Yeast mating repurposed for drug discovery: an interview with David Younger

One of the most exciting aspects of synthetic biology is the use of a biological system in a completely new way. Who could, 10 years ago, have imagined the use of a bacterial immunity system (CRISPR) for precise gene editing or gene localization within the chromosome? And who could predict that the yeast mating system can be used to assess protein interactions? David Younger, the CEO and co-founder of A-Alpha Bio, was kind enough to answer my questions on  the company’s technology. A-Alpha Bio just received $ 2.8 million in seed funding and is aiming to change the way we study protein interactions.

Kostas Vavitsas: David, tell us about the company.

David Younger: A-Alpha Bio is a biotechnology startup that helps pharmaceutical companies characterize protein interactions for accelerated drug development. I founded the company with our CTO, Randolph Lopez, after working together at the University of Washington’s Institute for Protein Design and Center for Synthetic Biology.

Our mission is to accelerate the drug development process for pharmaceutical companies using synthetic biology and improved DNA sequencing tools. To achieve this, we’ve developed “AlphaSeq,” our drug discovery platform that uses genetically engineered yeast cells to test the ability of a drug to bind to multiple protein targets in a single, time-saving step.

What pharma companies are doing today is measuring very small numbers of protein interactions at a time. So, for biologics discovery, they’re using approaches like phage display, where they’re screening a large library of candidate molecules, but against just one target. And for many biologics discovery and optimization, as well as for small molecule discovery projects, it’s really valuable to be able to screen protein interactions on a library scale.

We can take a large library of biologic candidates and screen them against hundreds, thousands, potentially millions of targets in order to optimize for a particular binding profile and to optimize for specificity.By allowing them to test millions of interactions between proteins at once, AlphaSeq allows pharmaceutical companies to develop treatments for difficult disease targets with a significantly quicker and less expensive process than they were previously able to achieve.

Kostas: And how does “AlphaSeq” work?

David: In effect, what we’ve done is reprogram yeast mating. Yeast exist as haploid cells and diploid cells. Haploids have two mating types, MAT a and MAT alpha. And natively, when you mix MATa and MATalpha cells in a liquid culture, the cells will fuse and form diploid cells.

What we realized from the literature is that it’s a single protein interaction that’s governing this process. So there’s a protein that’s expressed on the surface of MAT a cells called aggat 2 and there’s a protein that’s expressed on the surface of MAT alpha that’s called sag 1, and it’s the interaction between these two proteins that drive cellular glutination and then mating.

What we’ve done is knock out these native yeast proteins and replaced them with arbitrary proteins of interest. It can be human proteins, pathogenic target proteins, whatever you’re interested in studying. We express them on the surface of these yeast cells and then use yeast mating as a driver for measuring protein interactions.

Kostas: Is there any limitation on what kind of protein you can express?

David: One of the really nice advantages of this platform is that we’re starting from a very conventional, well-known system. We’re starting with yeast surface display. And there’s already a very rich history of proteins that people have already successfully expressed, and there’s a lot of literature about what is challenging to display. We can use that as a starting place, and we don’t have to reinvent the wheel and test every different class of protein. Instead, we can look into the literature. For example, multi-pass transmembrane proteins are very challenging…

Kostas: So basically the yeast is mating with each other and then giving the signal on if there is interaction or not.

David: Yes, and then we extend this to a library. So instead of just adding a single MATa strainand one single MATalphastrain, we can add a whole library of MATa strains and a whole library of MATalpha strains. When we mix them, we end up with diploid population that is dependent on interaction strength. Strong interactions will produce many diploids. Weak interactions will produce very few diploids. And then we have developed a proprietary method that basically gives us a next-gen sequencing output where we can trace the frequency of diploids in that final population back to a quantitative measurement of protein interaction strength.

Kostas: Congratulations on your seed funding. What are you going to use all this money for?

David: The primary focus of the funding will be to validate and improve the AlphaSeq platform against a number of high-impact disease targets, largely in the immuno-oncology and infectious disease space. We’ll also begin drug discovery and optimization partnerships with pharmaceutical companies.

Kostas: And you also received a Bill and Melinda Gates Foundation grant. What is the action plan on that?

David: The Gates foundation grant really highlights one of the exciting application areas of this technology. They [the foundation] are really interested in infectious diseases and therapeutics that can make a real positive impact on global health. And one of the challenges for infectious disease therapeutics is that you aren’t really going after just one target. You’re going after a wide diversity of targets. You don’t want to hit just one strain of flu or Ebola. You want to develop a therapeutic that is as broadly binding as possible while remaining specificity for that target class.

Clearly this is a major challenge for pharma companies. But what we can do is take a library of biologic candidates and instead of measuring their binding to just a single version of a flu protein, we can characterize interactions with a very wide diversity of targets in order to find the  therapeutics that bind most broadly, or to identify a cocktail of therapeutics that will hit as many different strains as possible. That project is in collaboration with Lumen Biosciences and MassBiologics.

Kostas: When did you decide you wanted to become an entrepreneur?

David: There was a really exciting time during my thesis work, when we realized that this platform actually works. And not only did it work, but it exceeded our expectations for how well it worked. Coming from a bioengineering background, the hope is that you develop something with functional utility. Once we were able to see the promise that this could have for the pharma industry, the bells started to go off.

And I think a lot of that had to do with the environment that I was doing my thesis work in. I was co-advised by Eric Klavins and David Baker, the two scientific advisors for A-Alpha Bio. David Baker in particular has an enormous amount of experience commercializing and spinning companies out of his lab. There are a number of really successful companies that I’ve gotten to see and learn from. Also, the ecosystem of the lab is very centered on commercialization and how to maximize the impact of technology coming out of the lab. We also have investors like OS Fund who are very familiar with the bioengineering and synthetic biology space, which is very important for us.

Kostas: Where do you see the company and yourself in the next five years?

David: One of the real motivations for starting this company is seeing the potential that synthetic biology can have on drug development and drug discovery. I think there has been a lot of focus in the synthetic biology community around building cellular therapeutics. But I also think there is an enormous amount of potential in applying synthetic biology towards improving the way we develop conventional therapeutics – biologics and small-molecules.

I really see A-Alpha Bio as becoming a leader in this space: taking synthetic biology and using it to really make a positive impact in the efficiency and effectiveness of therapeutics that come out of the pharma industry.

David Younger is the CEO and Co-Founder of A-Alpha Bio. David invented A-Alpha’s underlying technology, AlphaSeq, with Scientific Advisors David Baker and Eric Klavins while earning his PhD in Bioengineering at the University of Washington. Prior to graduate school, he received bachelor’s degrees in Bioengineering and Economics from Rice University. He is passionate about improving the efficacy and availability of therapeutics by harnessing the enormous power of biology and genetic engineering. Outside of his role at A-Alpha Bio, David enjoys spending time outdoors – climbing, hiking, and biking – in the beautiful Pacific NW.    

All images are courtesy of  A-Alpha Bio