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BioFPR Interviews

Sarah Teter – Staff Scientist, Novozymes, Inc
You work on improving enzyme performance: how is this achieved?

The enzyme performance refers to the biochemical activity of the protein. It’s achieved by looking for better protein candidates t of the same protein class (to replace candidates in our cellulase mix); engineering better proteins from the best available backbone; and by adding new components to the mixture that were either not there or not really active to start with. Those are the three main ways.

What do those improvements mean for consumers, further down the line?

What they mean is that there’s usually a direct correlation with a decrease in amount of enzyme productthat the biofuel producer needs to add in their process, and lower costs. That said, a lot of our partners choose to use the same amount of enzyme when we make a performance improvement, and use that higher enzyme power to save money somewhere else in the process. So it’s not always just a linear reduction in the enzyme use cost: sometimes you can save more than you would guess if you optimize your process around a more powerful enzyme. But a simplistic way to look at it is that you save money in one of the steps, and this allows you to complete the process at a lower cost.

You explain that you have over 1,100 enzymes in your collection: where do these come from?

The majority of the enzymes that I spoke about, for biomass at least, (that was just our biomass active enzyme collection), the majority of those come from fungi. And a lot of those come from thermotolerant fungi, so things that can handle in the range of 50-75 degrees Celsius. And a lot of those are found in compost piles. A lot of them are soil fungi, many are organisms that we collected ourselves, via Novozymes scientists around the world. We comply with the Rio Convention, in terms of collecting organisms, which deals with nationalities around the world. So we have a pretty extensive micro-organism collection. And then a lot of them actually come from publicly available genome sources, in addition to the ones that we’ve sequenced ourselves.

How do you begin to work through them all? Do you select the biomass you’re going to work on and then search for the right enzyme, or is it the other way round?

What we’ve tried to do is build up a core base of enzymes that will work on anything. So we have a set of biomass feedstock products that we know are important commercially. And we try to select enzymes that work well on all of those biomass feedstocks. We can do a little bit of tailoring to individual substrates, biomass substrates, but we need to have a core set of cellulases in particular that work across feedstocks. So what we do is identify a gene; we insert it into another fungus in order to make experimental quantities of it; we purify it; and then we run tests on those substrates of interest, to make sure that it works well across feedstocks, and that it can play well with the other components in the mix. That’s sort of a brief flow chart, if you will, of our screening process.

Leading on from that, Novozymes have a hot new enzyme for lignocellulosics: did this come about using the same process?

Well, there was a slight twist to that one. It was very much in the type of screening where we went to nature and looked for new activities. I can explain a little about how we discovered the importance of this enzyme. So, what we did was collect all of the enzymes that were secreted by a fungus called Thielavia terrestris. Thielavia we knew was pretty darn good at degrading cellulose, so we wanted to figure out why. What we did first of all was combine it’s enzymes with our currently best enzyme cocktail at the time, and we saw that not only did Thielavia make a really nice enzyme mixture, but when you mixed it with our starting mixture you got synergy: the two parts together worked better than the sum of the components. These were unexpected results.

So, we wanted to know what it was in the Thielavia mix that was synergizing with our best mixture. And so we did this classical biochemistry approach where we separated all of those components and looked at them pretty much one by one to find it. So, that was in 2003 and 2004 when we did that initial work, and said “Hey this is GH61”. People in the literature had said that it was just another endoglucanase, it’s a weaker glucanase, and that was actually not true, it was mischaracterized: it’s not a classic endoglucanase, and so, over time we identified that it was an oxidoreductase, and doesn’t use classical acid-based catalysis to hydrolyze cellulose. Instead it can reach this high energy state and use oxygen to bust open the cellulose.

And there are other groups that are working on it too, it’s a pretty hot new area, so I want to make clear that we aren’t the only ones who have published details of the mechanism. There have been a lot of groups working simultaneously on it: it’s pretty exciting.

Once an enzyme and a biomass have been “matched” what happens next in the process in terms of getting that to market?

Well, when we have an enzyme candidate that we know works well with all the other enzyme candidates, what we need to do is make sure that we can make it at higher levels: get production hosts that allow us to make the enzyme really cheaply. So, we’ll take it out of an experimental fungus host, and put it into a production host. Then we make sure we can make it at the really high titers in order to sell it at a viable price to the market. And then after that’s done we do scale-up, in terms of production, and we work a lot with the new enzyme mixes in our application development unit, to try and find what the lowest possible cost is in terms of process design: we call that your sweet spot. You might hear about that at the conference! Basically the idea is that the enzyme can allow you to do things like maybe run a process at higher solids, that would allow you to save process costs in unexpected places, by application engineering.

You work in collaboration with, for example, the Department of Energy (DOE). How does a company such as Novozymes go about securing that sort of funding and convincing potential investors, particularly from the private sector, that you’re going to get the results?

Specifically with regard to the DOE funding, it’s a very formal process: they publicly announce a solicitation, so they announce that funds are available, and you have to apply for them. It’s a peer reviewed proposal. So that’s how we got funding for this work.

But in general Novozymes is pretty unique with regards to how much we invest in R&D, just from internal funding. We invest 14% of our revenues into R&D, which is pretty huge. So actually we don’t really have to secure investment to finance the research usually. In fact it is is very unusual for Novozymes to have external funding. What is critical for us is demonstrating to ethanol producers, and other people who are building biorefineries to make things other than ethanol, that we have a cost competitive and highly-effective enzyme, that is going to allow them to have lower costs than any other enzyme that are out there. Novozymes is known as not only a good enzyme provider but we also have really good customer support, what we call customer solutions: we have scientists that go out to industries and work with them to design the best process. And I think it’s partly that reputation that gets us in the door, and then they can see theenzyme performance speak for itself.

It’s been predicted that there’ll be a 40% rise for fuels by 2035 and that 50% could be met with biofuels. Do you think these predictions can be realised?

The prediction was from the IEAE, and we have our own internal forecasts of what we think we can do based on mostly other industries’ forecasts of sustainably harvestable biomass around the world. For example, in the US, the USDA put out a study originally called “The Billion-Ton Study” that looked at how much biomass can be made available to biorefineries in a sustainable way: so those forecasts are based on what you could make from that biomass.

In general, Novozymes believes there is huge potential for cellulosic ethanol around the world. This is why we have dedicated 150 researchers globally over 10+ years toward developing the enzymes for this industry.

So do you think that’s going to be achieved?

I think it could be achieved. I think it’s really critical to make sure that feedstocks are grown in a sustainable manner, and we certainly believe that this can be done. Novozymes supports an international certification program, to show how the feedstocks were produced. So we’re working with external groups to hopefully bring some sort of similar certification to the table, because we’ve realised that all feedstocks are not created equal in terms of footprint: carbon footprint and water footprint.

So there should be a transparency throughout the whole feedstock process?

Yes, we think there should be transparency and we really support an international consensus on how to measure that. We actually have a sustainability group with world-renowned life-cycle assessment experts that’s based in our Copenhagen office that works actively on such issues.