Gene editing corn for nutrition

Description of proposed project

One paragraph TLDR: Malnutrition is bad, one elegant solution is to make the food people already eat more nutritious. Prime editing is a new biotechnology that’s just starting to work reliably in plants and should enable some nutrition-increases we can’t achieve with basic gene editing, and we’ve found a lab just starting to get it working in corn. We’ve already convinced them to use some biofortification genes as their proof-of-principle, and are looking for dedicated funding to a) move their troubleshooting at faster-than-academic pace and b) help them continue past the minimum for a scientific paper and get to a more practical real-world proof-of-principle.

Detail: Malnutrition is one of the largest-scale and highest-tractability problems in the world, responsible for a huge amount of DALYs. We’ve made amazing progress over the last 5 decades, but 20% of people are still deficient in essential vitamins and nutrients. This causes slower physical and mental growth in children, higher risk of infections, and increased mortality. One elegant solution is biofortification - making crops more nutritious. Biofortification’s basic logic is that both economics and culture lead poor people to eat a ton of a staple food, and it’s really hard to change that (we’ve tried!).

The most famous biofortification project is Golden Rice, designed to solve vitamin A deficiency. It’s super cool (it got me into plant biotechnology), but it has failed to have much impact because it’s GMO and ran up against political opposition. Semilla Nueva is having a lot of success with non-GMO biofortified corn, and we’re in the process of expanding into gene editing. USDA regulation (which many other countries follow) is that gene edited crops can generally avoid GMO designation, so we think this could be a powerful technology without the political and regulatory blocks that stopped Golden Rice.

Gene editing changes existing genes rather than putting new ones in, and generally the goal is one of these three: eliminating expression of a gene, increasing the amount of expression of gene, or making a very targeted change to the gene product such as shifting a specific amino acid in the resulting protein to change binding or enzymatic function. Basic CRISPR is great for the first of these goals, pretty bad for the second two (in plants - it’s better in some other organisms).

A newer tech that’s much better at the second two goals is prime editing. Prime editing lets you make the exact change you want, rather than just making a random indel at the location you want like basic CRISPR. To increase gene expression, you can use prime editing to change a promoter to include a binding site for a transcription factor that, say, increases expression in kernels - this could be a useful tool to increase expression of a nutrition biosynthesis or transport gene in that tissue. Changing a particular amino acid in a protein is even simpler, you just put the right nucleotides to code for that amino acid into a pegRNA and re-write that specific part of the gene.

Semilla Nueva’s breeding program finds high-yielding and well adapted seeds, and then uses a slow (4-7 years) and expensive (200-500k per seed) backcrossing process to convert them to be more nutritious. My primary job at Semilla Nueva has been to make converting seeds from conventional to biofortified faster and cheaper using gene editing. To do that, I’ve built a huge list of all the genetic changes one might make to improve the nutritional properties of corn for the most important nutrients missing in widespread diets - zinc, iron, and protein quality. This list is derived from ~all academic literature on the topic as well as some of our proprietary data from testing the nutrient levels of over 10,000 types of corn in our breeding program. In many cases, these genetic changes have been demonstrated to improve nutrition in an academic lab setting, but not under field conditions with modern cultivars rather than academic “lab-strains”. We are testing many of these changes with basic CRISPR, but some targets will only work with prime editing.

We already partner fairly extensively with CIMMYT (a giant in this space, Norman Borlaug’s org), and recently they got prime editing working in wheat. They’re just starting the project of getting it up and running in corn. Given their extensive success doing basic CRISPR on corn and the fact that they got prime editing working well in wheat, they’re pretty likely to succeed, and to get a nice scientific paper showing they can do the benchwork.

Currently they have no funding dedicated specifically to the prime editing work, and are funding it from scraps from various other grants. Dedicated funding would allow this work to move faster and test a larger number of candidate genes, increasing the odds we get a good proof-of-principle to drive additional funding to get prime-editing-biofortified corn all the way into farmers’ hands.

Why are you qualified to work on this?

Me as an individual: I was inspired to work in this field by EA reasoning about 15 years ago when I learned about Golden Rice, and have spent the bulk of that time doing the long training process to become an expert in the field - a broad scientific study focused on biology for undergrad, a masters in plant synthetic biology at Cambridge, and a PhD in plant biology begun at UC Davis and completed at UC Berkeley. I have done a lot of bench plant biology - my papers are spread across a variety of sub-disciplines, but the overarching goal was always to build the skillset to be good at biofortification. I’ve closely followed the field for many years, and either personally know or am familiar with the work of many of the leading scientists.

Since joining Semilla Nueva, I’ve been responsible for our gene editing program, which has resulted in many dozens of different “lines” of plants edited for nutrition-relevant genes, which are currently being grown in the field in preparation for nutritional phenotyping.

Semilla Nueva as an organization: While I was in academia, Semilla Nueva was out in the world figuring out what works. After a few false starts including trying to convince farmers to grow a greater variety of crops, the organization settled on biofortification as a way to improve human nutrition. Unlike Golden Rice, Semilla Nueva’s biofortified corn is not GMO, and therefore has faced much less political opposition, allowing for rapid growth - in 2024, over 30,000 farmers in Guatemala grew our seed, and we’re starting to see population-level nutritional effects. Our corn is higher in zinc and iron than conventional, and has higher “protein quality”, meaning a higher level of the normally-rare-in-corn essential amino acids lysine and tryptophan. In addition to the improved nutrition, we have two other pillars of our model: we use a subsidy to incentivize seed companies to sell the seeds at reduced prices (since we’ve figured out poor people won’t pay more for more nutritious foods, a key false assumption that we think ruined some previous attempts at biofortification). This allows our medium-yield biofortified seed to be sold at prices normally expected for low-yield outdated seeds, which means most farmers growing our seed see their yield and profits substantially increase.

Initially, that subsidy has been funded through donations to our organization, and as we transition to better seeds the subsidy amount should decrease over time. Our final pillar and path to truly huge scale is through convincing governments (mostly by letting the farmers growing our seeds convince their own representatives) to cover the cost of the subsidy of biofortified seeds as a public health program. Currently the Guatemalan government is covering 70% of the subsidy there, El Salvador is piloting the implementation of a similar program, and we hope to see other governments do the same or even take on the full subsidy cost as we scale across Central America and into Africa.

What would you do if not funded?

We are already engaged in a purely academic version of this project, which our partners have agreed to do without any further incentive than scientific publication and the resulting prestige. However, this is happening only at academic science pace, and only for the minimum viable number of prime edits required to get a nice paper, rather than the larger scale that one would pursue for the development of a product aiming to ultimately reach farmers’ hands.

This project is too early-stage for most of our donors, who prefer donating to either our existing program (backcross breeding-generated biofortified corn) or our more basic gene editing program. If this works well, we probably will be in a position in a year or two to push this from “proof of principle” to getting it into competitive seeds and out to tens of thousands of farmers.

We will probably reach out to other funders of more basic research that stands to potentially unlock cost-effective humanitarian interventions, but other funding is uncertain and likely much slower than an ACX grant, so the most likely counterfactual is that this project remains without dedicated funding and progresses slowly and at minimum-academic-paper scale.

How much money do you need?

$10,000 will be enough to significantly accelerate our efforts in this area. We will spend that funding on: 1. Greenhouse space: The first stage of the prime editing protocol (as well as most corn gene editing protocols) is dissecting out immature embryos, which are then sterilized and go into axenic growth in petri dishes to do the editing. To iterate and troubleshoot at a reasonable pace, you need fresh embryos every week, which means you need to plant weekly and grow the plants “out of season”, which means using greenhouse space which is always scarce. CIMMYT (like the universities I’ve worked at, I think this is pretty standard) has an internal “greenhouse space renting” system to allocate that space and pay for the running costs (people to plant, water, weed, etc - it’s better to have a dedicated team do this than have your postdocs doing it). Currently they’re basically just growing in whatever space happens to be available, but they’ll get prime editing working much faster if they have a dedicated chunk of space to have a couple plants each at every stage of growth between sowing seed and harvesting embryos from mature plants. 2. Targeting more genes: Biotechnology is fickle, specific genes end up failing for all sorts of reasons at all stages in the process. Some failures are technical (e.g. can’t prime edit that gene), others are biological (you make the change you want, and either it doesn’t give the phenotype you want, or it causes some other negative effect that prevents it from being useful). The main way we prepare for these inevitable failures is to take many shots on goal - I have over 170 genes in my candidate list, of which about 60 are best suited to prime editing (rather than basic CRISPR KOs, which we’ll use preferentially if they work since the technology is tried-and-true at this point). CIMMYT primarily cares about getting a scientific paper, which pretty much just means they need to show that prime editing makes the genetic change they want. We’re more interested in an improved seed that works better in farmers’ fields, so we’ll need to take more shots on goal. Having dedicated funding will enable the CIMMYT team to iterate and troubleshoot with just a few targets, then run prime editing on a larger set of targets once they’ve gotten it working. This vastly increases the chances that we end up with a viable proof-of-principle that has the genetic change we targeted, has the nutritional change we actually care about, and doesn’t have any dealbreaker side-effects.

Supporting documents

A background review on biofortification: https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2022.1043655/full

The seminal prime editing paper: https://pubmed.ncbi.nlm.nih.gov/31634902/

CIMMYT’s website: https://www.cimmyt.org/