CRISPR is rocking, Inscripta too, but there’s the Coco Chanel problem

December 20, 2017 |

The term CRISPR-Cas9 may not mean anything to you yet, but CRISPR will re-shape everything around including possibly the color of your children’s eyes, so listen up.

Time to have a chat about Inscripta, which generated a colossal amount of publicity last week for releasing one of its own, unique CRISPR enzymes, which will be free for all researchers to use.

You see, every CRISPR gene-editing system comes with a pair of scissors — an enzyme to snip DNA — and the one that almost everyone knows is Cas9. As in CRISPR-Cas9.

Now, that’s a pair of scissors you can’t pick up cheap at Wal-Mart. And if you think the enzyme technology is complex and crazy expensive, just wait until you’ve seen the licensing deal.

Because MAD7 could be a big deal in democratizing research, that’s the reason for the wave of free publicity. Inscripta has outfitted this 21st century technology with 21st century deal terms — the enzyme is now available for all research with no up-front licensing fees or onerous “reach through royalties” on products made using this technology. If one wants to use MAD7 for non-R&D uses – such as manufacturing, inclusion of the enzyme in therapeutics, or for resale – then Inscripta will charge a low, single-digit royalty, which is far below the standard industry terms.

“The potential is so vast, the app space is so vast, we want to liberate the community and spark it,” Inscripta CEO Kevin Ness told The Digest. “There are a beautiful amount of products that now can be developed unencumbered. We’re removing the barriers.”

Inscripta is doing the world a favor, but there’s commercial rationale to it. By releasing MAD7 broadly at this early stage, Inscripta believes that it will catalyze the testing, improvement, and adoption of MAD7 and expedite the development of the MADzyme family.

As said Stanford bioengineering professor Michael Fischbach observed, “This will be of keen interest to the research community. By making CRISPR enzymes free to use, Inscripta is helping to drive innovation across the genome-editing field. Improved RNA-guided enzymes hold great promise for breakthroughs in academia and industry.”

The Inscripta gambit

Here’s what Inscripta is avowedly up to: developing a broad family of CRISPR enzymes and gene-editing technologies. Specifically, over the coming months, Inscripta will continue to characterize and test MAD7 on mammalian cells, develop new MAD enzymes including bespoke enzymes for researchers and commercial partners, and work on a full suite of gene-editing tools (software, instruments, and reagents) that will significantly increase the speed and efficiency of CRISPR gene-editing.

The bigger question: where is Inscripta going?

Whither goes Inscripta? There are a couple of telling clues which are in the public domain — let’s look at the name change from Muse Biotechnology, and some of the new faces around the investment table, and we can glean a lot from that.

In short, think Illumina —  the company that revolutionized DNA reading. Just adjust your sights away from reading DNA and move over to editing it.

(Backstory for readers: Illumina was founded in 1998 and “provides a line of products and services that serve the sequencing, genotyping and gene expression and proteomics markets”. It’s a NASDAQ 100 and S&P 500 component stock. Inscripta chairman John Stuelpnagel was Illumina’s co-founder and CEO).

“Writing is worth vastly more than reading,” Ness told The Digest, and we’ll think upon the opportunities and the tools — in the long-term — to write DNA as well as edit it. Editing, for now.

Mining the miners

To describe the CRISPR revolution in Gold Rush terms, Inscripta is not a mining company, it is a Tool Co. Someone else is heading up into the gilded Yukon to get rich, and Inscripta is going to operate next to the docks and sell gear. Just like John Nordstrom did, hustling shoes near the Seattle docks.

So think of this as a free pick-and-shovel to get the Gold Rush started, and you’ll see why there’s quite a bit of Nordstrom in the Inscripta story. Only, in this case, the Yukon lies in the microscopic world of genes. And the workhorse organisms that produce via fermentation everything from beer to prescription drugs.

Remaking the code, editing genes, will be the biggest chase of our time until we industrialize the writing of it. So, let’s turn for a second to the essential CRISPR need-to-knows

The CRISPR backstory

CRISPR is a gene editing technique. You may be familiar with the alphabet soup of DNA – A,C,G.T . A lot of those combinations running around inside your genome don’t mean anything, don’t do anything.

Consider it this way.

Adjacent to a very useful instruction such as “make baby blue eyes for this nice person” sits something in the genome like:

Make GJETbdg hkb.jhi  ljbck.hojc

and next to that might be:

Dial me up some kszjhvsk and from that make ew;xw[pew9 and from that make px284b  and from that make p813p9ug and from that make baby blue eyes for this nice person.

So, there’s junk and there are also inefficient metabolic pathways.

How did we evolve with so much junk?

Why are we shunting precious energy away from making blue eyes and in to making a whole bunch of kszjhvsk?

So here’s the problem. The genome is built up through mutation and copying, nothing else. Inefficiencies build up. CRSPR could become a story with many dimensions, but it is fundamentally about having the ability to edit.

If the gene is a fabric, then MAD7 is a scissors with which we cut it, and CRISPR is the sewing machine by which we assemble the cuttings into the stuff of high fashion.

The editing problem

Efficient metabolic pathways, helping organisms to make stuff better, faster, cheaper. That’s the promise of CRISPR. Now, here’s the problem.

If you alter Chanel, is it still Chanel? Even if still Chanel, is it Coco’s?

Or try this exercise in editing for size. You’ll know the original:

We hold these truths to be self-evident, that all men are created equal, that they are endowed by their Creator with certain unalienable Rights, that among these are Life, Liberty and the pursuit of Happiness. — That to secure these rights, Governments are instituted among Men, deriving their just powers from the consent of the governed,That whenever any Form of Government becomes destructive of these ends, it is the Right of the People to alter or to abolish it…

But who owns:

People derive their unequal rights from the consent of Governments that are endowed with certain self-evident powers to alter or abolish Life, Liberty and the pursuit of Happiness.

You note, all that was required in this edit was a pair of scissors and a sewing machine to put it back together. Editing is the power to alter. You can see the roots of the philosophical debate shaping up.

The Coco Chanel problem

What is copyright when what is being edited is the manuscript of life? Who owns the rights, who has the right, who has the power to say yes, who has the power to say no?

Does Coco Chanel have a say in what becomes of a dress? Does Coco have a say in the editing of her genes, or those of her neighbor, or her competitor? Who can alter what? If your organism is fundamentally altered by me, is it mine, or yours? If an organism that belongs to itself is altered by me, is it mine?

How complex can life become, yet I still can own it? I can own a dog, but not a man, but who owns the dog edited into a man?

We are, all of us creatures, products of that A.C,G,T code – species differ only in the length and arrangement of those acids. Zip-zip-zip, we have your genes, zip-zip-zip, we have a dog’s, zip-zip-zip, we have Coco Chanel’s.

It is not really enough to say, though it is said and correctly, that CRISPR lacks this power and this direction, that you can’t really edit a dog into a man, that we don’t have the tools to make changes on that order, and that the costs would be fantastic in any case. But look at the speed of genomic innovation. The tools for profound change might arrive in a thousand years, or in 10, no one can say for sure.

It is more than a story of tools, of scissors and sewing machines. Long before we run out of gene-editing ideas we are going to run out of philosophical runway. Meanwhile, the miners have seen the gold, and are heading for the Yukon. And there’s Inscripta making cost-effective and worthy gear. Brava!

But who shall sit in the judgment seat and say what can be sold and what cannot, what can be invented and what cannot, what can be held as intellectual property and what cannot?

“A Topic for another Day”

At this stage we usually say things like “that’s a topic for another day,” but now that Inscripta has set the cat amongst the pigeons, you might see in the democratization of gene editing the same potential for the unleashing of forces we have seen in the internet age.

We live in a golden age of information — but also in a world of hackers, fake newsers, digital pettifoggers, pornographers, sniffers, snoopers, currency manipulators, charlatans, spammers, wikileakers, merchants of innuendo and exposé. The winds that freedom unleashes are not always gentle zephyrs that bring noble souls safely to righteous shores.

First come the powerful and terrifying forces, then riseth the priesthood. Who shall wear the robes and hold the power? Faceless bureaucrats meeting in dank basements? Nominees of investors? Luddite, agenda-ranting NGOs? Demagogue legislators who struggle with the science? Trial lawyers?

Many of the next chapters in the CRISPR story are about “What?” but there is also the all important question of “Who?”.

Here, we are exploring the very language inside us and having conversations with our DNA and RNA. There’s good reason to pick our overlords carefully.

Of stewards and stewardship

“We need to be stewards,” said Kevin Ness. “We need to get this out, but we need to be good stewards.”

As the Stewart family were good stewards to the Kings of Scotland. Until, one day, they overthrew them and became the Stuart kings in their own right. Come to think of it, that was Pepin’s route to the Merovingian kingship, and we know what changes his son Charlemagne wrought across Europe.

Lenin cried “All power to the Soviets!” but in the world that is fast approching, you might as well cry “All power to the Stewards!”

And if stewards become kings, then the selectors of stewards are kingmakers. Yes, we mine the miners, but who’s minding the mine?

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