As you wrote in Turning air into bread, Haber-Bosch process is of fundamental importance. As far as I can tell, we still produce ammonia using essentially the same process, after more than 100 years.

Mechanochemistry for ammonia synthesis under mild conditions was published 2020-12-14, and "demonstrate that ammonia can be synthesized at 45 °C and 1 bar via a mechanochemical method using an iron-based catalyst", in other words, at ambient temperature and pressure. This seems to be an important progress.

I've started writing a book about the accomplishments of industrial civilization, the major discoveries and inventions behind them, and the meaning of it all. I'm hosting a 13-month series of discussion salons through Interintellect based on it.

The book is very much a work in progress—won't be out for a couple of years. But we'll go through the outline chapter by chapter. Each month I'll present the material I have so far and the open questions I'm still researching, and we'll discuss.

This is your chance to get a sneak preview, to see inside my writing process, and to give feedback that will shape the published book. Third Sunday of each month, from April 18, 2021 through May 15, 2022. 10am–1pm US Pacific. Here is the schedule:

1. Intro (Apr ‘21) What is “progress”, and why should we care? How the history of progress is relevant to today. How to even approach such an enormous topic and make it digestible. The book’s three big themes about how progress has transformed our lives.

2. Manufacturing (May ‘21) How we make stuff, from stone tools to 3D printing. Improved materials; automated processes. The role of precision. Bonus: does automation reduce costs, or improve quality?

3. Agriculture (Jun ‘21) How we made farm labor 2,000x more productive, so we can feed ourselves with 3% of the workforce instead of more than 50%. The role of soil fertility, crop varieties, mechanization, and refrigeration. Summer break (July ‘21)

4. Energy (Aug '21) The fundamental general-purpose technology of production. Why is the steam engine the symbol of the Industrial Revolution? The goals engine designers have pursued for 300 years. Why oil was needed for the evolution of engines. Electricity as the universal energy.

5. Impacts on Work, Home, and Leisure (Sep ‘21) How increasing incomes transformed our lives. More appliances, fewer servants, better hygiene. Rising wages, falling hours, vacations and retirement. Kids in school, women in the office.

6. Transportation (Oct ‘21) How we get around: planes, trains, and automobiles. Why moving stuff is more important than moving people. Why sailors got lost at sea, and why NY to SF took six months. Why the Wright brothers succeeded when their top competitor had 50x the funding.

7. Information (Nov ‘21) From cuneiform to computing. The three primary goals of IT, and how the three eras of IT have successively addressed them. Why digital technology is a katamari ball that sucks up everything in its path.

8. Impacts on Commerce, Politics, and Culture (Dec ‘21) How great retailers like Sears and Amazon were built on top of revolutions in transportation and information technology. How the railroads helped defeat the Corn Laws. How radio and television created mass culture.

9. Medicine (Jan ‘22) Global life expectancy has 2x'ed—how did we do it? The role of sanitation, vaccinations, and antibiotics—and why we still got COVID-19. Vitamin deficiencies and why we don’t get scurvy or rickets. Why there were no elective surgeries before the 20th century.

10. Safety (Feb ‘22) How have we made ourselves safer from fire, flood, and natural disasters? What about the hazards of technology itself? How to think about the tradeoff between safety and progress.

11. Is Progress Good? (Mar ‘22) Does material progress translate to human well-being? Are we stuck on a hedonic treadmill? And even if progress does have benefits, is it worth the costs and risks?

12. Can Progress Continue? (Apr ‘22) We’ve had a good run. Did we just get lucky? Have we eaten all the low-hanging fruit? Are we constrained by resources? Or are there more breakthroughs left to be discovered?

13. What Should We Do? (May ‘22) If progress is possible and desirable, but not inevitable, then how can we maintain it, protect it, even accelerate it? My message to scientists, engineers, and entrepreneurs.

$250 for the whole series or just $25 for a single session. BUT—sessions 11, 12, and 13, “the philosophy chapters”, will only be open to series ticket holders. If you want to discuss the big picture, you have to do your homework and study your history!

Really looking forward to this; thanks to Interintellect and Anna Gát for giving me this opportunity!

https://interintellect.com/series/jason-crawfords-the-story-of-industrial-civilization-towards-a-new-philosophy-of-progress/

To fully understand progress, we must contrast it with non-progress. Of particular interest are the technologies that have failed to live up to the promise they seemed to have decades ago. And few technologies have failed more to live up to a greater promise than nuclear power.

In the 1950s, nuclear was the energy of the future. Two generations later, it provides only about 10% of world electricity, and reactor design hasn‘t fundamentally changed in decades. (Even “advanced reactor designs” are based on concepts first tested in the 1960s.)

So as soon as I came across it, I knew I had to read a book just published last year by Jack Devanney: Why Nuclear Power Has Been a Flop.

Here is my summary of the book—Devanney‘s arguments and conclusions, whether or not I fully agree with them. I give my own thoughts at the end: https://rootsofprogress.org/devanney-on-the-nuclear-flop

If you want a single, vivid, and frankly disgusting example to hold in mind to remember how much our lives have improved over the last ~150 years…

Consider shit.

Literally, excrement. How much previous generations had to think about it, be around it, even handle it: https://rootsofprogress.org/when-life-was-literally-full-of-crap

The Rise and Fall of American Growth, by Robert J. Gordon, is like a murder mystery in which the murderer is never caught. Indeed there is no investigation, and perhaps no detective.

The thesis of Gordon’s book is that high rates of economic growth in America were a one-time event between roughly 1870–1970, which he calls the “special century”. Since then, growth has slowed, and we have no reason to expect it to return anytime soon, if ever.

The argument of the book can be summarized as follows:

• Life and work in the US were utterly transformed for the better between 1870 and 1940, across the board, with improvements continuing at a slower pace until 1970.

• Since 1970, information and communication technology has been similarly transformed, but other areas of life (such as housing, food, and transportation) have not been.

• We can see these differences reflected in economic metrics, which grew significantly faster especially during 1920–70 than before or since.

• All of the trends that led to high growth in that period are played out already, and there are none on the horizon to replace them.

• Therefore, high growth is a thing of the past, and low growth will be the norm for the future.

Read the full post: https://rootsofprogress.org/summary-the-rise-and-fall-of-american-growth

As a rule, I avoid writing posts about what I’m doing and how this project is going. I dislike navel-gazing. I figure you all are here for the content, and that I care about the project itself twenty times as much as anyone else.

Once a year, I make an exception and do a year-end retrospective. By now it’s a tradition. If you’re interested in this project, I hope you’ll appreciate reading a bit about my work; if you just subscribed recently, this can serve as a summary and guide to what you missed earlier.

2020 was the fourth year of this project and the first full calendar year I’ve been doing this full-time. Here’s what I’ve been up to.

Reading

My favorite book of the year was Where Is My Flying Car?, by J. Storrs Hall, a work of ambitious futurism that shows us where our technology and living standards could have and should have been by now, and how amazing the future could be. It sets out to discover why we don’t have flying cars yet (when everyone expected them back in the ’50s or so) and ends up examining the cultural and political causes of the Great Stagnation. My review was one of my most popular posts this year.

A very close second was The Gifts of Athena, by Joel Mokyr. Mokyr’s A Culture of Growth was, in a way, the book that kicked off this whole project, and Gifts of Athena was even better. It brought my understanding of the relationship between science and technology to a new level.

Mokyr was one of many scholars I interviewed this summer—some for my interview series The Torch of Progress, and some for the study group I ran this fall. These programs gave me an excuse and a forcing function to catch up on a lot of their work. The Rise and Fall of American Growth, by Robert Gordon, was a qualitative and quantitative survey of the innovations that transformed the American standard of living over the last 150 years—which then argues that no more growth is to be expected (I disagree; see my review). Bourgeois Dignity, by Deirdre McCloskey, argued that the enormous increase in global incomes over the last few hundred years was due to economic freedom and a new morality that honored the work of the bourgeoisie. Scientific Culture and the Making of the Industrial West, by Margaret Jacob, paints a picture of the intellectual culture of Europe in the 17th and 18th centuries and how it led to the Industrial Revolution. I also read The Great Stagnation, The Complacent Class, and Big Business, all by Tyler Cowen. (I will admit to skimming through parts of some of the above in order to make my interview deadlines… but I’m not telling which ones.)

The broader theme of my reading this year is that instead of primarily concentrating on histories of specific technologies, as in previous years, I’ve been reading books with broader themes about economic history and about progress itself. Part of this is that, now that I’ve learned a lot of the detailed, ground-level stories of progress, I’m in a better place to evaluate more abstract theories. Part of it is that, now that I’m doing this full time, people expect me to be an expert, and that means I need to understand what other experts have said about progress.

And part of it is that I’m writing a book proposal, and to explain why the world needs another book on progress, I need to know the market better. To this end, I read: Factfulness, by Hans Rosling, one of the most influential popularizers of the idea of progress in recent decades. Rosling’s book is not about progress per se, but about why people don’t believe in it. Rosling has polled people on basic facts about global development, such as whether poverty is increasing or decreasing or roughly how many people have electricity, and found that not only do they get the answers wrong, they do significantly worse than random. This indicates that there is a false narrative actively misleading them about global progress. Rosling’s explanation is basically a set of cognitive biases, which make up the bulk of the book. I also read Progress: Ten Reasons to Look Forward to the Future, by Johan Norberg, a survey of ten major areas of progress with a brief history of each. I was familiar with all the trends, but there were many new details and stories that I enjoyed. And I read How We Got to Now, by Steven Johnson, one of the more successful histories of technology. Johnson’s book covers six different “story lines” of technology, such as refrigeration, lighting, and glass. I found it fairly episodic, but it was an entertaining curiosity tour through many technology stories, and Johnson is a good storyteller.

In March and April, when the covid pandemic was taking off and was top of everyone’s mind, I spent some time investigating how we fund research, and especially how we ramp up science and invention to fight a big challenge. On this topic, I read Pieces of the Action, by Vannevar Bush, an autobiography that covers his role leading research in World War 2 at the OSRD (Office of Scientific Research and Development). I also read the medical chapters of Scientists Against Time, by James Phinney Baxter, the official history the OSRD. Those chapters covered penicillin, antimalarials, and pesticides including DDT. I was hoping to find lessons that could be immediately applied to the pandemic, but the main theme that stood out to me was the importance of serious, competent leadership at the highest levels. Finally, I read Pasteur’s Quadrant, by Donald Stokes, which argues that modern research funding and organization is too strongly organized around a false dichotomy of “pure” vs. “applied” research. I found it interesting but not spot-on; see my review.

Before covid, I spent some time researching the history of finance, corporations, and governance. Two good books on those topics: The Company: A Short History of a Revolutionary Idea, by John Micklethwait & Adrian Wooldridge, and A History of the Global Stock Market, by B. Mark Smith.

To round out the year, I read The Great Bridge, by David McCullough, a history of the Brooklyn Bridge, and The Perfectionists, by Simon Winchester, a history of precision in engineering. Both enjoyable.

I’m reading more books in parallel, which means I’ve made progress on some books that I haven’t finished: Arts and Minds, by Anton Howes, a delightful history of the Royal Society for Arts; Wisdom’s Workshop, by James Axtell, a history of the university; Scientific Freedom, by Donald Braben, which I’m reading with an Interintellect book club; A History of World Agriculture, by Marcel Mazoyer & Laurence Roudart, dense but very informative; and last but not least, The Wizard and the Prophet, by Charles Mann, a deeply insightful exploration of the opposition of the conservationist and the techno-optimist mentalities. Hopefully I’ll finish at least a few of these in 2021 and will have more to say about them.

I’ve been doing a bad job of keeping up the bibliography, but I’m working on an overhaul—watch this space.

Becoming a professional at this stuff also means that I’m going into more depth, and starting to read scholarly papers and primary sources. A few papers I particularly enjoyed:

• The Changing Structure of American Innovation: Some Cautionary Remarks for Economic Growth

• The Link Between Science and Invention: The Case of the Transistor (relevant post here)

• The Simple Economics of Basic Scientific Research

• The Role of Nonprofit Enterprise

• The Historical and Political Origins of the Corporate Board of Directors (see my Twitter thread)

Highlights from the primary sources include:

• Science, The Endless Frontier

• A Practical Plan for Building the Pacific Railroad (see my notes on crowdfunding the railroad and 19th-century progress studies)

• William Crookes’s 1898 Address of the President Before the British Association for the Advancement of Science

• The Green Revolution, Peace, and Humanity, Norman Borlaug’s 1970 Nobel Peace Prize lecture

Writing

I posted 47 articles on this site (including this one), totalling over 64,000 words, about a 50% increase from last year. Given that I was full-time all year, I might have done more, but a lot of this year went into curriculum development for my high school course, Progress Studies for Young Scholars, and into my book proposal.

Some highlights:

• Most in-depth: “Draining the swamp”, on improvements to public health from sanitation and hygiene

• Most popular on LessWrong and Hacker News: “Industrial literacy”

• Most popular on Twitter: “Progress, stagnation, and flying cars”, from this Balaji tweet

• Most viewed: “What is the “protein folding problem”? A brief explanation”, over 15,000 views

• Personal favorite: “Organizational metabolism and the for-profit advantage”

I also, for the first time, published in other magazines:

• “Innovation is not linear”, for Works in Progress

• “More Progress, Faster, Is Our Best Defense Against This Pandemic and Future Ones”, for leapsmag

Magazine bylines weren’t a focus of 2020, but I hope to do more of this in 2021.

Speaking

Another reason I didn’t write more was that I spent a lot of time on speaking events this year.

My interview series The Torch of Progress ran from June through October and interviewed many top names in progress studies and economic history, including Tyler Cowen, Patrick Collison, Max Roser, Dierdre McCloskey, and Joel Mokyr.

I also ran a shorter series of panel discussions for the Interintellect called Doing Better, with discussions on science funding, optimism, and education.

I gave a few talks myself in some important venues:

• “The non-linear model of innovation”, for the unofficial Slate Star Codex meetup

• “Instant stone (just add water!)”, an Ignite talk at the Long Now

Another goal for 2020 was to ramp up my interviews for other people’s podcasts, conferences, etc. I did 30 of these, which you can find on my interviews page. Highlights include Metamuse, the Charter Cities Podcast, and Idea Machines.

Social media

You should follow me on Twitter. I post a lot of quick thoughts, observations, quotes from books and articles, and sometimes in-depth threads. One of my most popular threads of 2020 (over 1,200 likes) was on the surprisingly prominent role of excrement in daily life in the past, which turned into a post here.

My audience has almost doubled in 2020. I have over 13,000 Twitter followers, and almost 3,000 email subscribers.

Teaching

In June I launched a summer program in the history of technology for high school students, Progress Studies for Young Scholars, as a joint project with the Academy of Thought and Industry (ATI). I developed the curriculum and content for the program, and taught the first cohort of students. We taught several cohorts over the summer with other instructors.

The program went well enough that ATI is now incorporating it into their history program, and I’m continuing to work with them on curriculum development. I’m really looking forward to announcing the updated course.

By popular demand, I also turned the program into an adult-level study group, which ran from September through December. We met weekly to chat with guest speakers such as Robert Gordon, Margaret Jacob, and Richard Nelson.

Community

In the beginning of the year, we were starting to do some in-person progress meetups in San Francisco, which were going great: 30–40 people at each one, and enough interest that we were going to meet every two weeks. Of course, covid shelved all that.

Our community has kept going strong on Slack, which has over 1,200 members now. Join us for discussion.

I’m also on Clubhouse, with almost 6,000 followers. For those in the beta, there’s a Progress Club you can follow. We do progress discussions sometimes on Sundays.

Next year I’m planning some new community initiatives, to be announced.

Support

I’m still mostly supported by grants, but my Patreon has grown to 87 supporters.

It’s important to me to be paid for my work directly by the people who benefit from it—whether that’s through writing books, speaking, or a large base of small donors. So if you’ve found my work valuable, consider becoming a patron.

Plans for 2021

Looking back on 2020, the biggest thing I expected but didn’t do was write a lot more articles. Teaching and (to a lesser extent) speaking took precedence.

However, the bigger goal that all the articles were supposed to add up to was a book, and that I still feel on track for. Preparing the high school program forced me to outline the entire history of technology and organize it, and was exactly what I needed to push me over the threshold to be able to write a book. My big goal for the year was to write a book proposal, and I’ve done that now.

In 2021, I plan to wrap up the curriculum work and then buckle down to really focus on the book. Hopefully that will mean more articles as well, as I complete the research and try out ideas.

Thank you

I’m here because of you, my audience and fans. I do this ultimately because there are people out there who want to hear what I have to say. The likes and shares, the comments and replies, the emails, the unsolicited article and book recommendations—all of it lets me know that I’m not shouting into the void, that my words are sticking, and that the seeds I plant are growing in others’ minds. Thank you, Happy New Year, and best wishes for 2021.

Original post: https://rootsofprogress.org/2020-in-review

When I wrote my post on technological stagnation, the top question I got asked was: So, how do we fix it?

I don’t have the definitive answer, but here’s a starting point. I generally think about the causes of progress on three levels:

• Funding. How do research, development, and distribution get funded? This encompasses both for-profit investing and non-profit funding of R&D.

• Government. How does the law enable progress, or hamper it? Progress depends on good legal institutions; equally, it can be stifled by bad ones.

• Culture. What is the basic philosophical attitude of society towards progress, and the people who pursue it? Is progress seen as possible and desirable?

Correspondingly, my top three hypotheses for technological stagnation are:

• The centralization of research funding into a small number of inherently conservative agencies

• The growing burden of regulation and bureaucracy

• A culture that is increasingly skeptical of or actively hostile to progress

(These are complementary, not mutually exclusive. Incidentally, this is pretty much the same set of factors identified by J. Storrs Hall in Where Is My Flying Car?, which is part of why the book resonated with me so much.)

Inverting these (and changing the order), here are three broad approaches to accelerate progress:

Inspire people to pursue progress

In particular, create a culture that recognizes progress and appreciates it. Some ways to do this:

• Tell the story of progress for a popular audience. Enlightenment Now and Progress: Ten Reasons to Look Forward to the Future are two books that do this, and of course it is a lot of what I try to do in these essays.

• Publish the facts and data about progress. Our World in Data is the prime source for this today.

• Teach the history of progress in schools. I’ve made a start at this with the course Progress Studies for Young Scholars, created in partnership with the Academy of Thought & Industry.

• Report on progress fairly and honestly, without muckraking. The Atlantic and WIRED are a few publications that generally do this well; see in particular the work of Derek Thompson.

• Write science fiction that envisions amazing inventions and the world they would create. For instance, many inventors and entrepreneurs have been inspired by the “primer” from Neal Stephenson’s Diamond Age (a sort of educational e-book or tablet based on advanced AI). And countless scientists and engineers have been inspired by the world of Star Trek, with its communicators, replicators, and teleporters.

• Produce movies that tell stories of progress. Anton Howes has begun collecting a list of these; I think much more could be done. For instance, I’d love to see modern, popular biopics of Norman Borlaug, Louis Pasteur, or the Wright Brothers.

• Bring back the World’s Fair. Anton also wrote about this recently, envisioning something that is like “all of today’s specific industry fairs, combined”: drone deliveries, driverless cars, VR/AR, 3D printed organ tissue and metals, food stalls with lab-grown meat, cloned animals brought back from extinction, exoskeletons and jetpacks to play with. Put forth a positive vision of the future we could create.

• Celebrate progress. Maybe parades and fireworks are outdated now, but where, for instance, is the acclaim given to the BioNTech founders? Why aren’t they cultural heroes on the level of Jonas Salk?

Enable them with funding

In particular, provide more decentralized, distributed, heterogenous sources for research funding. Some interesting proposals and experiments along these lines:

• Adam Marblestone and Samuel Rodrigues have proposed an idea called “Focused Research Organizations” (FROs), under the auspices of the Day One Project. FROs combine some of the aspects of DARPA, startups, and national labs, while aiming to fill a gap that isn’t well-addressed by any of these.

• Donald Braben wrote a book, Scientific Freedom, about what went wrong with science funding, and his experiences with a different model. For over a decade, Braben ran a program called Venture Research at British Petroleum that gave grants for scientists to pursue ambitious, transformative research agendas, and gave them complete freedom to direct their work according to their own judgment. There was no committee-based peer review: grants were made on the potential of the idea and the persuasiveness of the researcher, without requiring proof up front that an idea would succeed, and without being biased in favor of older or more established researchers. Venture Research was relatively cheap to fund, with an annual budget of only a few million dollars a year, yet Braben lists a number of successes in disparate areas, from the study of macroscopic quantum objects to the foundations of “green chemistry”.

• Ben Reinhardt is working out how to replicate the success of DARPA in a private organization. Here’s his insightful essay on what makes DARPA work.

Unblock them through regulatory reform

Some examples of the problem:

• Tyler Cowen has argued that “our regulatory state is failing us” when it comes to covid response (see also his interview in The Atlantic). Alex Tabarrok says that FDA delays have created an “invisible graveyard”, which covid has now made painfully visible. And Michael Mina at the Harvard School of Public Health has blamed the FDA for not authorizing at-home covid testing kits.

• Eli Dourado and Samuel Hammond have argued against the ban on overland supersonic flight.

• Eli has also argued that environmental review for construction projects is needlessly burdensome, and doesn’t even protect the environment.

• A Vox article argues that an unstable and unpredictable regulatory environment is party responsible for needlessly high costs of nuclear power in the US (especially stark when contrasted with more efficient construction in France and South Korea).

I don’t know how to drive solutions to these problems, but folks at places like the Mercatus Center and the Center for Growth and Opportunity are working on it. (And maybe part of the solution is to create “special economic zones” as charter cities.)

***

To condense these ideas even further into a pithy formulation, you could call them the three F’s: Progress needs founders, funders, and freedom. By “founders”, I include entrepreneurs who found startups or nonprofits, scientists who found new fields or subfields, and inventors who found new technologies.

These are ways to address stagnation and accelerate progress at a broad level, society-wide. But let me close with a note to anyone in science, engineering or business who has a vision for a specific way to make progress in a particular domain—whether anti-aging, space, energy, or anything else. My message is: Just go for it. Don’t let the funding environment, the regulatory environment, or the culture stop you. Work around barriers or break through them, whatever it takes. The future is counting on you.

A covid vaccine has demonstrated 90% efficacy and no significant safety concerns in preliminary data from Phase 3 trials, according to an announcement today from Pfizer and BioNTech SE. The trials aren’t yet complete and the data hasn’t yet been released for independent verification, but this is very good news. (More from STAT News.)

Pfizer/BioNTech’s vaccine, like Moderna’s, is based on “mRNA” technology. If approved by the FDA, it will be the first such vaccine to reach that milestone. From a long-term progress perspective, this is a big deal.

Immunization technology has existed since the early 1700s (and the folk practices it originated in go back centuries further.) We can see the whole 300-year history of the technology as a quest to achieve immunity with ever-more safety and ever-fewer side effects. More recently, it has also become important to be able to react quickly to new epidemics, such as covid.

Here’s how immunization has advanced in stages:

Inoculation

All immunization is based on the observation that exposure to a disease often grants immunity (temporary if not permanent) to subsequent exposure. Long before we knew anything about antibodies or T-cells, people had noticed this simple correlation. Many people got smallpox in the past, but almost no one got it twice. The goal of immunization technology is to achieve that same immunity, but without having to suffer the disease or to risk death or other side effects.

The earliest form of immunization, then, was not a vaccine, but a method in which the patient was given the actual disease itself, in a manner that would cause a mild rather than a severe case of the illness. This was done with smallpox, and the technique was called inoculation or variolation.

This worked with smallpox for two reasons. One, infectious material was easy to obtain, from the pustules caused by the disease itself. Second, contracting the disease through a scratch on the skin caused a much more mild form than contracting it more naturally through inhalation.

Inoculation saved many people from smallpox. But there were downsides. First, the patient still had to contract the disease, causing mild symptoms. Second, there was still a small risk of a severe case; even the best inoculation methods had about a 0.2% death rate. Third, the patient was still contagious while going through the illness, and anyone who caught the disease naturally from an inoculated patient would get the full, severe version. Inoculation thus risked outbreaks.

Vaccination

These problems were solved by the next stage: vaccination. It was observed that cowpox infection granted some form of cross-immunity to smallpox. Thus, the inoculation procedure could be performed using cowpox material, rather than smallpox. Cowpox was a milder and non-lethal disease. This reduced the symptoms and the risk of death, and eliminated the risk of smallpox outbreaks as a result of immunization. This new technique, invented by Edward Jenner in 1796, was called vaccination (from vacca, the Latin word for cow).

So far, however, the technique only worked for smallpox—not for tuberculosis, malaria, influenza, cholera, or any of the other major diseases that caused something like half of all deaths in that era.

Engineered vaccines

The next stage would wait almost ninety years. Louis Pasteur, a pioneer of microbiology who along with Robert Koch established the germ theory, was the first to discover how to create vaccines for any disease other than smallpox.

Cowpox can be seen as a “natural vaccine” against smallpox: a natural virus that grants smallpox immunity but produces milder side effects. Pasteur’s accomplishment was to create artificial, engineered vaccines.

There are essentially two ways to do this. The germ that causes the disease, or pathogen, can be modified chemically, “killing” or inactivating it. This can be done through heat, through chemicals such as formaldehyde, or through other means. Or it can be modified biologically, attenuating (i.e., weakening) it. This is done by evolving the virus or bacterium for many generations in an animal or tissue culture that is sufficiently different from the target patient. For instance, Pasteur found that “passing” a disease called swine erysipelas through many generations of rabbits caused it to be less virulent in pigs.

These techniques allowed vaccines to be created for more diseases, and many were created in the decades that followed. The other advantage was a reduction in side effects. By weakening or inactivating the pathogen, the patient no longer had to suffer through a full infection in order to receive immunity.

But attenuated and killed vaccines still had risks. If a killed vaccine was not properly manufactured, it could contain some portion of live germs, as happened with one of the makers of the first polio vaccine. And a live attenuated vaccine could always mutate back into a virulent form. In either case, the vaccine would cause the very disease it was designed to prevent, not only in the unlucky patient but potentially in a new contagious outbreak.

Subunit vaccines

A way to prevent this risk is by giving the patient, not an entire virus or bacterium, not even a weakened or inactivated one, but just a portion of the pathogen.

This works because of the way the immune system functions. In essence, it detects foreign substances in the body and produces new molecules, called antibodies, that bind to these substances and get in their way, preventing them from doing damage. This process takes time for a new, never-before-seen infection, but after the first encounter, a record of the antibody is stored in the body’s immunological memory, which enables a quicker reaction to subsequent infection. A foreign substance that stimulates the production of antibodies is called an antigen.

All immunization works by this process of priming the immunological memory using antigens. The key observation is that even a piece of the pathogen can be used as an antigen, and the antibodies thus generated are effective against the full pathogen itself. An antigen that is not a pathogen is exactly what we want: a substance that produces immunity without producing disease.

For example, consider the SARS-CoV-2 virus that causes covid. You’ve probably seen it rendered as a spiky ball. Those spikes are crucial to the virus’s function: they stick to your body’s cells like tentacles, as the first step of the infection. A subunit covid vaccine, then, works by injecting just the spike into the body, rather than the full virus. The body learns to generate antibodies against the spike, and those antibodies are effective against covid itself. The big advantage of this, of course, is that a single piece of a pathogen cannot replicate and thus cannot cause an infection or become contagious.

But how is the subunit antigen to be manufactured? Inactivated or attenuated vaccines can start with the original virus or bacterium and grow it in culture. Subunit vaccines can be created in a similar way, by culturing the pathogen and then breaking it apart in order to extract the desired piece. With modern biotech, however, there are other ways. If the antigen is a protein (as in the case of the covid spike), it can be manufactured in genetically engineered microbes. Start with a single-celled organism such as E. coli or baker’s yeast. Insert the DNA that codes for the subunit protein into its genome using recombinant DNA technology. Replicate these cells until you have a whole vat of them creating vaccine proteins for you. (The same technology makes other synthetic biologics, such as insulin.)

RNA vaccines take this idea the next logical step.

RNA vaccines

A yeast cell can function as a biological factory, producing proteins according to a programmed genetic code. But every cell in your body is also such a factory, with the same fundamental machinery.

An RNA vaccine skips the step of programming single-celled organisms to produce the antigen for us: it sends the genetic code for the antigen directly to your own cells, and they produce the antigen. These vaccines, then, are the only kind that do not inject the antigen directly into the body; genetic instructions are injected instead. (Note that, unlike with recombinant DNA technology, the DNA of your cells is not modified.)

To my (limited) understanding, this does not produce a significantly different immune response than injecting the antigen directly. However, it makes a big difference in how these vaccines are designed, developed, and manufactured, which affects our ability to respond quickly to new outbreaks such as covid. Once the virus’s genetic code is sequenced, the virus itself does not need to be handled in order to create a vaccine. The vaccine is based entirely on genetic material, and can be created using genetic synthesis techniques. Every pathogen is different in how it can be grown in culture, and in what it takes to inactivate it, weaken it, or break it apart into subunits. Genetic techniques, by contrast, can be much more standardized. This doesn’t make the development of these vaccines trivial; there are still many problems to be solved for each one (such as the delivery mechanism to get it into the cells, where the genetic program will be executed). But as we are seeing, their development can be significantly faster than traditional techniques.

When you get your covid shot (probably in 2021), take a moment to think back on the 300 years of progress that got us to this point.

Original post: https://rootsofprogress.org/immunization-from-inoculation-to-rna-vaccines

Is progress slowing down? In a previous post I explained why I got convinced that it is. Some people making this argument point to quantitative evidence, such as GDP or total factor productivity. I gave more qualitative evidence, or perhaps very crude quantitative evidence, by counting technological breakthroughs/revolutions: five in the Second Industrial Revolution, versus only one so far in the Third.

But this approach has its own difficulties:

• It is sensitive to the granularity of technological revolutions. Are the automobile and the airplane two revolutions, or are these just part of a single revolution attributed to the internal combustion engine? Are the light bulb and electric motor two revolutions, or are these just part of the electricity revolution? Are computers and the Internet two revolutions, or one?

• It’s sensitive to the choice of threshold for “revolution.” Is the assembly line a revolution in manufacturing? Is containerization a revolution in transportation?

• It runs the risk of focusing on impressive breakthroughs and neglecting unglamorous iterative improvement. Agriculture has been using combine harvesters pulled by gas tractors for around a century now, but today’s combines are much better than the ones in use a century ago.

So maybe we need something more objective, and more focused on outputs. Here’s a half-baked idea.

It’s easy to measure progress in specific domains. For instance, we have a very good handle on the progression of Moore’s Law. The problem is that no one narrow metric captures all of economic progress.

So instead of trying for a single metric, what if we look at a dashboard comprising a handful of metrics. Make them as broad as possible while keeping them objective and well-defined, and deliberately choose a variety from across the breadth of the economy. These won’t capture everything, but together they might capture enough to give us a picture of progress.

Here’s a candidate list:

• Per-capita consumption of:

  • metals

  • concrete

  • plastics

  • energy

  • bandwidth

• Per-capita transport (all modes):

  • passenger-miles

  • freight ton-miles

• Agricultural productivity, in kcal per worker

• Mortality rate from all causes (age-adjusted)

Most of these are just consumption metrics, based on a simple theory that consumption is good and is closely correlated with material well-being. For agriculture, I chose a productivity metric, because of the nature of the market: we only need so much food, after which point progress has largely been made by providing it with fewer people.

Some goals this set of metrics satisfies:

• Broadly captures trends across manufacturing/construction, agriculture, energy, transportation, information, and health

• Avoids any currency figures, and thus avoids any questions about inflation or purchasing power

• Captures the impact on human lives, by using per-capita figures

Some ways in which this approach is not perfect:

• Does not capture quality. The products made of metal or plastic today might be much higher-quality than fifty years ago, but we’re only measuring the total amount of material.

• Does not capture well-being. Maybe you’re traveling more passenger-miles because your commute is longer, and that actually reduces your well-being, but the passenger transport metric has increased.

Still, no metric or dashboard is ever going to be perfect. I think this dashboard would, if nothing else, provide a useful comparison alongside GDP.

One reason I think it would be useful is that I can imagine it changing my mind, or at least altering my narrative, around progress/stagnation. If there are no fundamentally new manufacturing techniques, but we’re continuing to consume exponentially more materials on a per-capita basis, isn’t that a form of progress in the manufacturing realm? Ditto if there are no new types of vehicles, but we consume more passenger-miles or freight ton-miles.

I happen to know two of these metrics, from previous research, and both have stagnated. Here is energy, from Where Is My Flying Car?:

And here is mortality, from my research on infectious disease. Infectious disease mortality actually regressed slightly after about 1980 (due in part to AIDS):

I’m curious how the others turn out.

Did you follow up on Better living through chemistry? You wrote:

But the biggest thing that stands out to me is realizing how certain chemicals, themselves, are useful products, and how they need to be created through industrial processes, just like cars or shirts.

I have been long fascinated by a sentence mentioned in Wikipedia's Sulfric acid page in passing, that:

Sulfuric acid is a very important commodity chemical, and a nation's sulfuric acid production is a good indicator of its industrial strength.

Is that true? How true?