Complete biosynthesis of penicillin in tobacco plants. Every year, farmers in the US harvest about 840 billion pounds of corn. For comparison, there are only a few million liters of bioreactors, by volume, in the US. If we could engineer corn to make insulin at a titer of 1 g per kg of leaves (which is low; researchers previously engineered tobacco plants to express recombinant proteins at titers of 4-5g per kg), then we could make the global supply of insulin in an area of 1,230 acres; or roughly a square measuring 2.2 kilometers on each side. In other words, biomanufacturing with plants (or, recently, chicken eggs; see Neion Bio) feels highly underrated. There is a lot of “spare capacity,” and the farming industry has already built the infrastructure needed to scale! Alas, there are many things we cannot make with plants. Their chemical repertoire is fairly limiting when it comes to making human medicines. Many antibiotics, immunosuppressants, and antifungal medicines are made by enzymes that are missing from the plant kingdom. In particular, plants do not have non-ribosomal peptide synthetases, which are huge proteins that build peptides separately from the ribosome (hence their name). These proteins are used by fungi to make antibiotics, antifungals, and even many anticancer drugs (like bleomycin). For a new preprint, researchers in Texas engineered tobacco plants to make penicillin. They did this by engineering the plants to express seven fungal genes. This is not particularly impressive in terms of the size of the metabolic pathway (I recently wrote about tomato plants engineered to synthesize tobacco, for example, and that also required seven added genes and, arguably, way more work). The penicillin yield is also super low; just 25 micrograms per gram of dry weight, which is waaaayyyy lower than the titers were get from engineered yeast. But that’s not why this paper is important! It’s important because this is the first time that anyone has expressed a non-ribosomal peptide synthetase in a plant, so now we can engineer crops to make lots of other things, too. (The penicillin biosynthesis pathway, if you care, goes like this: The giant non-ribosomal peptide synthetase enzyme is in the cytosol. It grabs onto α-aminoadipate (a side-product when plants break down lysine), cysteine and valine. The enzyme snaps them all together, and also flips the valine from its normal "left-handed" shape to a "right-handed” one. A second enzyme, also in the cytosol, then pinches these amino acids together to make the β-lactam ring. Next, this molecule moves into the plant cells’ peroxisomes, where a third enzyme swaps the α-aminoadipate for a phenyl group, thus creating the active form of penicillin! The authors were worried that these chemical movements between the cytosol and peroxisome would not work by default, and might require engineering, but the proteins went to the appropriate compartments without any coaxing. That was a surprise.)