome works.
No Need For A Lab?
Another effect of these digital tools is that they can give way for researchers who do not have access to facilities to do advanced genetic labs to contribute to new findings.
Not all the best minds in biology and medicine necessarily have access to millions of dollars of budgets and top-of-the-line labs. We also know from the history of science that sometimes, the most transformative ideas come from out of mainstream research.
So not only AI tools like CREME can help researchers currently working with CRISPR and other genomic transformation tools, but it could also empower other scientists with fresh ideas, especially in non-Western research institutions that might be less well funded.
For example, we could see CRISPR and CRISPRi more widely used for agriculture or synthetic biology.
Investing in CRISPR
With the approval of the first gene therapy using CRISPR, the focus of CRISPR investment has been on rare diseases and gene therapy.
But the technology is much more versatile than that, with potential in cancer therapy, metabolic diseases, aging, agriculture, synthetic biology, etc.
You can invest in CRISPR companies through many brokers, and you can find here, on securities.io, our recommendations for the best brokers in the USA, Canada, Australia, the UK, as well as many other countries.
If you are not interested in CRISPR companies solely, you can also look into biotech ETFs like WisdomTree BioRevolution UCITS ETF (WBIO), VanEck Biotech ETF (BBH), or First Trust NYSE Arca Biotechnology Index Fund (FBT) which will provide a more diversified exposure to capitalize on the growing biotech economy.
Or check our article on the “Top 5 CRISPR Companies To Invest In”.
CRISPR Companies
1. CRISPR Therapeutics
What sets CRISPR Therapeutics apart is the all-star team of founders, including 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.
Source: CRISPR Therapeutics
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 CREME 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 CREME, Enformer, and 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 leverage CRISPR techniques specific to a plant species or more effective on some cannabinoid genes, plastic-eating enzymes, etc.