Genus envy

Ethan O. Perlstein

In 1997, a breakthrough was made in rare/orphan disease research. An evolutionarily conserved gene called NPC1 was shown to be responsible for Niemann-Pick disease type C, a degenerative lysosomal storage disorder that affects 1 in 150,000 people on Earth, half of whom manifest symptoms as children. The discovery of NPC1 should have unleashed a torrent of follow up studies in simple model organisms like yeast, worms and flies, all of which have an ancestral version of NPC1. Instead, what followed was a trickle, with clunky rodent models getting all the basic research attention. Is that partly why 16 years later we still don’t have a cure for NPC?

It was once axiomatic to say that model organisms illuminate cellular bits that have been conserved by evolution over the eons. Despite this overwhelming evidence of commonality, the biomedical establishment operates with a mindset of human exceptionalism. According to this mindset: 1) any organism simpler than a mouse or a rat is not relevant to drug discovery; 2) technological advances in human cell in vitro culture and genetic manipulation obviate the need for non-human models. I believe this view is both conceptually flawed and economically inefficient. The basic understanding we so desperately need to cure NPC and thousands of rare/orphan diseases like it will only come from painting meticulous physiological portraits of human disease on a canvas of simple model organisms, starting with our far-removed unicellular cousins.

Here I present Saccharomyces cerevisiae, which goes by several aliases: budding yeast; brewer’s yeast; baker’s yeast. As you can tell from the monikers, we and yeast go way back. Thousands of years ago the lucky bastard who first stumbled upon a natural fermentation put brew and brew together, and our fates have been entwined since. The use of fungi as model organisms in experimental biology dates back to the 1930s and 1940s to the seminal “one-gene, one-enzyme” auxotrophy studies of George Beadle and Edward Tatum on the bread mold Neurospora. The genome of S. cerevisiae (hereafter yeast) weighs in at 12 Mb, or megabases, and boasts around 5,000 genes. Depending on how the calculation is done, 20% – 30% of yeast genes have a statistically significant match to a human gene at the DNA level. For scale, the human genome is 3000 Mb, or 200 times larger than the yeast genome, and features ~20,000 genes. Yet most biomedical researchers appear to treat that 20% – 30% as though it were 1%, or ignore it altogether. Have they simply forgotten the literature, or is it the hex of human exceptionalism?

It’s not as though that conserved bloc of genes is chopped liver in terms of cellular functions. Obviously included in this tally are enzymes involved in central metabolism, e.g., glycolysis, or the breakdown of the sugar glucose into chemical energy. But non-metabolism genes and the proteins they encode are also part of the mix. There’s actin and tubulin, two proteins that comprise the dynamic scaffolding, or cytoskeleton, of cells; histone, a protein that wraps DNA double helices in a regulatory embrace; clathrin, the triskelia-shaped protein that forms Bucky Ball coats around lipid droplets called vesicles. And it’s not just the pipes and dry wall that’s shared. Even complex enzymes like kinases are conserved from yeast to humans, including one of my favorites TOR, which stands for Target Of Rapamycin, an ancient nutrient sensor.

The full force of evolutionary conservation is no more persuasively felt than in gene-replacement experiments. If DNA sequence alignment indicates that two genes are related in organisms separated by over a 1 billion years of evolution, how do we know that this DNA sequence similarity translates into functional interchangeability? Swap the modern version for the ancient one, and see if the cell or organism behaves normally. It’s a concept from genetics called complementation. It must have been in those heady days that the expression “the awesome power of yeast genetics” was born. Once I got a taste for yeast in my first-year graduate school laboratory rotations, there was no turning back. In my graduate and postdoctoral research over the last decade, I’ve been trying to connect basic discoveries made in yeast to human diseases, and now my focus is rare/orphan disease.

Studying yeast alone is not going to cure NPC, but if you take evolutionary conservation at face value, the awesome power of yeast genetics is a modest down payment on a cure.