Science Corner: When the Bloom is off the Rose

Imagine if you will a holiday on which it is customary to bring flowers, chocolates, and the like to another person for whom one has romantic feelings. I know, I know, a preposterous proposition, but sometimes an outlandish thought experiment can be helpful. And so on this holiday, you bring a gift of flowers and observe how happy they make your crush. The next year, you are late to the florist and cannot get flowers so you bring chocolate instead and notice an equally happy reaction. The following year you are extra prepared–flowers ordered in advance and just-in-case chocolates; you give both and notice your crush is even happier, but not really twice as happy as with either gift alone. Now you are curious, and so the next year you supplement flowers and chocolate with provocative loungewear only to discover this makes your crush less happy than if they had gotten no gift at all. O dear! What is going on?

What’s happening is that you have discovered epistasis–situations in biology where a combination is different than the sum of its parts. The combination might be two or more genes, or two or more mutations in a single gene, etc. In the paper I want to highlight today, the research looked at different mutations in a single gene, dihydrofolate reductase, in Plasmodium falciparum, one of the species of parasite that causes malaria. The mutations in question affect how susceptible the parasite is to certain drugs. Without epistasis, you’d expect that if each mutation by itself confers drug resistance, any two would make the parasite twice as resistant, any three would make it three times as resistant, and so on. But by observation, epistasis occurs and so the effects of the multiple mutations are harder to predict, just like it was hard to predict the happiness inspired by your gifts.

In the worst case, any combination of mutations would have a completely different effect that might as well be random. Nothing you learn from one set of mutations (or gifts) would apply to any other. However, biologists have discovered that sometimes epistasis follows a pattern called global epistasis. Under global epistasis, if we consider one specific mutation and the change in fitness it confers in the presence of a variety of different combinations of other mutations, that fitness change has a predictable relationship to the fitness prior to the change. Often, that relationship is negative, meaning the better off (e.g. more drug resistant) the parasite was prior to the specific mutation, the smaller the change in fitness the mutation provides. Or the happier your crush is, the less additional happiness they get from receiving a specific additional gift. But there can be positive relationships too, meaning an already resistant parasite might get even more benefit from a specific mutation than a non-resistant one. We can’t know in advance where global epistasis occurs and whether it is positive or negative when it does, but once we know it applies we can predict the impact of adding specific mutations to different contexts without having to try every possible combination.

Global epistasis was already known, but what Juan Diaz-Colunga, Alvaro Sanchez and C. Brandon Ogbunugafor demonstrate in a recent paper is that external conditions can change features of global epistasis. In particular, they looked at how different doses of the anti-malarial drugs impacted the relationship of different mutation combinations. For example, for one mutation, at low drug concentrations it demonstrated negative global epistasis; the more resistant the parasite already was, the less benefit it got from the additional resistant mutation. But at high drug concentrations, the relationship flipped to a positive one, where that additional mutation was even more beneficial if the parasite was already more resistant.

In our gift scenario, that might work something like the following. At times when your crush is relatively content and at ease, adding flowers to chocolate doesn’t elicit as much additional happiness as flowers alone, and adding flowers to chocolate and a card inspires even less. But when they are stressed or frazzled, adding flowers to chocolate makes them way happier than just flowers would have.

The gift analogy is hypothetical and your mileage may vary, but for malaria these results are real and potentially meaningful. The evolution of drug resistance is an ongoing concern, and therefore so is the proper management of medication administration to minimize its impact. The more we understanding about how evolution proceeds and how our choices can impact it, the better decisions we can potentially make.

I chose this paper because I wanted to highlight the work of a black scientist for Black History Month. It’s the most recent paper from the lab of C. Brandon Ogbanu. I discovered him via a podcast (listen above or read the transcipt) and I’ve found his work and the work of others he promotes on social media to be worth paying attention to. If I can call your attention to one other paper, check out Viral Evolution Shaped by Host Proteostasis Networks, a review he contributed to with Jimin Yoon, Jessica E. Patrick and Matthew D. Shoulders. The broad theme is similar, looking at the importance of context and interactions to the evolution of pathogens.

In this case, the context which changes the impact of mutations is the suite of mechanisms host cells have for managing protein folding. The behavior of a protein depends on its three-dimensional shape. Mutations which change the linear sequence of amino acids can perturb that shape, but there are enough degrees of freedom that the original shape may still be achievable with the right nudge. (Similarly, those degrees of freedom also mean the unchanged sequence may still result in a perturbed shape that could also benefit from a nudge.) And so cells have proteins called chaperones and others to provide those nudges. This can afford some latitude in sequence for mutations to occur without disrupting the shape and function. For virus proteins, this could mean they might be able to accumulate several mutations to get from one fitness peak to an even higher one whereas without the chaperones the intermediate mutants might not be viable enough to persist.

There’s also a flip side; proteins can also be identified as beyond remediation and instead targeted for recycling. Our cells need different proteins at different times, and all of them are made of the same modular pieces–amino acids. So there are always new proteins to make, and the raw materials can come from old proteins that aren’t needed any more. Thus cells have processes for taking apart proteins, and those processes can be applied to misfolded proteins and other potentially harmful proteins like those encoded by a virus. Mutations which make viral proteins more like to wind up in the recycling bin can reduce viability of the virus, even if those same mutations might also help the virus be more infectious if there were no recycling apparatus.

There are obvious medical implications for this as well, but I also wanted to highlight this concept because it made me think about filling in valleys and leveling hills as described in Isaiah 40 and Luke 3. We could probably all use a little chaperoning now and again, and we probably all have opportunities to be a chaperone to someone. With so much talk about deconstructing theology, I wonder to what extent a theological chaperone can ease the transitions or prevent one’s theology from getting so undone that it gets broken down entirely.

Have you ever had help from a theological chaperone, or wish that you had?