Help, I’ve Fallen and My Enterprise Can’t Get Up: Goldilocks, right-sizing and synth-bio

The story of Pareto Biotechnologies, RuBisCo, the pesky failures of evolution, and help for those who have fallen and can’t get up, via a right-sized approach.

Not too high a goal, not too low. Not too much reinvention of the genetic code. Not too little.

Will Pareto’s approach be “just right”?

The odds are good that some time in your lifespan your doctor will prescribe a life-extending therapeutic for you. The unsung hero behind the scenes will possibly have been a mouse, who took the drug before you did to ensure there were no vicious side effects and that the therapy proceeded as expected.

You might wonder, as we do, how feeding a drug to a mouse can in some way predict how it will react inside you. Enter a class of mice who have had their mouse immune systems replaced with human immune systems.

“They have mouse ears and tails, but on the inside, in their immune systems, they are like you and me,” explained Mike Mendez, one of the team who first engineered the genetics of placing human immune systems inside mice.

Clearly a winning idea. But if you’ve yawned at some stage that “we’ve heard about synthetic biology for years. Where are the other big winners?” You’ve asked a good question, and don’t feel alone.

In the case of Mike Mendez, he continued to work on building platforms — that is to say, genetic platforms — that can benefit the earth and its inhabitants. For several years, you could have found him at Sapphire Energy, where he was a key leader in establishing a synthetic biology toolkit for algae.

Algae as an energy platform

Now, there’s nothing revolutionary in making crude oil from algae. In fact, all crude oil is algae. Mother Nature makes it naturally, using geologic pressures, heats and time-scales.

To replace fossil petroleum, all we have to do is make a whole bunch of algae, dump it on the ground. Mother Nature will take care of the rest.

In 60 million years or so.

Given an understandable investor impatience with that time-scale, Sapphire Energy has been hard at work since 2007 on a time machine — replacing the natural process into an industrial equivalent that takes a few days.

Building out that capability in algae has been the major factor in ensuring that, for Sapphire Energy, results would not come in a day and would cost a lot of dollars. There’s been a lot of brute force biology employed to advance the science of algae. Sapphire has, to some extent, built an entire industry inside one company.

Now that much of the platform work has been done at Sapphire, Mendez has moved on to a new challenge, and finds himself at Pareto Biotechnologies.

Another co-founder of Pareto, Jamie Bacher, serves as CEO and is fairly well-known in the community after signature stints at both Sapphire Energy and Amyris. But his background goes back to the Rincon adventure — a technology that predated and catalyzed Sapphire — which we profiled here. Other co-founders of the company include Joe Noel and Michael Burkhart.

So, it’s a company with a “name brand” team. But what’s the name brand problem and opportunity?

Pareto’s technology is the result of over a decade of academic and private sector research and intellectual property focused on one particular polyketide pathway. Building on Dr. Joe Noel’s groundbreaking research at the Salk Institute, this pathway – previously dismissed as the “poor man’s pathway” – is the foundation of Pareto’s platform, capable of generating known products and novel molecules.

In the near term, Pareto will introduce  “designer molecules” as cosmetics, flavors and fragrances including molecules with properties unlike anything previously experienced. In the long term, Pareto’s molecules will be designed to enhance nutraceuticals, pharmaceuticals, and industrial commodities.

Why synthetic biology at all?

Let’s go back to the problem that brings synthetic biology into focus, and to some extent dampens its horizons. Namely, the biosphere is filled with box canyons that organisms and business models are stuck in, and can’t get out. “Help, I’ve fallen and I can’t get up” — as the old late-night commercial refrain goes.

Let’s start with something old and well-known to illustrate. Consider the problem of photosynthesis.

It’s pretty deeply flawed. That is, remarkably inefficient in terms of converting solar energy to plant energy. A typical corn plant, for example, might pick up as little of 2-4 percent of the sun’s energy.

As Mendez explains, nature had a whole bunch of inefficient instruments, and responded by just making more and more of them. Measured by weight, RuBisCo, which is a phenomenally flawed organism that performs a critical function in photosynthesis, is the most successful protein ever developed by Nature.

It’s true. RuBisCo — the enzyme that converts CO2 to usable carbon for energy, plant-building, and anything else —has no structural chance at all, as currently designed, of achieving anything close to a maximum potential in terms of converting carbon. It’s one of Nature’s mess-ups.

The problem of technology losers as marketplace winners

Which beings to mind the terrifying days on 1944, when Germany was bringing forward its vaunted and fearsome wunderweapons — technologies like the V-1 and V-2 rockets and the Messerschmitt Me 262A, the first jet fighter.

How did the Allies counter the development of technologies that could have eventually rained destruction on their cities and possibly altered the outcome of the war? Though the Allies’ technologies were not as strong, they built enough fighters and bombers to knock out Germany’s advanced war technology production capacity, and wrapped up the war before the wunderweapons could have the material impact they were designed to have.

Now, after the Second World War, the Americans and Russians did everything they could to locate and spirit away the German technologists — and replaced their platforms with missile and jet fighter technologies, which they combined with their industrial might.

But in the world of biology, we can’t just as easily toss out a failed technology and start over. Sure, failures disappear through the mechanism of extinction. But successes are built only through modifying the current code, one gene at a time.

Imagine if you could only evolve an aircraft by changing one rivet at a time, then building the new aircraft, then changing another one, and so on. Sure, you’d get a superior plane eventually. In 60 million years or so.

Therein lies one problem of evolution, the time-scales are massively inefficient. But there’s another problem.

RuBisCo and the problem of time-scales in biology

That is, the time-scales are so vast that evolution itself is exposed to the problems and challenges imposed by geologic time scales.

In the ancient past — when evolution was already hard at work — the atmosphere was radically different. In ancient times, there was about as much free oxygen in the atmosphere as there is in the ocean today — which is to say, not much at all. Oxygen was once a trace atmospheric element. The sky was filled with CO2.

Which brings us back to our friend RuBisCo. One of the key inefficiencies in that enzyme is that its performs carboxylation and oxygenation, both. Which is to say, it fixes carbon — but if oxygen happens to be present, it reacts with oxygen too. The oxygenation product is wasted.

So, why did RuBisCo evolve at all, in the way it did? Because, back in the day, there wasn’t much free oxygen around to react with. RuBisco was a lot more efficient when it first evolved and became dominant.

Now, you have abundant free oxygen, RuBisCo is quite problematic in terms of efficiencies, and there it is — embedded in the cells that make up every grain of rice on Earth, for example. The world’s staple food crop, limited in its productivity by a problem that dates back to the shift in the atmosphere that occurred millions of years before the emergence of rice, or people to eat it.

And evolution only has that rivet-by-rivet methodology to fix its problem. We might have the problem of RuBisCo for millions of years more. Perhaps, for as long as people exist, or longer.

Just to mention one problem that biology presents us with. Hence synthetic biology — designed to leap over structural problems by reimagining the genetic code.

The pivot to flavors and fragrances

Which raises the question — why are smart companies like Pareto focusing on flavors and fragrances instead the monumental challenges in cancer research and energy — the big problems?

As Mike Mendez explains, there are some box canyons not only in biology — such as the problem that RuBisCo has gotten itself stuck in — but in commercializing technologies as well.

“Developing high-end therapeutics? Such as a cure for cancer? It’s one thing that everyone has looked for via synthetic biology for years. So, where are the big, signature breakthrough successes? The problem is, it’s practically impossible to attract investors for a venture that will have an outcome in, maybe, 15 years after a series of expensive and risky clinical trials that only big companies really have the patience and capital to survive.”

“And look at the other end of the equation, such as biofuels. There, you might get the biology right, but what about the systems you have to build to industrialize and get the costs down. Look at Sapphire. The imagination that has to go into that is really amazing, and even then it goes slower than you would like.”

Mendez pauses for emphasis. “You need winners.”

“So, we’re looking at flavors, fragrances and chemicals. You can get quickly to market. Not like energy or cancer, which for different reasons take huge amounts of investment and time. That’s the basic idea behind the company.”

Will it work?

A winning approach? Just might be, so long as Monsanto or equivalent doesn’t strut into the room shouting. “Who’s been sleeping in my bed? Who’s been eating my porridge?”

We’ll see how that goes. Goldilocks’ fate varies in the many tellings of the Story of the Three Bears. In some, she manages to get home safely; in others, she vanishes into the forest. The story itself is evolving rapidly since it first appeared with an old woman and three male bears in the 1830s.

As is synthetic biology, faster every day. This time, will the porridge will prove to be just right?

More about Pareto Biotechnologies here.