Ciro Santilli @cirosantilli 34

This is one of the the key innovations of the Illumina (originally Solexa) sequencing.

This step is genius because sequencing is basically a signal-to-noise problem, as you are trying to observe individual tiny nucleotides mixed with billions of other tiny nucleotides.

With bridge amplification, we group some of the nucleotides together, and multiply the signal millions of times for that part of the DNA.

DNA amplification is one of the key DNA technologies:

What big companies have been created in Europe after World War II, that have not been bought or utterly defeated by American or Japanese companies?Because of all these failures, much fanfare was made as Spotify reached a $50B market capitalization in 2020. An art company, so cute!

As of 2023, the LVMH was the most valuable company in Europe by market capitalization^[ref]. Luxury goods. An area of industry that borders between the useless and the evil.

Europe has basically become an outsourcing hub for the United States. The fact that its starts are all sold if they become large enough just means that R&D is also outsourced.

ASML, and perhaps more maeaningfully its parent/predecessor ASM International from 1964 is perhaps the biggest exception.

The key problem is that there are so many small countries in Europe, that any startup has to deal with too many incompatible legislation and cannot easily sell to the hole of Europe and scale. So then a larger company from a more uniform country comes and eats it up!

Talent mobility is another issue:

So why can't Europe unify its laws?

Because the countries are still essentially walled off by languages. Europe is the perfect example of why having more than one natural language is bad for the world.

There isn't true mobility of people between countries.

You just can't go study or work in any other country (except for the UK, when it was still in the EU) without putting a huge effort into learning its language first.

Without this, there isn't enough mixing to truly make cultures more uniform, and therefore allow the laws to be more uniform.

Europe can't even unify basic things like:

Equally so, it can't force little fiscal paradises who effectively benefit from being in Europe like Ireland, Luxembourg, Monaco, Switzerland ("not European", but should that be allowed?) and Cyprus (the EU can't even maintain its territorial integrity, let alone fiscal) to not offer ridiculously low taxes and incentives which make them entry points for foreign companies to rape Europe.

For this reason, Europe will only continue to go downhill with the years, and the United Kingdom will continue to try and endosymbiose into a state of the United States (although at times it seems that it would rather endosymbiose with China instead).

Historically, this disunion is partly due to the European balance of power, whereby countries would form alliances with old enemies to prevent another country from taking over. Also linked are failed military unification attempts by Napoleon and Hitler, though we are likely better off without the latter succeeding!!! Though those also partly failed due to wider balance of power issues involving the United Kingdom, the Soviet Union and USA, not only due to internal balance. Of course, none of that matters anymore after World War II, where other more unified Europe-sized potencies rose, first the USA and the Soviet Union, and then China, and now European disunion is nothing but a burden.

Evidence such as those makes it clear that the European Union is a failure.

One thing must be said in favour of Europe's mess however: it favours international collaboration in huge projects as a more neutral middle ground. This can be seen more clearly in the ITER and the fiasco that was the Superconducting Super Collider that was cancelled a couple of billion dollars in partly because it failed to attract any foreign investment, compared to the Large Hadron Collider which went on to find the Higgs boson as mentioned at www.scientificamerican.com/article/the-supercollider-that-never-was/.

The by far dominating DNA sequencing company of the late 2000's and 2010's due to having the smallest cost per base pair.

Illumina actually bought their 2010's dominating technology from a Cambridge company called Solexa.

To understand how Illumina's technology works basically, watch this video: Video 1. "Illumina Sequencing by Synthesis by Illumina (2016)".

The key innovation of this method is the Bridge amplification step, which produces a large amount of identical DNA strands.

See also: github.com/cirosantilli/awesome-whole-cell-simulation

As of 2019, the silicon industry is ending, and molecular biology technology is one of the most promising and growing field of engineering.

Such advances could one day lead to both biological super-AGI and immortality.

Ciro Santilli is especially excited about DNA-related technologies, because DNA is the centerpiece of biology, and it is programmable.

First, during the 2000's, the cost of DNA sequencing fell to about 1000 USD per genome in the end of the 2010's: Figure 2. "Cost per genome vs Moore's law from 2000 to 2019", largely due to "Illumina's" technology.

The medical consequences of this revolution are still trickling down towards medical applications of 2019, inevitably, but somewhat slowly due to tight privacy control of medical records.

Ciro Santilli predicts that when the 100 dollar mark is reached, every person of the First world will have their genome sequenced, and then medical applications will be closer at hand than ever.

But even 100 dollars is not enough. Sequencing power is like computing power: humankind can never have enough. Sequencing is not a one per person thing. For example, as of 2019 tumors are already being sequenced to help understand and treat them, and scientists/doctors will sequence as many tumor cells as budget allows.

Then, in the 2010's, CRISPR/Cas9 gene editing started opening up the way to actually modifying the genome that we could now see through sequencing.

What's next?

Ciro believes that the next step in the revolution could be could be: de novo DNA synthesis.

This technology could be the key to the one of the ultimate dream of biologists: cheap programmable biology with push-button organism bootstrap!

Just imagine this: at the comfort of your own garage, you take some model organism of interest, maybe start humble with Escherichia coli. Then you modify its DNA to your liking, and upload it to a 3D printer sized machine on your workbench, which automatically synthesizes the DNA, and injects into a bootstrapped cell.

You then make experiments to check if the modified cell achieves your desired new properties, e.g. production of some protein, and if not reiterate, just like a software engineer.

Of course, even if we were able to do the bootstrap, the debugging process then becomes key, as visibility is the key limitation of biology, maybe we need other cheap technologies to come in at that point.

This a place point we see the beauty of evolution the brightest: evolution does not require observability. But it also implies that if your changes to the organism make it less fit, then your mutation will also likely be lost. This has to be one of the considerations done when designing your organism.

Other cool topic include:

It's weird, cells feel a lot like embedded systems: small, complex, hard to observe, and profound.

Ciro is sad that by the time he dies, humanity won't have understood the human brain, maybe not even a measly Escherichia coli... Heck, even key molecular biology events are not yet fully understood, see e.g. transcription regulation.

One of the most exciting aspects of molecular biology technologies is their relatively low entry cost, compared for example to other areas such as fusion energy and quantum computing.

At the time of the experiment, Illumina equipment was cheaper per base pair and dominates the human genome sequencing market, but it required a much higher initial investment for the equipment (TODO how much).

The reusable Nanopore device costs just about 500 dollars, and about 500 dollars (50 unit volume) for the single usage flow cell which can decode up to 30 billion base pairs, which is about 10 human genomes 1x! Note that 1x is basically useless for one of the most important of all applications of sequencing: detection of single-nucleotide polymorphisms, since the error rate would be too high to base clinical decisions on.

Compare that to Illumina which is currently doing about an 1000 dollar human genome at 30x, and a bit less errors per base pair (TODO how much).

Other advantages of the MinION over Illumina which didn't really matter to this particular experiment are:

Bought by Illumina for 600 million in 2007 for 600 million dollars.

This is one of the prime examples of Europe's decline.

Instead of trying to dominate the sequencing market and gain trillions of dollars from it, they local British early stage investors were more than happy to get a 20x return on their small initial investments, and sold out to the Americans who will then make the real profit.

And now Solexa doesn't even have its own Wikipedia page, while Illumina is set out to be the next Microsoft. What a disgrace.

Here are some good articles about the company:

Cambridge visitors can still visit the Panton Arms pub, which was the location of the legendary "hey we should talk" founders meeting, chosen due to its proximity to the chemistry department of the University of Cambridge.

In 2021 the founders were awarded the Breakthrough Prize. The third person awarded was Pascal Mayer. He was apparently at Serono Pharmaceutical Research Institute at the time of development. They do have a wiki page unlike Solexa: en.wikipedia.org/wiki/Serono. They paid a 700 million fine in 2005 in the United States, and sold out in 2006 to Merck for 10 billion USD.