CRISPR changes the world and unlocks GMO 2.0
“Scientific research is a strange endeavor”. Dr. Orlando de Lange has an interesting point….in his April 18th, 2026 Modified Podcast he describes the process of laboring over a research question for years, packaging up the results, giving it to the world, and then waiting to see if someone can prove it wrong-or perhaps they might use those results to build something that changes the world!
Dr. de Lange begins his podcast with an overview of the ‘strange endeavor’ so many of us undertake and then goes on to weave the story of CRISPR—how a paper in 1987 by a student in Japan was the first step towards a Nobel Prize winning discovery and programmable biology applied in a myriad of ways. Yoshizumi Ishino’s work was focused on sequencing an E. coli bacteria gene, a formidable task at that time—but he also detailed an unusual repeating DNA pattern he saw just outside the area of interest. No one knew what their function was—1980 is fewer than 50 years ago but the Dark Ages, from the perspective of genomics. The foundation of CRISPR was in this tangential finding, an oddity that might not even have been reported, but luckily was, thanks to Ishino.
These 29 basepair repeats were found in most bacteria, and their associated spacer sequences came to be known as Clustered Regularly Interspaced Short Palindromic Repeats. The proteins that managed these repeats—there are a number of them--were dubbed CRISPER Associated Proteins, or Cas proteins. By 2010 it was understood that these proteins were part of a bacterial immune system that cut DNA to allow the bacterial cells to keep small chunks of previously seen viruses as an early-warning identification system for defense. Although scientifically intriguing, not very many people noticed the finding as the field of bacterial immunity was small—but in 2011 a French professor who worked in Germany named Emmanuelle Charpentier approached an American professor who worked at UC Berkeley, Jennifer Doudna, and the two formed a formidable collaboration to explore an idea Charpentier felt held promise.
The two teams worked to understand Cas-9 and the repeats, now called CRISPR—and in doing so sparked a series of innovations that have been transformative in the lab and in medicine, and led to a Nobel Prize nine years later. A new era of DNA engineering began.
Dr. de Lange is a self-described ex-plant scientist and current science teacher at Shoreline Community College. His podcast focuses on the implications of CRISPR on the production of plant crops—an application Dr Charpentier felt was particularly important to strengthen food production while managing environmental changes.
de Lange has previously worked with Transcription Activator-Like Effectors (TALEs), proteins that are also candidates for use in endonuclease programming systems. From the 1980’s to 2010’s vast amounts of money and effort went into finding a way to manipulate and improve DNA sequences, with applications in medicine and plants. When TALEs were discovered in 2009, they appeared to be the programmable tool that would support precise transgenic manipulations. But CRISPR came on the scene, and is now used more widely, being smaller, cheaper, and easier to manipulate and program. CRISPR also had the built-in advantage of being a nuclease, while TALEs had to be engineered to cut DNA. Why is cutting DNA so useful? Because if you can target and cut a specific DNA sequence then you can work towards a system that disrupts a gene you want to inactivate with the precision necessary to avoid unwanted side-effects.
So far in America there is only one CRISPR/Cas9 based treatment for a disease—sickle-cell anemia. CRISPR is used to disrupt the mutant adult hemoglobin gene that causes the sickle-cell symptoms, and the body responds by switching back on the fetal hemoglobin gene that normally shuts down when a baby is born—which, although it is not a complete cure, does significantly improve patient health. This approach is successful because of two facts—CRISPR is precise, and fetal hemoglobin can switch back on to take the place of adult hemoglobin.
How could CRISPR be used in crop plants? One of the major approaches to making plants more resilient is to disrupt, or ‘knock-out’ the plant proteins that are used as receptors by pathogens to attach and cause damage. These ‘pathogen receptor proteins’ did not evolve to be a pathogen receptor, they have a plant function as well, but frequently the function is not essential and the ‘knock-out’ plant is still viable.
When DNA is cut by an endonuclease, the natural repair mechanisms can cause a disruption in a gene and lead to a knock-out. But the elegance of nature also provides another DNA repair system. Under the right circumstances, the DNA can repair itself using an introduced DNA template—a template that will introduce a specific change during the repair that can be determined ahead of time by a lab. This is gene editing—using the specificity of the CRISPR/Cas-9 endonuclease system along with predetermined template DNA to orchestrate a change in genomic DNA. This process does introduce a mutation—but unlike random mutations which often cause damaging changes, this new gene editing approach can precisely ‘fix’ a pre-existing mutation and bring a gene back to a functional state.
So back to sickle-cell disease. Wouldn’t it be great to just go in and fix the sickle-cell mutation? Yes, it would. But cells generally prefer the non-template repair mechanism so it is difficult to ‘fix’ DNA with a template. In addition, introducing the CRISPR/Cas-9 & template repair system into the human body so that all the red blood cells’ adult hemoglobin genes (or at least most of them) are repaired back to functional is a challenge that has not yet been solved.
The Charpentier/Doudna team filed a patent. But the Zhang lab at the Broad Institute did also. Zhang had been pursuing the approach as well, as frequently occurs in science. The 10-year patent fight was finally resolved in 2017, in favor of the Zhang group. The legal battle had made commercial investment risky, but many companies are working with the system regardless of this issue, and now with multiple variants available (each with their own patents), companies can choose which license to pursue.
Crop scientists are working on multiple uses of CRISPR/Cas-9. Plant genetic research has been going on for decades, and ideas to improve traits such as drought or pathogen resistance are all on the table now that this tool is available. But one of the biggest ideas is to edit callus cells’ DNA (plant stem cells) and then grow the cells all the way to plants. The original CRISPR/Cas-9 proteins, guide sequences and DNA templates would be destroyed by the cells over time, but the genomic changes would be permanent, propagating through the entire plant and inherited by its progeny. These plants don’t have any ‘outside’ DNA, all its genes are from the original species, simply changed a bit to enhance properties of interest. Would these crops be considered genetically modified or is this just a case of DNA changes that could have occurred naturally, along with natural selection for traits of interest? Companies are hoping for the latter—so that crops made this way could be sold without any costly extra regulatory approvals, added regulations, or even complete restrictions such as the European Union’s ban on food made with genetically modified organisms (GMO).
The USA has had a mixed reaction-first loosening the regulations for any crop made with CRISPR/Cas-9, and then vacating that decision leaving companies wary, but still willing to move forward with developing products. Although America does not have any CRISPR/Cas-9 crop products yet, Japan has one. A high GABA tomato, created and sold by Sanatech Seed, has been modified to knock-out the enzyme that degrades the naturally present enzyme that normally degrades GABA. However, because there is no exogenous DNA in the plants, the Japanese government has ruled that it is not a GMO crop.
This podcast was incredibly informative and quite entertaining! Developments in science influence the world around us, and it is good know enough to make informed choices. How will this story unfold? Keep an eye on the news, and on Modified podcasts, as de Lange continues to cover GMO 2.0. Catch up on the previous episodes and hear about the first commercial GMO food crop—also a tomato!