Critical Drinking

Critical Drinking — Chris White of White Labs and Sequencing Yeast Genes

In a nondescript lab on the aptly named Candida Street in northern San Diego, the future of beer multiplies. Not the future that includes marketing campaigns or corporate mergers or experimental hop breeds. Rather, the living, breathing component of beer that, until now, had remained a chromosomal mystery. As part of an ongoing collaboration with several genomics groups that took nearly three years, the White Labs team has painstakingly sequenced—or, in layman’s terms, mapped—the genetic information contained in 157 different strains of the brewer’s ale yeast Saccharomyces cerevisiae.


Chris White, the biological patriarch of White Labs and author of Yeast: The Practical Guide to Beer Fermentation, championed this research as soon as he heard about it, which culminated in a comprehensive report published by Cell Press in September of 2016. The data that makes up the nucleus of the report solidifies not only the previously guessed-at history of brewing yeast domestication and divergence, but also opens the door to future research which could dramatically change (read: improve) the way beer is brewed. Without hyperbole, thanks to genomics research and application, it’s all but assured that beer will boldly go into the future not on the back of barley or hops or water, but in the cells and genes of our favorite eukaryote.
GBH called up White to talk science, designer yeast strains, and what all this means for a drinking public that’s constantly seeking new tastes and experiences.


The sequencing and phenotyping that comprise the backbone of this report took a lot of money and years of work. Given that globally we're producing excellent beer with more varied strains of yeast than ever, what was the impetus to unravel the yeast genome now?

I thought, ‘why hasn’t this happened yet?’  Saccharomyces cerevisiae had its whole genome sequenced at the beginning of the Human Genome Project, back in 1996, but that hasn’t really helped brewers, because that wasn’t a brewer’s strain. That research highlighted how different Saccharomyces cerevisiae brewers strains are from those used in labs and in nature. It’s got all these unique properties.

We don’t really understand a lot about why yeast does what it does. From a science perspective, I felt if we have the tools to understand yeast better, we should do it, and the collaboration sort of just came our way.

You mean the research collaboration with White Labs, Synthetic Genomics, Illumina, and VIB? 

 

Yeah. Some people think the project was all White Labs’ idea, but I really want to focus on the collaboration. It’s all those people on the paper and their contributions over the past few years. And a lot more people did a lot of work on it that aren’t even on the report because the journal had very strict requirements about who could be listed.

 

Sounds like quite the effort. So the reasoning was more “it’s about time,” not any specific reason?

 

Yeah, from my perspective, it wasn’t about trying to make a product out of it. We have these tools for full genome sequencing, and a company, Illumina, making equipment right here in San Diego. They were interested in collaborating. It was an exciting thing to be a part of.

 

Now we’re at the question of how does the yeast make flavor compounds? We still don’t know that. Why does one strain create different flavors from another? We can finally figure that out with genetics.

Did you start the collaboration?

 

No, we didn’t start it. We opened the tasting room at White Labs to the public in 2012, and that helped get us excited about studying and formulating our ideas about yeast.  We became part of the collaboration with Illumina and some homebrewers, originally. We’d been talking about it internally for a few years, but they asked us if we were interested. 

I was like, “Yeah!” I’ve been interested for a long time.

While modern application is obviously a major reason to study yeast, there's a lot of beer history tangled up in those strands of DNA. Did the finding of the report illuminate how, where, or when yeast mutated? Did it help lock down the divergence of cerevisiae and uvarum/carlsbergensis?

 

I wrote the yeast book back in 2009-2010, and came across a reference I’ve never been able to find again, that said scholars believed people started pitching yeast back in the Middle Ages. That’s been a story that has been passed down, but I’ve often wondered: how do we know that’s true? Using sequencing data you can go back and see how related things are, and backtrack in the genome to see that it’s happening, changing. You can point to two different domestication events, one around 1600, one around 1650-1700. Those dates may change as more research comes in, but it gives a really nice backup the belief that humans did actually start reusing yeast in the Middle Ages. When we started reusing yeast, we started putting it under our own direction, our own control, which turns into domestication.

Did the history reveal anything unexpected?

 

The records were pretty accurate. I think how the groups are different—how the physiology and the genomics put yeast in different groups—was the most surprising. We call a certain yeast a Lager yeast or an Ale yeast, or a European yeast or an American yeast, but to see that backed up by the genetics is super interesting. It’s not just something people made up. They are truly different, genetically.

 

That’s kind of amazing, really, that is stayed true, genetically.

 

Yeah! There’s an Asian group which is mostly sake yeast. The genes showed that these yeasts are distinctively different—they weren’t just transported from somewhere in Europe. It is a completely different strain, yet it acquired some of the beer-like properties of the brewing strains, because it was domesticated. 

For example, the Asian strains have the one or two mutations that make them phenolic negative. Like the European brewing strains. That phenolic negative is something our palate knows. In beer we describe that as Belgian-like, as people associate the taste of phenols with Belgian-style beers. Some people really don’t like it.

I’m one of them.

 

Oh, you’re one of them! It’s in the genes of the yeast, so you’re probably not just going to learn to like it.

 

It would be fascinating if there was some genetic component to taste preferences, too, but I’m sure that’s way down the line.

 

I’m sure there is. That’s exactly the kind of thing people are discovering everyday as we explore genetics—and the regulation of those genetics. 

 

At the American Hombrewers Conference this year, you said that we'd discovered yeast's "chemistry before its biology." Can we expect changes in terms of yeast development now that we better understand the latter?

 

Maybe. That’s one of those “science things” I find very interesting. Different French scientists before Pasteur supposed that ethanol came from carbohydrates. Then the early biology came, and we realized that ethanol came from fermentation. And back then, they thought that was all of it. Yeast makes beer.

But it’s more than that. It also makes flavor compounds. Now we’re at the question of how does the yeast make flavor compounds? We still don’t know that. Why does one strain create different flavors from another? We can finally figure that out with genetics. 

Which is the impetus for this whole effort, right?

 

Yeah, exactly. We make yeast. People use yeast. We have these very old descriptions that we consider “normal.” But it’s not really normal. I think we’re going to look back on this time and say, “Wow, that’s how we were choosing yeast? Just based on these couple lines of description? We didn’t know what they would make, or how we could ferment to enhance specific characteristics?”

Now we can choose a similar yeast strain not just based on a name and a description, but on its actual genetics.

It seems like this report marries the history of beer with the future of beer—you still have to brew a beer, but the genetics take out the guess work.

Exactly. It’s not even about what some people go straight to—“designer yeast.” It’s about being able to make better decisions with the yeast strains we have right now.

Not designer strains, but better choices. So you could theoretically split an existing yeast into four different yeasts by turning off certain phenotypes, and voluntarily pick specific flavors that accentuate what you’re going for in your beer.

 

Yep!

That’s a pretty big development.

 

Absolutely. 

We want to give people the vocabulary to discuss yeast from a sensory perspective. Brewers want to talk about it. They know yeast is making that beer. But it hasn’t translated to the consumer yet.

The general beer drinking public seems somewhat unaware of yeast's impact on beer flavor. Now that we can attribute phenotypes to specific flavor compounds, and even styles, do you think it will be easier to explain to the average drinker why they like Belgian-y phenols in the same way they describe their love for mosaic hops? Can yeast ever be sexy?

I use that word all the time. I think that’s another reason we opened the tasting room based on yeast. We want to have fun talking about it, and give people the vocabulary to discuss yeast from a sensory perspective. Brewers want to talk about it. They know yeast is making that beer. But it hasn’t translated to the consumer yet. I think people think it’s gross or something.

 

There’s also a science jargon barrier. Hops are easy. You get the name of the cultivar and what it smells or tastes like in simple terms. Breweries even put that into the names of the beers. But that doesn’t happen with yeast. All the terms are somewhat complex. Could they ever become part of the beer vernacular?

 

Maybe they could. Sour beers are a great place to discuss the microbiology of beer. They’re becoming more popular, but you still don’t hear a lot of people mentioning lactobacillus when describing the taste yet. But they probably will. 

So understanding the genes behind flavor compounds could lead to an entirely new way to market beers. If consumers knew what they liked in terms of yeast flavors, breweries could use those descriptors on packaging?

 

Sure.

Genomics are playing a larger role in many agricultural products as sequencing becomes easier and cheaper. With that comes "smart" selection and the potential for genetic modification to turn genes on and off. Do you think we'll see specifically modified yeasts commercially any time soon?

 

I don’t think soon, but I’ve been asking that question for 20 years. I think every yeast person has. It hasn’t happened yet, so I can’t say it’s going to happen fast. But I would think it would happen eventually, when the benefits outweigh the worry.

There’s still concern about genetic modification on the food and beverage side. There have been no genetically modified yeasts used in commercial brewing, even though some strains have been made. I think there needs to be a really good reason to modify a strain. Strains created by non-GMO methods are probably the future. 

GMO scare tactics aside, couldn’t modification potentially open the door to entirely new styles of beer?

 

Oh, sure. All of the very experimental craft breweries—especially in the United States, which is more GMO-neutral—will very likely do something like this in the future. 

 

I can’t imagine what Sam Calagione would do if he could design his own yeasts.

 

Right! [laughs] Probably design a yeast strain that might have been around in Egyptian times. But that’s just it: all the artists creating all these unique flavors in the brewing world will drive the want. What do they want to brew? I think it’s hard on the yeast side to really know.

 

We’ve never really thought much about the returns. ROI is kind of a joke here.

If brewers could design their own yeast from the ground up, does that mean that modification could eliminate off-flavors?

Phew, yeah, definitely. Some of the compounds like sulfur, diacetyl, ethyl acetate? Yeah, we could get rid of those.

 

A lot of those are currently handled by temperature control, right? In theory, could you create a yeast that’s much easier to manage and control?

 

Yeah, but it’s still a difficult process for brewers. They have to keep it going, keep it alive. There’s not even a good test for how alive yeast is right now. We can test if it’s alive or dead, but how powerful is it? We don’t have an assay for that. It shows the challenges of managing yeast, even just evaluating it. Fermentation tests take days, making it hard to use as an evaluation tool.

 

So this research could potentially give us a level of detail that goes beyond the flavors a yeast produces?

 

Perhaps. You might be seeing that a yeast strain is going through a bit of genetic drift and it’s more unstable. Even if there’s a buildup of mutations, you don’t see it until seen it demonstrated in the brewing process or taste with, say, flocculation or phenolic flavors.

If you could see that happening, and a lab had a machine to sequence the genome regularly, you would know when you needed to swap it out. That would be pretty amazing, as an analytical tool.

That would improve quality and reduce loss.

 

Yes, you’d be able to identify exactly what yeast strain you’re using, that there is no cross-contamination, no change. Hopefully there’s a time in the future when that becomes a more regular assay. If you noticed a change, you could revert back to the original strain. You could eliminate drift entirely if you tested regularly enough.

 

Wow. For large scale brewers, that’s going to be amazing.

 

Oh, yeah. That’s a level of control they’ve always wanted. 

 

It would also benefit small brewers, too, if it was cost effective. Might it also open up jobs for in-house biologists?

They wouldn’t necessarily read the DNA, but work with the data. Right now, only the big players have sequencing machines. Most smaller breweries send out samples—to places like our lab—for analysis. As the price of the machines comes down, you’ll probably see more sequencing.

 

Does the collaboration group—or White Labs specifically—have plans to study other non-Saccharomyces yeasts?

Yeah, I think so. We’re really interested in Brettanomyces and other organisms. Verstrepen Lab, part of the collaboration team, just released a paper on bread yeast. But not really bread yeast—it focused on making bread with non-Saccharomyces cerevisiae yeasts. That’s the kind of research that will happen in brewing, too. What other strains can we use that make our beers taste different?

If you go far enough down the sci-fi rabbithole of the Krebs cycle, and look at how the actual fermentation process works, might we find non-yeast organisms that ferment?

It’s possible. That’s the unique part of doing this research: we’re going to discover things we had no idea about before we started this project. Obviously we do thinking and planning beforehand, but I like to be open-minded about research, and not say, “Here’s the exact plan of this research proposal.” It’s always going to lead to things you don’t expect.

 

Outside of the science, does this research help grow White Labs as a business? Are there plans to keep any of this information proprietary?

It was done in the mindset of open source. White Labs only supplied 96 of the 157 strains used in the sequencing. We wanted as much information as possible to be public. 

 

In the theoretical future, would White Labs ever commercialize proprietary strains that are legally protected?

 

It’s possible. That’s the challenge of any yeast maker right now. Talk to any company making yeast. You can spend a lot of time developing and releasing new yeast strains, but it can easily be taken by others. Yeast is easy to propagate. 

 

I guess it could go the same way as agricultural seed. Monsanto, for example, has patents on the genes for the corn seed.

 

But that also makes a lot of people mad at them. I don’t know where we’ll end up. Certainly there are some positives to having more control over what you sell.

 

So this indirectly improves the business, but do you see this improving your actual bottom line?

 

Honestly, I really don’t know. I can’t even tell you how much we spent on it, because I’ve been so passionate about this project. It helped us create a whole R&D department. We even hired a post-doc, Karen Fortmann, to continue the work. I really don’t know where that’s going to go.

I do hope this is the evolution of the understanding of brewer’s yeast, which will ultimately lead to brewers (and distillers and wine makers) making better decisions about the yeast they’re using. But it won’t just come from this paper. Hopefully more people jump on, we keep it going. This is just the beginning.

So you’re more like pioneers?

 

I think that’s accurate. That’s why Cell published it. They recognized that. 

 

It’s almost like an altruistic project for the organism itself.

 

Yeah, since we felt like a start-up for 21 years, we’ve never really thought much about the returns. ROI is kind of a joke here. We don’t approach our projects that way. We’ll have to someday. For now, we’re about making the yeast better.

Q+A by Oliver Gray
Photos by Matthew Rogers