New technologies are tough to see coming from afar, but if you know where to look, you may be one step ahead. Image Source: Col Ford and Natasha de Vere/ Flickr.
We have long used the same words ("coding", "sequence", and the like) when describing software programming and genomics. The DNA that comprises an organism's genome is often analogized to the software of life; dictating traits and cellular functions. Today, life is literally becoming digitized as researchers crave more predictable living systems that work as expected every time. The digitization of life is forcing companies in various industries to imagine how biotech could help boost their top and bottom lines, whether by shortening product development timelines or creating new products that were never before possible.
In human therapeutics, companies such as General Electric Healthcare and Novartis are seeking ways to correct -- and possibly cure -- diseases at the genetic level with greater ease and safety than current tools allow. In agriculture, Dow Chemical (DOW +0.00%), Syngenta, and Monsanto are always looking for faster and cheaper ways to enhance crops. Meanwhile, in industrial biotech, the literal survival of companies such as Amyris (AMRS +0.00%) hinge on how cheaply they can produce chemicals from engineered microbes.
Unfortunately, one limitation has slowed each company's progress. If DNA is the software of life, then the tools we have at our disposal for editing the code are akin to the room-sized, punch card computers of the 1960's. We can read the code, letter by letter, but we can only edit a few characters at a time -- and it's very time consuming.
What if we could add and delete instructions from nearly any location on a genome at will? We could possibly cure diseases such as sickle cell anemia, safely develop complex biotech crops, and engineer microbes that churn out cheap consumer and commodity products typically produced from petroleum. While it may sound too good to be true, one such genome editing technology does exist -- and companies are racing to use it.
What's going on?
The genome editing technology in question, called CRISPR/Cas9, has been around for a few years, but investors were only recently bombarded by Corporate America's interest in it. In late November, Novartis paired up with Atlas Venture and Caribou Biosciences to fund Intellia Therapeutics, a new biotech focused on commercializing CRISPR/Cas9 therapeutics, to the tune of $15 million. Intellia Chief Medical Officer John Leonard, former chief scientific officer at AbbVie, opted for an early retirement package to join the company. As he told FierceBiotech, "We talk about paradigm shifts a lot in this industry, but this really is."
The announcement likely didn't register with most investors, but earlier this month Sigma-Aldrich and General Electric announced that they had licensed patents for human medicine. (The licensed patents are being challenged by the owners of the patents central to Intellia's founding. As MIT Technology Review recently summarized, it's messy.) Look closer and you may find that Dow Chemical and its peers are developing crops with CRISPR/Cas9 tools, while Amyris used the genome editing system to help slash production costs of its flagship molecule from $12.50 per liter to under $3 per liter.
What is CRISPR/Cas9?
The CRISPR/Cas9 system is harbored by bacteria to defend against invading DNA, essentially acting as a microbial immune system. Really smart people figured out how to harness its power for human therapeutics, which then trickled down to industrial and agricultural uses. The two-part enzymatic system works quite simply to cut open a genome at a specific base pair of DNA, allowing researchers to:
- Permanently knock out genes or sequences.
- Introduce, or knock in, genes or sequences.
- Silence genes.
- Turn-on, or express, genes.
Why are companies rushing to use CRISPR/Cas9?
Better tools make for cheaper discoveries and innovations. In addition to being able to knock out and knock in genes, CRISPR/Cas9 tools can edit multiple parts of a genome simultaneously, which drastically reduces the time to engineer a living system. As General Electric noted in its press release, gene knockouts in human cells that previously took one month or longer with previous technologies, namely RNAi and zinc fingers, can now be made in one to two weeks -- driving development costs down significantly.
Ironically, thanks to long clinical timelines, industrial and agricultural applications will be the first to benefit from the new genome editing tools. Dow Chemical, through its Dow AgroSciences subsidiary, had previously developed herbicide-tolerant corn using zinc fingers before dropping the project. But CRISPR/Cas9 may bring crops back into focus. Due to the jumbled regulatory system catering to decades-old biotechnologies, crops developed using CRISPR/Cas9 systems would not be subject to federal regulations specific to genetically engineered crops (oddly, regulators do not consider it a genetic modification tool).
Similarly, editing microbial genomes can be done much more quickly, enabling more strains to be tested for commercial competitiveness. When coupled with automated platforms (robots), CRISPR/Cas9 has helped Amyris develop the industry's leading strain development platform for engineered yeast by increasing throughput and reducing production costs by as much as 95%. It will be a critical tool helping the company reach its goal of bringing two to three new commercial strains -- each producing valuable specialty chemicals -- online each year.
Image source: Amyris.
What makes CRISPR/Cas9 different?
CRISPR/Cas9 systems address many of the shortcomings of current technologies and could eventually render them unnecessary by exposing their flaws. In the long run, that could be bad news for shareholders in Isis Pharmaceuticals (antisense), Alnylam Pharmaceuticals (RNAi), and Sangamo BioSciences (zinc fingers). Consider the following table comparing each of the four gene therapy and gene editing technologies.
| Technology Comparison |
Antisense |
RNAi |
Zinc Fingers |
CRISPR/Cas9 |
|---|---|---|---|---|
|
Targets RNA |
Yes, directly |
Yes, directly |
Yes, upstream |
Yes, upstream |
|
Targets DNA |
No |
No |
Yes, directly |
Yes, directly |
|
Permanent Effects |
No |
No |
Yes |
Yes |
|
Enzymatic or Stoichiometric |
Stoichiometric |
Enzymatic |
Enzymatic |
Enzymatic |
|
Off-Target Effects, Chances |
Moderate |
Moderate |
Low |
Low |
|
Multiple DNA Targets |
-- |
-- |
No |
Yes |
Stoichiometric means the system is needed in 1 to 1 ratio to its target, whether a molecule of RNA or a gene. Source: Author.
The decisive advantages of CRISPR/Cas9 when compared head-to-head against previous-generation technologies helps to explain why so many companies are racing to use it.
What does it mean for investors?
In the near-term, investors won't be able to reap the benefits of CRISPR/Cas9 in a meaningful way. Consider that while investments in agricultural and industrial biotech companies such as Dow Chemical and Amyris would see the most immediate benefits, CRISPR/Cas9 remains a single tool in a deep toolbox. Moreover, numerous risks and variables will dilute the benefits realized from industrial deployment of the technology. The fact that Amyris uses CRISPR/Cas9 does not on its own make it suitable for your portfolio.
While not immediately threatened in the marketplace, previous-generation technology platforms might still be at risk of losing out to the promise of the pharmaceutical industry's nascent CRISPR/Cas9 pipeline in terms of partnership and investment deals. That's not to say there isn't promise in RNAi, antisense, or zinc finger therapeutics -- commercial success already demonstrates the opposite -- but CRISPR/Cas9 therapeutics have the potential to address the shortcomings of even the most successful existing products. It could be the more lucrative and less risky platform for partnering purposes.
Yet, despite the potential to revolutionize the treatment of genetic diseases, it's still much too early for investors to realize any benefits from CRISPR/Cas9 therapeutics. Remember, no CRISPR/Cas9 therapeutic has yet entered clinical trials, although partnerships and collaborations could be announced in the next several years, which could change how quickly you'll be able to tap into the value potential.
For now, it is best for investors to keep a close eye on how CRISPR/Cas9 systems are applied commercially and be ready to pounce on opportunities that emerge, especially given the diverse interest shown from companies in multiple industries.
