Jacobson started his research career working with the slime mold Dictyostelium discoideum, with a goal of understanding gene expression during development. “Dicty goes through an entire developmental program in 24 hours,” Jacobson says. Their strategy was to identify genes whose expression changed during development, with the hypothesis that these would most likely be involved in transcriptional control.
Once he’d identified some of these genes, he discovered that their expression levels were changing after transcription. “As we looked carefully, we found two kinds of changes,” Jacobson says. “These changes were genes that were translationally regulated, meaning their messenger RNA was made at time X but not used until time Y, or genes whose messenger RNAs had a certain half-life for part of development, and then it changed half-life later, at a different time in development.” These results were unexpected but, as Jacobson says, “When science gives you a result, you say, ‘OK, we’ll go with it.’”
As Jacobson continued with his work, he made the decision to switch to working with yeast, due to the robust tools and international community available. “You don’t want to be in a field that is too esoteric,” Jacobson says. “You really need colleagues who work in the same field. Not only will they help you with reagents or methods, but it also makes for conversations that are deeper and more thought-provoking.”
Bolstered by the robust yeast community and the available tools, Jacobson’s research group was able to work out a system for studying the decay rates of mRNAs. “We began to see results which said that for some messenger RNAs, the decay rate characteristics required that they be translated,” Jacobson says. “This involvement of protein synthesis struck us as a really interesting result.”
This result, in combination with other results from Francois Lacroute’s lab in France, suggested that there was something about a premature stop codon that caused a messenger RNA to be unstable. Around this time, he met a future collaborator, Michael Culbertson, who was working on frameshift mutations, at a meeting at Glacier National Park. Culbertson had identified a family of mutations that caused an increase in mRNA levels. “Frameshift mutations cause downstream reading frame shifts, which means you inevitably get a nonsense codon downstream,” Jacobson says. What he realized was that these mutants most likely had to do with the mechanism for stabilizing mRNAs with a nonsense codon.
He suggested to Culbertson that they collaborate, which included sending a graduate student, Peter Leeds, to Jacobson’s lab, where he collaborated with a postdoctoral fellow, Stuart Peltz. “They showed that the UPF mutations, in this case, UPF1, stabilized all the messenger RNAs that we looked at, that had premature termination codons, as well as the ones that had frameshift mutations,” Jacobson says.
In a number of follow up papers, they were able to identify, describe, and name the NMD pathway, and to identify additional substrates. “It became clear to us that the NMD pathway degraded mRNAs that had premature stop codons, but it wasn’t just mRNAs from genes that had nonsense mutations, but we found other substrates, including intron-containing RNAs that got into the cytoplasm, cellular RNAs that had frameshifts, and mRNAs with upstream open reading frames,” Jacobson says. “We had essentially uncovered this pathway and begun to elucidate all of its characteristics.”
As Jacobson and his research group continued their work, “it became clear over time that this was a cellular quality control pathway for multiple classes of messenger RNAs that somehow encountered a premature translation termination event,” Jacobson says. “That turned out to be a prototype for other quality control pathways in the cell, and this was the first good example of that.”
As Jacobson continued his research, he and his colleague, Stuart Peltz, started looking for ways to apply this to the treatment of human diseases. This included co-founding a company, called PTC Therapeutics, to do just that. “Once we realized that there was slow translation termination, we wondered if we could take advantage of that, and make a drug that would bind to a component of the terminating ribosome and allow at least some of those ribosomes to continue on, and make a full-length protein, where they ordinarily do that,” Jacobson says.
This included developing a drug, called Translarna, which PTC Therapeutics showed to be effective for patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Translarna was approved by the EU in 2014 for the treatment of nmDMD, and has since been used to treat patients in over 50 countries worldwide. “From understanding the genetic mechanism in yeast, we made a leap to treating disease in humans,” Jacobson says.