Dibs on a RNA Computer!

I’ve given DNA a lot of love over the years -- DNA as a storage medium, as a computing platform, as the basis for robots, as the tool for synthetic biology/biohacking, even used for the DNA-of-Things (DoT).   DNA is the basis for all life as we know it, in every category of life we’ve found anywhere on earth. That we are now using it to achieve technological goals seems like one of humankind’s greatest accomplishments.

But where’s the love for RNA, DNA’s putative ancestor and still-partner?  A few recent developments in RNA caught my eye that I wanted to give their due.

As you may remember from high school biology, RNA has a crucial role in how DNA transmits genetic information.  As one source explains it: “DNA holds information, but it generally does not actively apply that information. DNA does not make things.”  Instead, it transcribes the information onto RNA, which then actually makes things happen. 

Just last week researchers from Northwestern University were able to show RNA switching genes off and on, using a simulation model they “affectionately” call R2D2 (short for “reconstructing RNA dynamics from data”).  The researchers believe the “strand displacement” mechanism is what switches genes “on” or “off.” 

Professor Julius B. Lucks, who co-led the research, believes: “Many diseases are likely caused by something going awry at the RNA level.  The more we know about this, the better we can design RNA targeting drugs and RNA therapeutics.”  For example, genes could be “engineered to turn “on” in the presence of an environmental contaminant.” 

Amazing stuff.  But that’s not all. 

Researchers at the University of Tokyo have created an RNA molecule that can not just replicate but evolve.  There has long been a hypothesis, called “RNA World,” which speculates that RNA is the basis for the origin of life, with DNA coming along at some later point (DNA is believed not to be stable enough to survive, much less evolve, in the primordial environment).  The research makes that hypothesis even more plausible.

The team seeded an RNA molecule, which evolved into several lineages before stabilizing: “The final population, comprising five RNA lineages, forms a replicator network with diverse interactions, including cooperation to help the replication of all other members.” 

The results were somewhat surprising, even to the researchers.  “Honestly, we initially doubted that such diverse RNAs could evolve and coexist,” said Ryo Mizuuchi, corresponding author of the study.

We will probably never know how life on earth actually emerged, but the researchers claim:

Our results demonstrate an evolutionary transition scenario of molecular replicators from a single common ancestor to a multi-membered network…Thus, our simple experimental setup offers a unique approach to deeply look into evolutionary phenomena.

OK, that’s two long-time mysteries answered, or at least addressed, by RNA.  Here’s an even more fun one: RNA computers.

There has been discussion of DNA computers for many years.  However, as NIST (National Institute of Standards and Technology) says:

Tiny biological computers made of DNA could revolutionize the way we diagnose and treat a slew of diseases, once the technology is fully fleshed out. However, a major stumbling block for these DNA-based devices, which can operate in both cells and liquid solutions, has been how short-lived they are. Just one use and the computers are spent. 

Instead, in a new paper, NIST researchers used RNA to build computers.  Or, more precisely:

Here, we develop scalable cotranscriptionally encoded RNA strand displacement (ctRSD) circuits that are rationally programmed via base pairing interactions. ctRSD circuits address the limitations of DNA-based strand displacement circuits by isothermally producing circuit components via transcription.

Samuel Schaffter, the lead author and a NIST postdoc researcher, explained how DNA and RNA computing differs from typical computing: “The difference is, instead of coding with ones and zeroes, you write strings of A, T, C and G, which are the four chemical bases that make up DNA.”  The authors tested whether the RNA-based circuits could perform logical operations (I won’t even attempt to describe exactly how they did this).

Credit: Shaffter and Strychalski

Dr. Schaffter said: “For me, these needed to work in a test tube as predictively as DNA computing. The nice thing with DNA circuits is most of the time, you can just write out a sequence on a piece of paper, and it'll work the way you want. The key thing here is that we did find the RNA circuits were very predictable and programmable, much more so than I thought they would be, actually.”

The authors are quite excited about future applications.  E.g., “We envision ctRSD circuits enabling many new applications in nucleic acid computing and synthetic biology. For example, the inclusion of ribonucleases in ctRSD circuits would allow continuous circuit turnover. Circuits could then respond multiple times to changing input signals, overcoming a current challenge in DNA computing.” 

As for the next step, Dr. Schaffter sees: “We’re interested in putting these in bacteria next. We want to know: Can we package circuit designs into genetic material using our strategy? Can we get the same sort of performance and behavior when the circuits are inside cells? We have the potential to.”

I can’t wait for Raspberry Pi to come out with their RNA-based computer.  You watch.

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All this sounds very esoteric and perhaps not applicable to the immediate woes of our healthcare system, but I’m thinking about the rest of the 21^st century and beyond.  As I’ve said before, the 20^th century may have been the age of computers, but the 21^st century is going to be the age of biology.  

If we believe that the 20^th century ushered in “modern medicine,” with more rigorously trained professionals using more scientific tools (think antibiotics, imaging, laparoscopic surgeries, A.I., etc.), then 21^st century healthcare is going to be about synthetic biology.  Thinking about DNA and RNA isn’t going to just be something healthcare professionals do to satisfy their undergraduate requirements; it’s going to be integral to their toolset.

What’s going to be very interesting – and highly disruptive -- is not just how this change will impact our health and our healthcare, but also what happens to physicians, nurses, pharmacies in a world where biologists/biochemists/geneticists may play the more important role. 

ARPA-H Needs to Think Bigger

Everyone loves DARPA, the Defense Advanced Research Projects Agency that is credited with such hits as the internet and GPS, but is also responsible for things like the Boston Dynamics back-flipping robots and even Siri.  DARPA’s mission is to make “pivotal investments in breakthrough technologies for national security,” but, as the previous examples illustrate, we can’t always tell how those breakthrough technologies are going to get used. 

Healthcare is, at long last, getting its own DARPA, with ARPA-H (Advanced Research Project Agency for Health).  It’s been discussed for years, but just last week was finally funded; a billion dollars over three years.  But I fear it is already off on the wrong foot, even ignoring the fact that President Biden had requested $6.5b. 

Let’s start with the problem that it not only doesn’t have a leader yet, but it doesn’t even have a home.  By law, the HHS Secretary now has 30 days whether to make it part of NIH or establish it as a separate part of HHS.  Respected experts like Dr. Francis Collins, former head of NIH, advocate making it part of NIH, to take advantage of NIH’s resources, while others want it to be independent.  Congress is weighing bills to both effects. 

More worrisome, though, is that, according to President Biden, “ARPA-H will have a singular purpose: to drive breakthroughs in biomedicine.”   The mission wasn’t originally that limited, but priorities like the “cancer moonshot” tend to focus emphasis.  There are certainly huge breakthroughs ahead in biomedicine, and that’s both exciting and needed, but biomedicine isn’t going to solve all of our health and healthcare problems.

Take, for example, the developing fiasco that is the replacement VA EHR.  Decades ago the VA developed VistA, one of the first attempts at an EHR  (its origin story, as reported by Politico in 2017, is fascinating), but during the Trump Administration it was decided to move to a commercial EHR.  Cerner won the bid.  According to three reports issued by the VA Inspector General last week about the first implementation, it is not going well, to say the least. 

Politicians like Senator Patty Murray and Senator Jon Tester have expressed their concerns, not for the first time.  Senator Murray was clear: “Here is my message to VA: stop the rollout before there is another catastrophic failure.”  Apparently we’re already past the point of avoiding a catastrophic failure; now we’re trying to avoid “another.” 

Our bar is way too low.

Not to mention, the costs have already soared to over $16b, way over original projections.  It’s worth noting that not only is VistA open source, but it’s free: “VistA is public domain and freely available through the US Freedom of Information Act (FOIA).”  Just saying…

Now, I’m not intending to pick on Cerner – its DoD EHR rollout seems to be doing better – or advocating for VistA. I don’t want ARPH-A to help invent a new and improved EHR.  I want them to help invent the technology that is to EHRs as EHRs are to paper records.  I want a big leap.

I want the next generation of health information technology, allowing people to store, share, exchange, and use key health information, making all that look easy – like magic (as Arthur C. Clarke posited, “any sufficiently advanced technology is indistinguishable from magic).   I want it to be as useful for the people whose health it is as for the clinicians who help them with it.  I want technology that may not become mainstream until 2050, but which would still be useful in 2100.

I don’t know what technologies will be important to that. Maybe holograms, maybe digital twins, maybe DNA storage, maybe blockchain/Web3, maybe AI, maybe quantum computing.  Maybe all of those, and others.  The important thing is, think big enough.  About this problem, and others.

Biomedicine is doing amazing things (thank you, COVID vaccines!), and opening all kinds of doors for new treatments, but all those doors seem to be ones that are more expensive and more rooted in a medical approach to health. 

We should be looking at breakthrough technologies that get at health in our everyday lives.  How do we track it, how do we foster it, how do we improve it where we live?  Smart toilets, self-monitoring, AI assistants, 3D printing of prescription drugs and even devices (hello, nanobots!) – those are already 2022 technologies that can be used.  There are undoubtedly breakthrough technologies that will make those look primitive.  Those are the kinds of thing ARPA-H needs to help develop.

DARPA’s projects can take 20-25 years to reach commercial viability – if they ever do.  We can’t afford to think too short-term (e.g., anything less than 10-15 years) or too narrowly (e.g., only biomedicine). When we think about ARPA-H projects, we should thus be thinking about what we want to our health and our healthcare system to be in 2050. 

I hope the VA EHR recovers from its stumbles.  I hope it coordinates seamlessly with the DoD Cerner EHR.  I wish all Cerner EHR coordinated seamlessly with all other Cerner EHRs, that all Epic EHRs coordinated seamlessly with other EHRs, and, really, that it shouldn’t matter which EHR vendor information started in.  But wishing and hoping isn’t getting us where we need to be; we need breakthroughs. 

As Lisa Jarvis wrote in Bloomberg: “ARPA-H needs to foster a culture in which it’s possible to quickly test ideas that fall outside the norm. It needs to cultivate wildly promising lines of thinking that might lead to a breakthrough — or not.”

Based on DARPA’s experience, it’s not important that the leader be a visionary.  We don’t need a Steve Jobs or Elon Musk.  We need a leader who can separate the crazy from the wild, who welomes that wild, and who knows how to get out of the way of innovators trying to make the wild plausible.   

If what we’re debating is whether ARPA-H should be in or out of NIH, we’ve missed the point.  If we’re focusing ARPA-H on biomedicine, we’re missing the opportunities.  If we’re just trying to avoid more catastrophic failures, we’re having one.

Think bigger.  

Let's Play Jenga with Healthcare

Last year I wrote about work done by Professor Leidy Klotz and colleagues about the value of subtraction.  They had just published a paper in Nature and he was about to publish a book (Subtract), which is now about to be released in paperback.  Their research found that, on a variety of tasks, people tend to look for changes that involve adding instead of subtracting, even when subtraction produces more efficient/effective solutions. 

Playing Jenga.  Credit: Elite Learning

I want to return to how this applies – or should apply – to healthcare.

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Here’s a word that is not often used to describe our healthcare system: baroque.  Not in the sense of medieval art/architecture, but in the sense that 16^th century philosopher Michel de Montaigne defined it: “Bizarre and uselessly complicated.”  Yeah, that’s healthcare.

In his book, Professor Klotz often talks about Legos.  Kids love to build with them; the more Legos, the better.  Addition is the expected course of action.  I like the analogy, but I think healthcare is more like the new television show Domino Masters, where players build ever more elaborate, more baroque structures out of dominos.  One domino falling brings about collapse, usually in spectacular ways. 

Credit: Ray Mickshaw/Fox

In the show, the collapses are carefully engineered to be aesthetically pleasing, but when a domino in the healthcare system falls, there’s no telling what other pieces it’s going to bring down.  This part of the supply chain is late, those nurses are burnt out, some social media influencers put out disinformation, and soon we have our collapses.

If Legos are the additive analogy, the subtractive analogy Professor Klotz uses is Jenga.  In Jenga, one starts out with a stable structure, and players keep removing pieces until it collapses.  The surprising thing is how many pieces can be subtracted before that collapse happens.  It takes a careful eye and a strategic sense to recognize what a safe subtraction will be.

Healthcare needs plenty of subtraction, but carefully and strategically. 

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Let’s go through some potential healthcare Jenga moves:

Payors: the U.S. has a ridiculous number of payors.  In government programs, for example, there’s not only Medicare and Medicaid, but also CHIP, the VA, CHAMPUS, TRICARE, and the Indian Health Service.  The number of private payors is in the tens of thousands, considering that each self-funded employer is its own payor.  Even counting just health insurance companies and third party administrators, the number is in the hundreds, if not thousands.

Answer: too many. Credit: PolictAdvice

I am not a MedicareForAll person, partly because that term tends to mean something different to each person using it, and am similarly skeptical of the savings/efficiencies “single payor” advocates tout.  But there’s no doubt that we’d have a more effective healthcare system if our approach to payors was to start subtracting. 

Networks: I hate provider networks.  Payors/administrators may claim that networks allow them to exercise more effective oversight of the various providers, to the benefit of consumers, but networks are primarily about price. 

We should not be looking to steer people to the cheapest providers.  We shouldn’t even be steering them to the average cost providers.  We should be helping them get to the providers who are most capable of helping them the most.  Done right, the best quality care shouldn’t be the most expensive.

If I could wave my magic wand, I’d subtract all networks in healthcare, and focus on identifying which providers can best help who with which issues.

Prices: Speaking of price, legislators and policymakers are patting themselves on the backs for recent “transparency” accomplishments, which involve making public more of the negotiated deals between payors and providers. It’s an addition that sounds praiseworthy, but isn’t really.

For decades, and now moreso than ever (ICD-10, anyone?), healthcare prices have been so granular as to be meaningless to anyone not intimately involved in billing. There are just too many codes, with too many modifiers.  Trying to understand in advance what your cost will be is usually futile…and even understanding your bill once you get it is often equally baffling.

There are way too many things for which we have prices, and way too many different prices for those things.  Each payor has its own set. For years, Dan Munro has been calling for “Single Pricing” rather than Single Payor.  He may be right, but one thing is clear: when it comes to healthcare prices, we should be subtracting – fewer levels of pricing, for fewer things.

Administrative hurdles: everything in healthcare, it seems, involves filling out forms and waiting.  It doesn’t matter that you’re already filled out forms and/or waited; you’re going to do more of both.  It’s bad enough that we make it so hard for people to figure what they need, but it’s inexcusable that, even once they do, we put more barriers before they can get it.

If you’re working in healthcare, every time you ask a patient to do something, ask yourself: is this really necessary?  Does it improve their health?  Or is this a step that could, instead, be subtracted?

Cost-sharing: Almost every type of health insurance in the U.S. has some form(s) of cost sharing, including deductibles, coinsurance, and copays.  Advocates claim that cost-sharing deters unnecessary care, but let’s not kid ourselves; the purpose of cost-sharing is to transfer costs from healthy people (in their premiums) to people using health services.  Is that who we really are?

For example, as many have pointed out, what’s the point of cost-sharing for insulin?  Cost-sharing is just a financial burden on them; they can’t really skip insulin or use less. There are plenty of other examples.

There may be some role for some very targeted cost-sharing, but the general rule of thumb for it should be subtraction.

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Right now so-called digital health is having an explosion of venture capital investment in record numbers of health tech companies. Healthcare certainly needs to be more digital, but thousands of new point solutions is addition at its worst. Who is funding the companies who subtract from our healthcare system?

If you are a healthcare innovator, trying to bring change to the healthcare system, ask yourself: am I adding to our baroque system, or am I subtracting things that don’t need to be there?

People in healthcare act as though they are afraid that any subtraction, as in Jenga, might cause the structure to collapse. What they really should be worried about is that they’re adding the domino that causes the chain reaction of destruction.

When Crypto Comes to Healthcare

The conflict between Ukraine and Russia has been called many things.  To most of the world, of course, it’s considered an invasion, a war between the two countries.  To Russia, it’s a “peacekeeping” mission.  The description that I can’t get out of my head, though, is one that I believe The Washington Post first used:  it’s the world’s first crypto war. 

Credit: Bitcoinist

“There is something about the war in Ukraine that feels different,” a former U.S. intelligence official told Nick Bilton. “We’ve seen wars documented on Twitter and images shared on the internet before, but this time it isn’t just bombs and bullets; this war is digital from the top to the bottom.” And, Mr. Bilton says: “At the center are cryptocurrencies.” 

If crypto has come to war, can healthcare be far behind?

The Post article was in the early days of the war, and focused mostly on how Russia might try to use crypto to lessen the impact of many financial sanctions that have been imposed. That remains a concern, but what has transpired since has opened up many people’s eyes about the use of crypto.  Ukraine has raised around $60 million in crypto contributions, according to blockchain analytics firm Elliptic, both directly to the Ukrainian government and to Come Back Alive NGO.  These contributions are being used not only for supplies and humanitarian relief, but also for purchase of military equipment.  Ukraine is, in part, crowdfunding the war using crypto.

Credit: Good Word News

Crypto has become a favorite means of donating money because the transaction is quicker and cheaper than bank or other more traditional methods, and can be done even when banks or other financial institutions may be under cyber or physical attack (or, if they are in Russia, have been sanctioned). Professor Gavin Brown writes: “By going straight to the people of the world, Ukraine’s government has been able to raise finance quickly without the need for financial intermediaries.”

“Cryptocurrency is particularly suited to international fundraising because it doesn’t respect national boundaries and it’s censorship-resistant — there is no central authority that can block transactions, for example in response to sanctions,” Elliptic’s chief scientist, Tom Robinson told CNBC. 

Dan Primack of Axios asserts: “This is the crypto industry's moment of truth.” 

“For nearly a decade,” he goes on to explain, “crypto evangelists have said that one of the tech's greatest benefits would be in helping users avoid macro economic disruptions…Russia's war on Ukraine, including the financial impacts on both countries, is kind of what they had in mind.”  The tests, he believes, will be utility and adoption.

Ukraine was particularly ready for a crypto war.  Even before the conflict, Chainalysis had ranked Ukraine as the top European adaptor of cryptocurrency, and fourth in the world.  Last September it legalized cryptocurrency, and was already piloting its form of digital currency, the e-hryvnia.   It has a Ministry of Digital Transformation, whose 31 year-old deputy minister Alex Bornyakov is creating a lot of waves.

Cryptocurrency hasn’t always been known for its stability, but if you are a Ukrainian refugee, carrying cash might seen risky, so putting your money in a digital wallet might seem like a prudent strategy. Similarly, if you are a Russian citizen whose bank is collapsing, whose rubles’ value are crashing, and whose Mastercard/Visa no longer work, putting your money into cryptocurrency suddenly makes a lot of sense.

Mr. Primack suggested: “But it's hard for even the most hardened Luddite to not at least wonder if it's prudent to sock away a little "digital gold," just in case he finds himself suddenly living in the next Ukraine or Russia.”  

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This seems rather far afield from healthcare.  The U.S. isn’t at war (unless you count cyberattacks), and our healthcare system has no shortage of ways to get money.  Nobody really likes how healthcare’s payment mechanisms work, and everyone agrees they are wildly inefficient, but, so far, there’s no hue and cry to introduce cryptocurrency into them.  Oh, sure, there are some start-ups claiming to offer health cryptocurrencies, but they’re not close to being a threat to any payors or healthcare payment intermediaries. 

But, still, crypto is coming to healthcare.

Credit: Techbullion

The U.S. is still in the early stages of developing a digital currency strategy; last month, for example, the Federal Reserve issued a report on a Central Bank Digital Currency. “I think it's more important to do this right than to do it fast,” Fed Chair Jerome Powell has said.  Congress has held hearings, will undoubtedly hold more.  Advocates for digital currency point to lower transaction costs, and potential to help the unbanked.   

There is a need for regulation, most believe, but Senator Ron Wyden, chair of the Senate Finance Committee, warns: “There is obviously a debate [about stricter regulation] but I want to be on the side of the innovator,” comparing the current crypto environment to the early days of the internet.

That’s sort of the point. We don’t know what cryptocurrency will be used for – who thought it’d be a key part of an actual war? – but we’re undoubtedly not thinking big enough.  Lower transaction costs?  Hello, healthcare payments!  The unbanked?  Hello, the uninsured!  Bypass intermediaries?  Goodbye, health insurers!

Let’s just hope that healthcare isn’t as slow (and as limited initially) to crypto as it was to the internet. 

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The war in the Ukraine did not come as a surprise.  The U.S. told the world for weeks what President Putin was going to do, and he did.  But, as Alex Bornyakov told TechCrunch last week, “The war didn’t start four days ago.  It’s been going on for eight years,” referencing Russia’s 2014 occupation of Crimea.  One of the ways that Ukraine prepared during those eight years was to get ready for crypto, and now they are benefiting.

Similarly, no one paying attention can believe our current healthcare system can go on as it is.  It’s due for a fall.  It has to get cheaper, faster, more efficient, more equitable.  Crypto is not the solution, but it is going to be part of the solution.  We should be preparing.

So: cheer for Ukraine, donate to it if you can, and, if you care about your health or your pocketbook, start thinking more seriously about what crypto could mean for our healthcare system.