The Nobel Prize is the most prestigious award in the scientific world. It was created according to Mr. Alfred Nobel’s will to give a prize “to those who, during the preceding year, have conferred the greatest benefit to humankind” in physics, chemistry, physiology or medicine, literature, and peace. A sixth prize would be later on created for economic sciences by the Swedish central bank.
Who to attribute the prize to belongs to multiple Swedish academic institutions.
Legacy Concerns
The decision to create the Nobel Prize came to Alfred Nobel after he read his own obituary, following a mistake by a French newspaper that misunderstood the news of his brother’s death. Titled “The Merchant of Death Is Dead”, the French article hammered Nobel for his invention of smokeless explosives, of which dynamite was the most famous one.
His inventions were very influential in shaping modern warfare, and Nobel purchased a massive iron and steel mill to turn it into a major armaments manufacturer. As he was first a chemist, engineer, and inventor, Nobel realized that he did not want his legacy to be one of a man remembered to have made a fortune over war and the death of others.
Nobel Prize
These days, Nobel’s Fortune is stored in a fund invested to generate income to finance the Nobel Foundation and the gold-plated green gold medal, diploma, and monetary award of 11 million SEK (around $1M) attributed to the winners.
Source: Britannica
Often, the Nobel Prize money is divided between several winners, especially in scientific fields where it is common for 2 or 3 leading figures to contribute together or in parallel to a groundbreaking discovery.
Over the years, the Nobel Prize became THE scientific prize, trying to strike a balance between theoretical and very practical discoveries. It has rewarded achievements that built the foundations of the modern world like radioactivity, antibiotics, X-rays, or PCR, as well as fundamental science like the power source of the sun, the electron charge, atomic structure, or superfluidity.
CRISPR – The Revolution of Genetic Engineering
Gene Engineering Difficulties
Since the discovery of genes and how to analyze them through PCR (The 1993 Nobel Prize), scientists and doctors have dreamed of editing the genomes of humans, animals, and plants at will. In practice, this has proven to be very difficult, and most of the early methods developed have proven insufficient.
This is because it is not enough to just identify a gene or create the right genetic sequence in a test tube. The gene then needs to be inserted into living cells and integrated into the organism’s genome.
If the goal is, for example, “just” to create a new plant variety, a high failure rate and random insertion into the genome can be acceptable. Even if 99.9% of treated cells die or do not display the inserted gene properly, this also means 0.1% produces the intended results and can later be multiplied and sold to farmers.
However, such methods are fully inadequate for treating humans and have faced a backlash for their crudeness when applied to plants and animals.
A New Paradigm
This all changed when Jennifer Doudna & Emmanuelle Charpentier discovered a protein they called CRISPR-Cas9 in 2012. Both would receive the Nobel Prize in Chemistry in 2020 for their work. With only eight years passing between the discovery and the associated Nobel Prize, it is clear that this discovery was immediately identified as a game changer in the field of biology.
The CRISPR system allows us to “edit” genes in a targeted fashion, pinpointing a specific spot of the genome to be replaced by the sequence of interest. CRISPR can be used in multiple ways to interrupt a gene already present, delete a specific sequence, or edit/insert the right genetic sequence.
In each case, gene editing will only be done in one specific section of the whole genome in an entirely predictable fashion. This is important as undirected gene insertion has been linked to major problems, notably cancer risks.
Source: CRISPR Therapeutics
Perhaps more importantly, the gene modification process is mostly harmless for the targeted cells, reducing the treatment’s toxicity by an order of magnitude compared to previously used methods.
Many More CRISPRs
Because of its massive potential, CRISPR immediately became the center of a massive R&D effort across the entire biotech industry. New CRISPR systems got discovered, like Cas12, CAs12a, but also Cas13, Cas 5, Cas8, Csx10, etc.
For now, most of the research efforts for human medicine are concentrated on CAs9 and CAs12.
If you are technically minded and want to learn more about the difference between these two main CRISPR systems, we recommend reading this scientific publication and this article, as well as our article on CRISPR-CAs12a.
AI CRISPR
A common problem in modern biology is the overabundance of data. Entire genomes with billions of amino-acid bases, 3D structures of proteins where the configuration of a few atoms can change functionality, and entire microbiome maps with thousands of bacteria species—there is no shortage of data points to analyze and cross-examine.
Luckily, the emergence of AI is now helping researchers handle this flood of data, and CRISPR is no exception. Even better, open-source resources are becoming available, like OpenCRISPR-1. Such AI systems can help create millions of diverse CRISPR-like proteins that do not exist naturally, as well as “single-guide RNA sequences for Cas9-like effector proteins”.
When testing the real-life efficiency of these new CRISPR-like proteins and RNA sequences, the generated gene editors show comparable or improved activity and specificity relative to SpCas9.
CRISPR As A Miracle Cure
Genetic Diseases
The first and most obvious application of CRISPR is curing genetic diseases. Genetic diseases are often deadly or crippling, one in 10 Americans has one of the 7,000 rare diseases, and half of the affected patients are children.
Rare diseases, which have genetic causes for 72% of them, have been some of the hardest to cure diseases, in large part because an entirely missing biological function cannot be stimulated or activated with drugs. They are usually linked to a single gene displaying a faulty genetic sequence, or sometimes a missing gene, a gene in surplus copy, etc. In addition, the deficiency is at the intracellular level, making it difficult for any treatment to reach the right spot.
For each of these diseases, we can envision a way for a custom CRISPR-based system that would specifically target the defective segment of the genome and repair it.
First Success
The very first proven application of CRISPR was achieved in 2023 when a treatment for Sickle Cell Disease (SCD) was approved by the FDA. The company behind this accomplishment was CRISPR Therapeutics, founded by CRISPR co-discoverer Emmanuelle Charpentier.
(You can read more about all the companies working on SCD in our dedicated article).
The treatment that worked for CSD has since been also approved for curing another blood genetic disease, beta-thalassemia.
More Cures
Another medical use of CRISPR potential coming soon is to cure some forms of blindness, this time with the backing of Editas Medicine, a company founded by the other CRISPR co-discoverer, Jennifer Doudna.
“One of our trial participants has shared several examples, including being able to find their phone after misplacing it and knowing that their coffee machine is working by seeing its small lights.
While these types of tasks might seem trivial to those who are normally sighted, such improvements can have a huge impact on quality of life for those with low vision.” – Mark Pennesi, M.D., Ph.D. – Oregon Health & Science University’s lead scientist
What is unique about this blindness treatment is that it is an “in-vivo” therapy, modifying the genes of cells in the body.
This is a step above the SCD-approved therapy, which uses CRISPR to modify cells “ex-vivo”, in a lab once they have been extracted from the body, to be later re-injected in the patient.
A cure for congenital blindness might be only the beginning of such therapies, with other promising results from early-stage clinical trials:
Using CRISPR For Non-Genetic Diseases
CRISPR could be used for therapies beyond genetic diseases thanks to its ability to remove or add genes at will.
For example, Excision Bio‘s EBT-101 therapy for the human immunodeficiency virus (HIV) had its first positive trial results (safety profile), and is looking to start therapeutic evaluation, intending to “excise the integrated retrovirus from the genome of human cells”.
Or Verve Therapeutics and its two in-vivo gene therapies in the working, VERVE-101 and VERVE-102, both targeting cardiovascular diseases. The company’s technology relies on base editing, a potentially safer and/or more powerful option than classic CRISPR gene editing.
Diabetes
Another disease that CRISPR could contribute to cure is type-1 diabetes.
A leading candidate for this idea is CRISPR Therapeutics, through collaboration with ViaCyte (purchased by Vertex in July 2022)
The idea is to gene edit stem cells, incorporate them in a medical device that will shield them from the immune system, and implant the device in the patient, re-creating the lost functions of the pancreas.
Source: CRISPR Therapeutics
Phase 1 of clinical trials of this drug started in February 2022. The relation between CRISPR Therapeutics and Vertex is a complex one, with the 2 companies already partners for the first ever approved gene editing therapy for Sickle Cell Disease.
In January 2024, Vertex “has chosen to opt out of the diabetes gene-edited stem cell therapy it gained through the acquisition of ViaCyte, leaving CRISPR to take the clinical-phase program forward itself”.
It is unclear what motivated this decision, and it has cooled investor enthusiasm for the company. Still, the strategy to recreate insulin production AND protect it from the immune system is probably the right direction overall.
You can learn more in the systematic review titled “Gene Therapy – Can it Cure Type 1 Diabetes?” about other research efforts done to use gene editing to cure type-1 diabetes
CRISPR For Cancer
Base editing is a topic we discussed before, in “Gene Editing: CRISPR Therapeutics vs. Beam Therapeutics”, and is a variation around CRISPR-based technologies.
Beam Therapeutics looks to use base editing to edit CAR-T cells to treat blood cancers like T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LL)
The idea behind Beam therapies and other CRISPR-based cancer therapies is to modify immune cells (T-cells) so that they can identify and target cancer cells.
Source: Cancer.gov
Together with mRNA-based cancer therapies, CRISPR could prove that gene editing can go beyond specific applications, and become a multi-faceted tool to cure most diseases.
CRISPR Beyond Therapeutics
CRISPR precision can be leveraged for more than curing human diseases. One direct application of CRISPR-based gene editing is creating new varieties of plants and animals for farming and industrial production.
As we discussed in “CRISPR Beyond Human Health: The New Investing Frontier for Gene Editing“, this could create new crop varieties.
It could also create entirely new uses for farming like:
(For a deeper dive into the possibility and challenge of agricultural CRISPR gene editing, you can consult this page from the Innovative Genomics Insitute.)
CRISPR’s exact match with specific genetic sequences could see it replaces the now commonly used PCR tests, with new techniques permitting such testing out of a lab setting and with room-temperature reagents.
CRISPR could even be used to “resurrect” dead species, with the company Colossal Laboratories & Biosciences working on recreating a mammoth from frozen DNA, using CRISPR.
Investing In CRISPR
CRISPR is now entering the toolbox of many biotech companies, as well as blue-chip pharmaceutical giants. Still, the most advanced programs and companies were, maybe unsurprisingly, initiated by the two co-discoverers of CRISPR-Cas9.
So, investors interested in CRISPR might want to focus on the companies built by the brains that figured out how CRISPR worked in the first place.
You can invest in CRISPR-related companies through many brokers, and you can find on this website 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 picking specific companies using CRISPR, you can also look into biotech ETFs like the Ark Genomic Revolution ETF (ARKG) or the Global X Genomics & Biotechnology ETF (GNOM), which will provide a more diversified exposure.
After she discovered CRISPR-Cas9, Ms Charpentier went on to found CRISPR Therapeutics. From its inception, the company had a razor-sharp focus on Sickle Cell Disease (SCD) and beta-thalassemia, as both diseases could treated with the same approach. They are also crippling diseases with many patients, which are extremely expensive for the overall healthcare system.
So, this made SCD & beta-thalassemia a perfect candidate for the first FDA approval. The current cost of treating these patients (average lifetime cost is around $1.7 million) also helped justify a costly price tag of $2.2 million per patient.
As the first company with an approved CRISPR therapy, CRISPR Therapeutics is in a good position to be first to generate positive cash flow from the technology and expand its applications further. And this stellar track record will likely make the company a partner of choice for any other pharmaceutical company looking to catch up in CRISPR therapies.
CEO Samarth Kulkarni stated in 2024:
“We will continue to drive forward our programs and expand our pipeline with the goal of delivering paradigm-shifting gene editing therapies to patients. We are well positioned to execute our clinical trials across various therapeutic areas, including oncology, autoimmune, cardiovascular, and diabetes.”
CRISPR Therapeutics CEO Samarth Kulkarni
CRISPR Therapeutics is indeed aggressively expanding its horizons with 5 programs in oncology/immunology, 7 in-vivo therapies (mostly cardiovascular), 3 rare diseases, and 1 diabetes therapy (more detail above).
Among this rich R&D pipeline, the diabetes program is by far the one with the largest addressable market. So, investors in the company will want to keep a close eye on the associated clinical trials (CVTX211) and understand the technology well.
Jennifer Doudna Companies
The other CRISPR-Cas9 co-discoverer, Ms. Doudna, was among the co-founders of many companies, with an approach quite different from Ms. Charpentier’s:
Jennifer Doudna would also go on to create the Innovative Genomics Institute (IGI) in 2014, bringing together researchers from multiple California Universities.
She is also active at the Gladstone Institute of Data Science and Biotechnology and at her Doudna lab in Berkeley, managing the Center for Genomic Editing and Recording (CGER).
Lastly, Doudna is also present in advisory roles in Sixth Street, an investment firm, and in InvisiShield, developing intranasal preventive respiratory viruses.
If you want to know more, you can read a longer biography of Ms. Doudna on Britannica or her biography written by the biographer of Steve Jobs.
Editas Medicine, Inc.
Editas started working with CRISPR-Cas9 but is now focused on a proprietary version of Cas12 that they engineered: Cas12a.
You can read more about Cas12a’s unique properties in our dedicated article “What Is CRISPR-Cas12a2? & Why Does It Matter?”.
To put it shortly, Cas12as has unique features like:
- Hard-to-solve problems with Cas9 could be workable with Cas12a
- This results in higher chances of gene editing than with Cas9.
- More than one gene can be modified at once with CAs12a.
Source: Editas
Editas is focused on Sickle Cell Disease (SCD) and beta-thalassemia, 2 diseases where it lost the race for first treatment approval to competitors CRISPR Therapeutics and BlueBirdBio.
Overall, the SCD program (recently renamed reni-cell) has been delayed several times, sparking concern among investors, even with updates expected in mid-2024 and at year-end.
Nevertheless, Editas owns significant patents on CRISPR-Cas12, which has been used by researchers at the University of New South Wales, Australia, to develop a COVID-19 strip test.
Editas also signed a $50M deal with Vertex for the company to use Editas’ Cas9 IP, Showing the continuous interest of Vertex in the technology even after the recent apparent break with CRISPR Therapeutics regarding diabetes therapy.
Editas focuses on other CRISPR versions than the “classical” CRISPR-Cas9 and its research IP might come in handy in establishing partnerships and generating revenues without an FDA-approved product, on top of a cash runaway going into 2026.
Caribou Biosciences
The company was founded to commercialize and license out the CRISPR patents held by Berkeley. The list of such licensing is rather impressive, including large companies like Novartis and Corteva:
It also partners with AbbVie for cancer cell therapies (CAR-T) and its own cancer therapies (CAR-NK).
Similar to Editas, it is working on a Cas12 technology, chRDNA, using both RNA and DNA to guide the gene editing targeting system. It would be used for “multiplex gene insertions, with a high degree of specificity and lower levels of off-target editing than first-generation CRISPR-Cas.
“In the early research on the use of CRISPR-based technology for genome editing, it was found that all-RNA guides, which are used by bacteria in nature, carry a substantial risk of off-target effects, which can be dangerous in a mammalian therapeutic context. Caribou, on the other hand, is seeking to overcome this risk with the use of hybrid RNA-DNA guides, which preclinical research was able to achieve on-target edits without producing detectable off-target edits.”
Dr. Steve Kanner – chief scientific officer of Caribou Biosciences
Source: Caribou
Only 2 programs of Caribou’s R&D pipeline are already in clinical trial, both in phase 1. Overall this put Caribou in the category of early-stage biotech companies, even if the performance of chRDNA gene editing is impressive.
Jennifer Doudna Privately-Listed Companies
Mammoth Biosciences
Mammoth is not publicly listed and raised $195M in 2021, pushing its valuation to more than $1B.
It went out of stealth mode in 2018, aiming to use CRISPR technology to create easy-to-use kits and a smartphone app that can detect diseases in hospitals or even at home, with results in 20 minutes.
The company also wants to discover new CRISPR systems, like Cas13, Cas14, CasZ, CasY, and CasPhi.
These are aimed at creating a whole platform capable of performing base editing, epigenetic editing, and RT editing, with the right options picked for each specific target and disease.
Source: Mammoth
To some extent, it seems Mammoth’s business model will be more based on developing patents on CRISPR systems and licensing them out for therapeutic or industrial applications down the road.
Scribe Therapeutics
Scribe Therapeutics is not publicly listed and was founded in 2018. It is focused on engineering new SCRIPR systems, and the company has raised $100M in 2021.
It relies on Cas-X, a smaller protein than Cas9, making it more likely to work inside living cells. The company is relatively discrete about its progress, with only a general list of therapeutic areas and technical achievements being advertised.
Source: Scribe Therapeutics
Behind the public eye, it is nevertheless making great progress if we are to judge by its recent onslaught of partnerships.
The company has agreed with Biogen to investigate CasX for amyotrophic lateral sclerosis (ALS) for a total potential of $400M.
It also signed a $1B licensing deal with Sanofi to develop novel natural killer (NK) cell therapies for cancer and expanded this collaboration with Sanofi in 2024.