Barcodes Are Us

Usually I write about things where I see some unexpected parallel to healthcare, or something just amazed me, or outraged me (there are lots of things about healthcare like the latter).  But sometimes I run across something that just delights me.

So when I inexplicably stumbled across DNA Barcoding Technology for High Throughput Cell-Nanoparticle Study, by Andy Tay, PhD, my first thought was, oh, nanoparticles, that’s always interesting, then it hit me: wait, DNA has barcodes?

How delightful.

We’re all used to barcodes.  Pretty much every product in pretty much every store has a barcode.  The barcode was invented in the late 1940’s, but didn’t really take off in popularity until the UPC (Universal Product Code) barcode.  A Marsh’s Supermarket in Troy, Ohio, in 1974 was the first grocery item scanned (a pack of Wrigley’s Juicy Fruit Gum, if you are interested).  The UPC barcode encodes the Manufacturer of the product, and the product code. 

The now almost as ubiquitous QR codes are, essentially, two dimensional barcodes.  Accordingly, they can store significantly more information. 

But back to DNA barcodes.  The main purpose is, as you might guess from the name, is to have a standardized way to uniquely identify species, based on their DNA (think of species as the “product”).  The methods were first proposed in 2003, by Paul D N Herbert, et alia, and quickly gained traction. 

Guo, et. alia, describes DNA barcoding as follows:

DNA barcode is one or more short gene sequences (generally 200–900 base pairs) taken from a standardized portion of the genome to aid species identification and discovery by employing sequence divergence based on nucleotide alignment (Emerson et al. 2011; Hebert et al. 2003a, 2004). Thus, the fundamental function of this genetic tool seeks to compare barcode sequences to reference databases to efficiently and effectively assign any biological sample to its species regardless of the visual classification of the sample.

There are databases of DNA barcodes for a variety of life forms, including plants, animals, and/or fungi; these include the BOLD system (Barcode of Life Data system),  Unite, Diat.barcode, and iBOL (international Book of Life). 

Credit: University of Guelph

Unlike, say, UPC codes, which can be simply assigned, there’s not a universal way to decide which DNA sequences can be used to barcode an organism, and great care must be taken to extract and analyze it.  To complicate things further, there are mini-barcodes and meta-barcodes.  I’ll leave it as an exercise for the very interested reader to learn more about exactly how all that is done; for my purposes, it may as well just be magic.

DNA barcodes allow us to look at a relatively modest DNA sequence and determine what species it belongs to, which is a great help if one is identifying new species or trying to do an assessment of an ecosystem.  For example, students from a collection of 50 schools in Australia collected some 14,000 specimens, submitted 12,500 new DNA barcodes to BOLD – 3,000 of which were entirely new.  Project lead Dr Erinn Fagan-Jeffries said: “It is highly likely that all contributing schools have found species new to Western science which is really exciting.”

Lest you think that all DNA barcodes are good for are identification of species, researchers at the Garvin Institute of Medical Research barcoded cancer cells, in order to understand which ones were evading the immune system response and immunotherapies.  “We showed that there are rare cancer cells capable of escaping the immune system and escaping treatment with immunotherapy,” said first author Louise Baldwin. 

The researchers believe that “the mechanisms could be used as potential targets for therapies, to stop tumorous cells from adapting and spreading. Another future application could be in prognosis, where a high number of cells could indicate which patients might not respond to immunotherapy.”

Not bad for a barcode.

Back to the nanoparticles.  Dr. Tay says: “Recently, DNA barcoding technologies have been applied to generate barcoded cells and nanoparticles to investigate heterogeneous cell-nanoparticle interactions to boost the translational application of nanomedicine.”   The new techniques enable “millions of cells to be tracked over developmental and evolutionary time scales and to record cellular features in response to stimuli, including nanomedicine.” 

Dr. Tay points to research by Boehnke, et. al. that “made use of barcoded cell lines to discover cell and nanoparticle features to boost nanomedicine delivery.”  These and other new techniques made it easier and faster to understand which nanoparticle formulations are having the desired effects. 

I mean, really, is anything cooler than injecting DNA barcodes into nanoparticles to help achieve clinical results?   That’s some real 21^st century medicine.

Credit: Yaari, et. al./Nature

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We are DNA creatures.  All life that we know are based on DNA, and it’s not clear to me that we’d even recognize an organism based on anything else as life.   Barcodes are not DNA’s only amazing trick.  It is the nonpareil storage device; someday all our storage needs may be met using DNA (yes, I know, some argue to diamonds as the storage medium, but, really, DNA is way cooler).  As Zhang, et. al. noted earlier this year,  “DNA has emerged as a powerful substrate for programming information processing machines at the nanoscale.”

There ae going to be DNA/RNA computers, DNA neural networks/AI, and DNA robots.   Who knows what else? 

Given all that, I’m still holding out hope that we’ll someday have a DNA EHR, with both the processing done in DNA and the data stored in DNA, and that we store all that in our own DNA.  Tell me that’s not something that a visitor from the 22^nd century wouldn’t appreciate. 

There’s a whole body of work in information theory/mathematical logic about the shortest way to define statements, numbers, etc.  DNA barcodes may do well at more simply describing species, but I don’t know that we couldn’t each have a unique DNA barcode – shorter than our entire genome – that could be used for many applications.  

Our world would be much different without UPC barcodes, QR codes, and computers based on silicon chips, but that’s all so 20^th century.  In the 21^st century, we better be getting used to more ways we can use DNA.

DNA barcodes -- delightful, indeed. 

One Person's Trash...

Gosh, so much going on.  Elizabeth Holmes was finally sentenced.   FTX collapsed.  Big Tech is laying off workers at unprecedented rates, except TikTok, which should, indeed, be cautionary.  Elon Musk’s master plan for Twitter remains opaque to most of us. Americans remain contentedly unworried about the looming COVID wave.

With all that to choose from, I want to talk about space debris.  More specifically, finding opportunity in it, and in other “waste.”  As the old saying goes, one person’s trash is another person’s treasure, so one person’s problems are another person’s opportunities. 

And, yes, there are lessons for healthcare.

Trash to treasure

Getting to space has been one of humankind’s big accomplishments. We’re so good at it that earth’s orbit has become a “graveyard” for space debris – dead or dying satellites, pieces of rockets, things ejected from spaceships, and so on.  Space is pretty big, but the near-Earth debris is getting to the point when avoiding it becomes an issue for the International Space Station and other orbiting objects. 

Scientists now fear that climate change will impact the upper atmosphere in ways that will cause space debris to burn up in it less often, making the problem worse.

You see the problem. Credit: European Space Agency

Some countries see opportunity.  The Washington Post profiled how Japan, in particular, wants to be a leader in cleaning up space debris. “In space, Japan has always been a country of second gear. The first gear was always the United States, Soviet Union and, recently, China,” Kazuto Suzuki, a space policy expert at the University of Tokyo, told WaPo. “This is a golden opportunity for Japan, but the time is very short.” 

Jonathan McDowell, an astrophysicist at the Harvard-Smithsonian Center for Astrophysics, noted: “The problem is there’s no international air traffic controller for space.”  Getting countries to agree on the problem, he added, “only works if the countries are willing to put international interests ahead of their own paranoia about military concerns, and it’s not clear that China is, and the U.S. is definitely not.”

 

China’s space ambitions have become very clear – perhaps for commercial and scientific purposes, almost certainly for military – but so has its interest in space debris. China-based Space Technology Company recently demonstrated a robotic platform that uses a large net (or “sail”) to capture and “deorbit” space debris. “In the future, the NEO series satellites could clear space debris by dragging it out of orbit and burning it in atmosphere, and accurately capture space debris that may pose a threat to space spacecraft and other targets to protect the safety of space facilities," Su Meng, founder and CEO of Origin Space, told the Global Times.

 

Not to be outdone, British companies are competing for contracts for what Sky News called “Britain’s first garbage truck for space,” while the U.S. Space Force’s innovation arm has awarded 124 Phase 1 contracts that will focus on “Active Debris Remediation.” 

 

Japan wants help to set standards and precedents. “Setting a precedent is a great way to hold other countries accountable,” Professor Suzuki told WaPo. “It will — not legally, but morally — bind other countries.”  Its Commercial Removal of Debris Demonstration (CRD2) claims to be “the world's first technology demonstration of removing large-scale debris from orbit,” with hopes of an Active Debris Removal demonstration as early as 2025.  It hopes “to develop a new business market.”

I love it.

 

Of course, one country’s technology for Active Debris Removal/Remediation could be used to take out another country’s operating satellites and spacecraft, making some countries’ interests in it perhaps less than altruistic.

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The drive to make space debris not only a civic duty but also a business opportunity reminds me of the efforts to extract rare earth elements – critical to many electronics – not from mines (primarily located in China) but from landfills.  A 2020 study found e-waste from discarded electronics includes “14 rare earth elements, six platinum group metals, 20 critical metals, and 16 other elements, including some precious metals.” 

 

In Nature, Michael Eisenstein points out that “estimates suggest that precious metals might be up to 50 times more abundant in e-waste than in mined ores.” He goes on to argue: “The precious and scarce metals these devices contain can be reused near-indefinitely, and emerging technologies that make their recovery easier could drastically reduce the need for mining.”

 

E.g., earlier this year, a Rice University lab reported that its flash Joule heating process “has successfully extracted valuable rare earth elements (REE) from waste at yields high enough to resolve issues for manufacturers while boosting their profits.” 

 

There’s gold – and even more valuable rare earth elements -- in that waste.    

That does seem like a better idea. Credit: Purdue University

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Space debris and e-waste in landfills seem like a long way from healthcare, both figuratively and literally.  For most of us, they’re out of sight, usually out of mind, and, to the extent we think about them at all, problems for someone else to deal with, at some future time.

 

In other words, pretty much like most big problems in healthcare. 

 

But when we can’t get a smartphone because its manufacturers can’t source the necessary rare earth elements, or when those smartphones can’t access GPS because space debris has taken out the supporting satellites, then we’ll care.  Then we’ll be wishing more people had been looking for the new business opportunities each represents.

 

Most people look at problems in healthcare and just shrug; that’s just the way it is, we lament.  Some innovators develop incremental solutions that make things at least a little less bad. We graft solutions on top of the existing system, add more layers, take a new slice of all that spending.  But turning “wasted” byproducts of our dysfunctional healthcare system into new business opportunities – that’s harder.

 

Here's an example. Health systems take their medical debt – caused by their excessive charges and our inadequate health insurance system(s) – and monetize it.  That’s a creative way to make more money from a problem, but it doesn’t fix the problem for patients.   Toledo (OH) saw an opportunity: it is wiping out $240 million in medical debt for its citizens. Now, that’s some creative problem-solving. It doesn’t fix the problem of why there’s medical debt but at least it addresses the impact of it, at least for a time.

 

If only more of us turned problems into opportunities like that.

Credit: Deamstime

 

So, healthcare entrepreneurs: what is the space debris in healthcare, and what can you do about it?  Where are the rare earth elements in healthcare, and how do you reclaim them?   

Our Plants Should Be Plants

It seems like most of my healthcare Twitter buddies are enjoying themselves at HLTH2022, so I don’t suppose it much matters what I write about, because they’ll all be too busy to read it anyway.  That’s too bad, because I was sparked by an article on one of my favorite topics: synthetic biology. 

Credit: Shutterstock

Elliot Hershberg, a Ph.D. geneticist who describes his mission as “to accelerate the Century of Biology,” has a great article on his Substack: Atoms are local.  The key insight for me was his point that, while we’ve been recognizing the power of biology, we’ve been going about it the wrong way.  Instead of the industrialization of biology, he thinks, we should be seeking the biologization of industry.

His point:

Many people default to a mindset of industrialization. But, why naively inherit a metaphor that dominated 19th century Britain? Biology is the ultimate distributed manufacturing platform. We are keen to explore and make true future biotechnologies that enable people to more directly and freely make whatever they need where-ever they are.

He cites Gingko CEO Jason Kelly’s 2019 tweet:

"X doesn't grow on trees" ... biology is so much better at manufacturing than any human-invented tech that we use it as an idiom for free and abundant. if we all do our job well in synthetic biology everything will grow on trees.

Dr. Hershberg asks, “So…how do we get to a future where everything grows on trees?”

That’s a great question.  Remember, although the first definition of a plant is typically about living organisms like trees, flowers, and grasses, the second definition is about industrial factories, as in “a place where an industrial or manufacturing process takes place.”  How do we transform our grimy, polluting, resource-intensive factories into, well, trees? 

That’s the power, the potential, of synthetic biology.  He points out: “Biology manages to adapt and grow everywhere and is capable of both atomic precision and enormous scale. In other words, we inhabit a biosphere that is capable of producing more than enough to meet our needs.”

Dr. Hershberg’s title “Atoms are local” comes from bioengineer Drew Endy mantra that “biology teaches us that atoms are local;” i.e.,

The leaves on a tree don’t come from a factory and then get shipped to where the tree is going to be and taped and stapled to the twigs and branches. The photons and molecules arrive where the biology is going to grow and the biology grows locally.

Dr. Hershberg expects that within our lifetime we’re going to have DNA printers that produce any desired DNA sequence, and “desktop bioprinters” that use DNA sequences to print proteins, which could ultimately lead to a “personal biomarker” that could, in Dr. Endy’s words. “enable people to more directly and freely make whatever they need where-ever they are.”

That’s a “wow.”

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I’ll give a few examples of advances in synthetic biology in just the past couple weeks:

• “MIT researchers have developed a new way to precisely control the amount of a particular protein that is produced in mammalian cells.  This technique could be used to finely tune the production of useful proteins, such as the monoclonal antibodies used to treat cancer and other diseases, or other aspects of cellular behavior.” 
• Researchers from Technion-Israel Institute of Technology and MIT have developed “cells engineered to compute sophisticated functions -- "biocomputers" of sorts,” thuis creating “genetic "devices" designed to perform computations like artificial neural circuits.”
• Scientists at the Swiss Federal Institute of Technology have developed “bionic bacteria” that can deliver cancer-killing compounds precisely to tumors, and, once there, “you basically have a little nano-factory that continues to release molecules that can be toxic to cancer cells,” says one of the authors. 

The field is advancing on multiple fronts, at dizzying rates – faster than we’re reimaging what we might do with it.

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Meanwhile, Stat’s Matthew Herper warns that “we’re not prepared for the next wave of biotech innovation.”  Although he, too, is a believer that we’re living in “biology’s century, he fears: 

the biggest looming problem is that we will simply become lost and confused as to what works and what doesn’t, scuttling our own progress, wasting money, and missing opportunities to save lives. That’s what happens when new technologies in biology outpace our ability to assess them.

He worries that, in particular, our system of clinical trials is way too slow, way too expensive, and way too inconclusive to deal with the pace of innovation we’re seeing.  I like his analogy:

U.S. health care system tends to believe that inventing brand new gadgets is the answer to everything. The result is that we try to solve problems by building faster and more expensive Ferraris when what we really need are better roads. As a result, our sports cars end up stuck in the mud.

“Politicians and regulators outside the health care industry need to start to think about what success and failure look like in medicine,” Mr. Herper suggests, and “We, as a society, will need to change our understanding of what is true and what is not. The world's going to be transformed — we can't let our thinking about it fall behind.”

Credit: StatNews

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Mr. Herper was making a very different point than Dr. Hershberg, but I think the commonality is that, while we’ve embraced synthetic biology/biotech in terms of industrializing biology, we still have not made that conceptual leap to biologization of industry.  How do we revamp, remake, our various industries – not just healthcare ones -- to use biology as the core for production?

As venture capitalist Tom Baruch predicts: “We’ll see synbio disrupt every industry, whether building materials, agriculture and food, chemicals, medicines, water treatment, and environmental engineering.” 

Dr. Hershberg believes that combining synthetic biology with the internet means that “the marginal costs and distribution costs of actual material goods in the physical world could come to approximate the costs of distributing software products on the Internet.”  In other words, “one of the major lessons of biology is that planetary scale distributing manufacturing is possible.”

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If you’re not paying attention to synthetic biology, you need to be.  If you’re not thinking about how it is going to change your industry, you’re going to be disrupted by people who are. And if you’re only thinking about incremental changes, within our existing conceptual models of what biology is and can do, then you’re not thinking nearly big enough. 

Trees as factories, for almost anything we want.  Get ready for it. 

And You Thought Mastodons Were Extinct

Until last week, for me, “mastodon” only meant the giant animal that went extinct several thousand years ago (I was, it appears, unaware of the heavy metal band Mastodon).   Now, as the result of Elon Musk’s purchase of Twitter, many Twitter users are being forced to take a look at alternatives, such as the social networking site Mastodon.

It’s possible that we are about the witness the Myspace-ization of Twitter, brought down by competition, bad management, and bad product decisions.  In my usual “there must be a pony in here somewhere” fashion, there may be some lessons in the Twitter saga that healthcare might want to pay attention to.

As most know by now, Mr. Musk has been a Twitter power user for many years, and a frequent critic.  In March of this year he started discussions about purchasing it. In short order, he threw out a bold bid, was rejected then accepted by Twitter’s board, tried to get out of the deal, was sued by Twitter, and closed the deal late last month. 

Then things got really rocky.   

Mr. Musk tried to reassure squeamish advertisers, only to make them and others even more nervous when he retweeted some disinformation.  After a spike in hate speech on the site, he promised that, as much as he was buying Twitter out of his love for free speech, Twitter “cannot become a free-for-all hellscape, where anything can be said with no consequences!”  Then he shocked observers (and Twitter employees) by suddenly laying off half the workforce, including much of the content moderation staff. Some are now being asked back, being told they were laid off “by mistake.”   

He then floated a balloon about charging $20 a month for Twitter’s blue verification, had a tweet argument with Stephen King about it, then went forward with a $7.99 plan, only to be punked by users illustrating the flaws.  At this writing, the plan now appears to be on hold, at least until Tuesday’s mid-term elections. 

Advertisers appear to be fleeing, or at least curtailing spending.

As The Wall Street Journal put it: “In Elon Musk’s first week at Twitter Inc., he flouted much of the advice management gurus have dished out for decades.”  It’s no wonder many Twitter users are looking at Mastodon.

Mastodon has been around since 2016, but only recently has seen large increases in users, now up to a million users (versus, it must be noted, Twitter’s 230+ million users).  It was founded by Eugen Rochko, who may be the only actual employee.  He says: “The solution isn't a copy of Twitter without Elon Musk. The solution is a different paradigm of social media.”

The Mastodon paradigm is “decentralized, open source, not for sale, and interoperable.”  It is a collection of “servers” (there are reportedly some 3,000), each run by a different person or organization, with its own moderation policies and focus (e.g., geographic, topic).  Instead of investors, it relies on donations, grants, crowdfunding, sponsorships, and volunteers. 

Users must pick a server to join, some of which (like Mastodon social, the largest) are currently closed or require an invitation. Users can, however, follow users on other servers, although they cannot get as much information about them as ones on the same server.

If it seems like Twitter but more complicated, well, that’s because it is.

Credit: Digital Report

It’s not as though Twitter didn’t need change. It has long had content moderation issues, especially with attacks on women and people of color.  But thar’s par for social media; just look at Facebook. Equally problematic is that it simply has never been consistently profitable.  Layoffs may have been inevitable, as even co-founder and former CEO Jack Dorsey now admits that he may have grown the workforce too rapidly.

Mr. Musk has faced challenges with, and criticism for his actions at, his other companies – Tesla, Space X, Starlink – and yet managed to make each successful, so he may know what he’s doing with Twitter.  Or he may have finally bitten off more than he can chew. 

Of course, not everyone who leaves Twitter is likely to go to Mastodon.  They may opt out of social media, or make more use of established platforms like Facebook, LinkedIn, or Reddit.  Depending on their political views, they might try Truth Social or Tribel. 

Or they wait for Jack Dorsey’s new venture, BlueSky, which purports to be a “decentralized social network” that will foster a “social internet” without data silos.  Some 30,000 people joined its waitlist in the week after Mr. Musk took over Twitter.  The team emphasizes that corporations should not own your online identity, and that users must have control over the algorithms that decide what they see. 

In research done by Casey Fiesler, an information researcher at the University of Colorado, one participant described online migrations as “watching a shopping mall go slowly out of business.”   I.e., there start to be fewer stores or stores of lower quality, so fewer people go, and it becomes a vicious cycle. Twitter may become that dying mall in your community.  Or Myspace (which, to my surprise, still exists).

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When I think about the lessons of twitter for healthcare, the first thing that came to mind was what happens when Judy Faulkner gives up control of Epic?  She’s 79, she’s controlled Epic since its inception, and one has to suspect that her successor will make changes – ones that could threaten (or expand) its dominance.

Or what would happen if Cerner, the #2 EHR, was bought by another opinionated billionaire with big ideas for changing it – oh, wait, Larry Ellison already did that, and he’s not making little plans.

Larry and Elon are texting buddies. Credit: Getty

And I think about how something like 3D printing will revolutionize pharma and the medical device industry.  What about when synthetic biology changes our whole model of healthcare, knowing how to “program biology?  We’re going to see whole healthcare industries collapse.

When I think about Mastodon and BlueSky in particular, I also wonder when/where healthcare’s open source, decentralized solutions will come – and come they will.  Maybe they’ll be DAOs, or maybe a Linux or Wikipedia for healthcare.  The solutions won’t necessarily look like what we’re used to.

So the moral of Elon Musk and Twitter for healthcare is: you may think you are essential to your users.  You may think you can treat them however you want.  But you’re wrong. All you are doing is giving people more reason to leave when they have a choice.      

Mastodons aren’t the only thing that can go extinct.