Technologies to watch for in 2024: Large Fragment DNA insertion
I am obsessed with this “Seven technologies to watch in 2024” Nature technology feature published in January. I’ve gone back to it frequently to reserch a few of the technologies, and written a bunch of LinkedIn posts on it (much to the chagrin of my small audience who generally is interested in health data thoughts :)). I keep going back to it because I’m intrigued by both the wonder and hope that cutting edge tech can induce in all of us. We must never lose that sense of wonder and admiration for big ideas. The ideas that push our boundaries of possibility might veer in the realm of crazy… but nothing cool ever got accomplished without a smidge of madness.
I thought it might be worth to expand on one of my favorite technologies — large fragment DNA insertion, as its applications touch on some fields I’m particularly passionate about, including molecular biology, systems bio, chem/agriculture and biochemistry. Lots to discuss about this space, but think of the items below as falling into the category of “What Vera wishes existed that probably already exists 🤔”. If anyone reading this is working on any “dream applications” I’m highlighting, let’s chat! 🤓
First off, what do we mean when we say “large fragment DNA insertion”? By utilizing CRISPR and related techniques for precise and programmable DNA insertion, researchers are managing to insert or replace larger and larger DNA fragments into a cell’s complex genomic markup. By virtue of the DNA size that can be incorporated, this expands genetic engineering capabilities by broadening the molecular biology toolkit. These techniques promise advancements in agriculture and clinical care: from enhancing crop resistance, to treating genetic diseases.
Under that definition, here’s some personal “dream applications” for these techniques (some which already are being pursued!):
1️⃣ Genetically engineer fortified plants that produce vitamins found only in animal products. The ideal dream application would be a plant that produces Vitamin B12 (cobalamin). But some quick research showed that there are dozens of genes involved in the biosynthesis of cobalamin… plus there’s that pesky Cobalt atom. My search highlighted a more feasible option: the expression of vitamin D3 in tomatoes, which requires targeting a repressor gene, and a bit of sunlight. Targeting repressor pathways to up-regulate/re-activate an existing pathway seems a more feasible approach than introducing a network of genes that don’t already exist. But I’ll keep hoping for my B12-producing tomato. 🍅
2️⃣ Cellular trans-differentiation (e.g., instructing a cell to convert into another cell type, based on well-established cell signaling mechanisms). This is obviously super-complex, but it’s not entirely science-fiction to believe that someday we can instruct skin cells to have beta islet functions (produce insulin). In relatively more near-term applications, companies like Ivy Natal are investigating the ability to create egg cells from other cells, thereby offering a fertility path for those unable to produce their own functional gametes. While there are lots of ethical and technical considerations, changing a cell outside of a human’s body feels more feasible than in vivo work in the near future. 🔬
3️⃣ Targeted expression of “cleaning enzymes” in diseases caused by protein aggregation (e.g., Alzheimer’s). I’ll admit that this feels like the most far fetched out there, but research has already shown that enzymes like Neprilysin (a membrane metallo-endopeptidase) can degrade amyloid beta depositions. Efficiently expressing the enzyme — at the right yield in the right cells — would be extremely difficult though. Potentially encouraging the expression and activation of naturally occurring Neprilysin would be a future therapeutic opportunity to slow disease progression. 🧐
4️⃣ Genetically engineering novel bacterial species to create a super-healthy gut microbiome (because, what could really go wrong here? 😅). These could also be used as a vehicle to manufacture and deliver biologics in the gut. Do I hear “in house GLP-1 production”? (Through a tightly controlled on/off expression circuit, of course.) 🧫
5️⃣ Transform “white adipose tissue” (fat cells) into “brown adipose tissue” (also trans-differentiation themed). Since Brown Adipose Tissue (BAT) can burn fat/generate heat better than its white adipocyte cousins, it could be interesting to try to engineer different body concentration of BATs by incorporating a large DNA segment expressing a number of factors that could transform a white into a brown fat cell. Beyond the obvious challenge of identifying the right transcription factors, expressing them at the right concentrations, researchers would need to also selectively target white adipose tissue, and ensure the transformed cells respond the same way endogenous BATs would respond to hormonal, temperature, and nutrition signals. 🦇
6️⃣ Replacing defective enzymes — this is absolutely *not* a crazy idea, and there are many clinical programs already in place. ☑️
All of these are super worth-while ideas, but if I had a second life to live, I’d start a company based on idea #2. (For idea #1, I’d buy the B12-tomatoes rather than make my own!)
