Incoming links: Molecular biology
Co-founder of PowerDNS, an open source dNS implementation.
Homepage: berthub.eu/ says:.
All stuff Ciro cares about too! Cool dude! In particular Ciro loved his quote of I should have loved biology.
All stuff Ciro cares about too! Cool dude! In particular Ciro loved his quote of I should have loved biology.
He's writing a fun-sounding book about molecular biology as of 2022: berthub.eu/dna-book. Appears to be closed source though. Ciro wonders if he really needs to sell the book for money after all those years though, rather than just publishing it online for free.
Looking at Bert just brings the Dutch Golden Age, and more in particular Antonie van Leeuwenhoek to mind. Epic.
How life is Digital by Bert Hubert (2021)
Source. Just a "boring" overview of the central dogma of molecular biology ;-)Ciro Santilli is a fan of this late 2010's buzzword.
It basically came about because of the endless stream of useless software startups made since the 2000's by one or two people with no investments with the continued increase in computers and Internet speeds until the great wall was reached.
Deep tech means not one of those. More specifically, it means technologies that require significant investment in expensive materials and laboratory equipment to progress, such as molecular biology technologies and quantum computing.
And it basically comes down to technologies that wrestle with the fundamental laws of physics rather than software data wrangling.
Computers are of course limited by the laws of physics, but those are much hidden by several layers of indirection.
Full visibility, and full control, make computer tasks be tasks that eventually always work out more or less as expected.
The same does not hold true when real Physics is involved.
Physics is brutal.
To start with, you can't even see your system very clearly, and often doing so requires altering its behaviour.
For example, in molecular biology, most great discoveries are made after some new technique is made to be able to observe smaller things.
But you often have to kill your cells to make those observations, which makes it very hard to understand how they work dynamically.
What we would really want would be to track every single protein as it goes about inside the cell. But that is likely an impossible dream.
The same for the brain. If we had observations of every neuron, how long would it take to understand it? Not long, people are really good at reverse engineering things when there is enough information available to do so, see also science is the reverse engineering of nature.
Then, even when you start to see the system, you might have a very hard time controlling it, because it is so fragile. This is basically the case of quantum computing in 2020.
It is for those reasons that deep tech is so exciting.
The next big things will come from deep tech. Failure is always a possibility, and you can't know before you try.
But that's also why its so fun to dare.
Stuff that Ciro Santilli considers "deep tech" as of 2020:
- brain-computer interface
- fusion power. The question there is, when is "deep", "too deep"?
Huge interest overlap with Ciro Santilli, e.g. he's into
- molecular biology in general: I should have loved biology by James Somers
- JCVI-syn3.0: www.newyorker.com/magazine/2022/03/07/a-journey-to-the-center-of-our-cells
- cryo-EM: www.newyorker.com/magazine/2022/03/07/a-journey-to-the-center-of-our-cells
- David Goodsell: www.newyorker.com/magazine/2022/03/07/a-journey-to-the-center-of-our-cells
- History of Google: www.newyorker.com/magazine/2018/12/10/the-friendship-that-made-google-huge
As of 2019, the silicon industry is ending, and molecular biology technology is one of the most promising and growing field of engineering.
42 years of microprocessor trend data by Karl Rupp
. Source. Only transistor count increases, which also pushes core counts up. But what you gonna do when atomic limits are reached? The separation between two silicon atoms is 0.23nm and 2019 technology is at 5nm scale.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:
- computational biology: simulations of cell metabolism, protein and small molecule, including computational protein folding and chemical reactions. This is basically the simulation part of omics.If we could only simulate those, we would basically "solve molecular biology". Just imagine, instead of experimenting for a hole year, the 2021 Nobel Prize in Physiology and Medicine could have been won from a few hours on a supercomputer to determine which protein had the desired properties, using just DNA sequencing as a starting point!
- microscopy: crystallography, cryoEM
- analytical chemistry: mass spectroscopy, single cell analysis (Single-cell RNA sequencing)
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.
Molecular Sciences Course of the University of São Paulo Updated 2024-12-15 +Created 1970-01-01
Good Portuguese overview: www.scielo.br/scielo.php?script=sci_arttext&pid=S1806-11172017000300301&lng=pt&tlng=pt
A fantastic sounding full time 4-year course that any student could transfer to called that teaches various natural science topics, notably mathematics, physics, chemistry and molecular biology.
Many past students Ciro talked to however share a common frustration with the course: in the first 2 years at least, the "basic cycle", you have infinitely many courses, and no time to study, and no choice of what to study, it is only in the latter 2 years (the advanced cycle) that you get the choices.
Also, if you get low grades in a single subject, your out. And exams are useless of course.
Here's a Quora question in Portuguese about the course: pt.quora.com/Como-funciona-o-tal-do-curso-secreto-da-USP, the only decent answer so far being: pt.quora.com/Como-funciona-o-tal-do-curso-secreto-da-USP/answer/Victor-Soares-31. Very disappointing to hear.
On the advanced cycle, you have a lot of academic freedom. You are basically supposed to pick a research project with an advisor and go for it, with a small amount of mandatory course hours. Ciro was told in 2022 that you can even have advisors from other universities or industry, and that it is perfectly feasible to take courses in another university and validate the course hours later on. Fantastic!!!
Students from the entire University of São Paulo can apply to transfer to it only after joining the university, with the guarantee that they can go back to their original courses if they don't adapt to the new course, which is great!
Not doing it is one of Ciro Santilli's regrets in life, see also: don't be a pussy.
Around 2007, they were in a really shady building of the University, but when Ciro checked in 2021, they had apparently moved to a shiny new entrepreneurship-focused building. Fantastic news!!!
One of the Brazilians who came to École Polytechnique together with Ciro was from this course. The fact that he is one of the most intelligent people Ciro knows gave further credit to that course in his eyes.
Each of the omics studies a subset of molecular biology with a data intensive and broad point of view that tries to understand global function or organisms, trying to understand what every biologically relevant molecule does as part of the hole metabolism.
The main omics are:
Omics might be stamp collecting, but maybe it is a bit more like Trading card game/Magic: The Gathering collecting, in which the cards that you are collecting actually have specific uses and interactions, especially considering that most metabolic pathways are analogous across many species.
The natural sciences are not just a tool to predict the future.
They are a reminder that the lives that we live daily are mere illusions, religious concepts such as Maya and Samsara come to mind.
We as individuals perceive nothing about the materials that we touch every day really work, nor more importantly how our brain and cell work.
Everything is magic out of our control.
The natural sciences allow us peek, with huge concentrated effort, into tiny little bits a little of those unknowns, and blow our minds as we notice that we don't know anything.
For all practical purposes in life, there is a huge macro micro gap. We are only able to directly perceive and influence the macro events. And through those we try to affect micro events. Because for good or bad, micro events reflect in the macro world.
It is as if we live in a different plane of existence above molecules, and below galaxies. The hierarchy of Figure "xkcd 435: Fields arranged by purity" puts that nicely into perspective, shame it only starts at the economical level, not going up to astronomy.
The great beauty of science is that it allows us to puncture through some of the layers of reality, either up or down, away from our daily experience.
And the great beauty of artificial intelligence research is that it allows to peer deeper into exactly our layer of existence.
Every one or two weeks Ciro Santilli remembers that he and everything he touches are just a bunch of atoms, and that is an amazing feeling. This is Ciro's preferred source of Great doubt. Another concept that comes to mind is when you see it, you'll shit bricks.
Perhaps, the feeling of physics and the illusion of life reaches its peak in molecular biology.
Just look at your fucking hand right now.
Do you have any idea of each of the cells in it work? Isn't is at least 100 times more complex than the materials of the table you hand is currently resting on?
This is the non-science fiction version of the lotus-Eater Machine.
Alan Watts's "Philosopher" talk mentions related ideas:
The origin of a person who is defined as a philosopher, is one who finds that existence itself is exceedingly odd.
The toddler of a friend of Ciro Santilli's wife asked her mum:Our perception of the macroscopic world is so magic that children have to learn the difference between living and non-living things.
Why doesn't my tiger doll close its eyes when we sleep?
James Somers put it very well as well in his article I should have loved biology by James Somers, this quote was brought to Ciro's attention by Bert Hubert's website[ref].The same applies to other natural sciences.
I should have loved biology but I found it to be a lifeless recitation of names: the Golgi apparatus and the Krebs cycle; mitosis, meiosis; DNA, RNA, mRNA, tRNA.In the textbooks, astonishing facts were presented without astonishment. Someone probably told me that every cell in my body has the same DNA. But no one shook me by the shoulders, saying how crazy that was. I needed Lewis Thomas, who wrote in The Medusa and the Snail:For the real amazement, if you wish to be amazed, is this process. You start out as a single cell derived from the coupling of a sperm and an egg; this divides in two, then four, then eight, and so on, and at a certain stage there emerges a single cell which has as all its progeny the human brain. The mere existence of such a cell should be one of the great astonishments of the earth. People ought to be walking around all day, all through their waking hours calling to each other in endless wonderment, talking of nothing except that cell.
Alan Watts' "Philosopher" talk (1973)
Source. Lecture given at UCLA on 1973-02-21. Some key quotes from the talk:The origin of a person who is defined as a philosopher, is one who finds that existence itself is exceedingly odd.
Ciro Santilli is actively looking for donations and contracts so he can continue to work full time on OurBigBook.com sustainably, and develop free hardcore university-level STEM education for all ages!
At 100k USD, I quit my job to work full time on it for one year. During this year I will use my contacts with STEM students of a world leading university near where I live and solve as many of their problem sheets as possible, mostly by referring to OurBigBook.com articles I'll be writing. The goal is to get as much STEM knowledge as possible into the world, and highlight how flawed presencial and sequential Higher Education is, while positioning OurBigBook.com as an alternative way to organize humanity's knowledge. Quite grand.
Status: ~144k / 200k USD reached. 1st year locked in and started 1st June 2024 to 31st May 2025[ref], 2nd year stretch goal open. A second year greatly improve chances of success: year one I solve a bunch of courses, year two I come guns blazing with the content and expand further. Donation breakdown:More details: Section "Accounting method"
- 2024-03-18: $126,352 (!!!): anonymous 1000 Monero donation to self-custody wallet. Further comments: 1000 Monero donation.
- 2024-03-13: $1,375: anonymous 10 Monero donation to self-custody wallet
- 2023-11-20: $14.563: anonymous 100 Monero donation to Binance wallet
- 2023-09: $810: anonymous 0.032 Bitcoin donation to Coinbase wallet
- subscriptions up to 2024-01: $143,795
At 1M USD I retire and work on open STEM education forever.
Note to potential anonymous crypto donors: anonymous donations incur a regulatory risk. I cash out most of such donations and announce it very clearly to the government and banks. For example, at one point Barclays even froze my UK account. But things seem manageable for now. On one hand, such donations serve as a fun test of the financial system. But on the other, if all banks reject my money or if the government decides to take it, I will write off the anonymous donation at zero.
How to give:And if you have a different preferred payment mechanism not listed above, please contact Ciro, and he will set it up.
- one time donations:
- cryptocurrency: note that Ciro is not a regular crypto user, so you might want to make a smaller test donation and confirm that it worked by contacting Ciro before going for colossal amounts (one can dream):
- Monero address: 4A1KK4uyLQX7EBgN7uFgUeGt6PPksi91e87xobNq7bT2j4V6LqZHKnkGJTUuCC7TjDNnKpxDd8b9DeNBpSxim8wpSczQvzf. Secret view key: 7ccaf885ff5540b0ff18927e6ac5da30130afb1eaee09ad95d3c4536a6337e0f. This is a self-custody wallet on a "clean" dedicated Monero laptop connected the Internet. I check for incoming transactions from my dirty main laptop via a view-only wallet each weekend. The cash out method used is latest simplest thing that wasn't yet blocked in my country on a given week, the last time that was centralized swappers[ref]. The fact that the cash out method changes weekly confirms that Monero privacy hadn't yet been broken by countries and that Monero is still one of the most useful cryptocurrencies: Section "Are cryptocurrencies useful?". For transparency, I announce all non-trivial transactions on social media, and the full list of transactions can be seen by anyone with the secret view key provided. I previously had different addresses, so pre-existing donations on older addresses will not be visible there.
- Bitcoin address: 3KRk7f2JgekF6x7QBqPHdZ3pPDuMdY3eWR. This is a Coinbase wallet, off-chain transactions with no transaction fees accepted from other Coinbase users. This method has been tested, I have been able to receive funds from this address in 2023. Fees: non-fixed trading fees[ref] + 0% withdrawal fee on top of any Bitcoin network for on-chain transactions[ref]
- Ethereum address: 0x44cF8C9C015F46d3b2Df730b6492823FD7A91044. Test transaction recommended.
- Solana address: DjdaGawoVFdqxJEqpBGsSWuR4G4MVFNiNkAEu89HuKcE. Test transaction recommended.
- TransferWise tag: wise.com/pay/me/cirod3. It shows as "Ciro Duran Santilli" and that's correct. No fees apparently? Love it!
- PayPal: paypal.me/cirosantilli. Note that dots in Gmail address are ignored, and it is perfectly normal if the email you see has some extra dots in it. Fees: 2.9% + 0.30 GBP[ref].
- cryptocurrency: note that Ciro is not a regular crypto user, so you might want to make a smaller test donation and confirm that it worked by contacting Ciro before going for colossal amounts (one can dream):
- monthly subscriptions of 1$/month or more on either:Symbolic 1 dollar/month donation are extremely welcome to signal your interest! This way if a certain critical mass of sponsors is ever reached (~100?), Ciro can start to more actively asking slightly higher amounts to really try to achieve full time self sufficiency.
- GitHub Sponsors: github.com/sponsors/cirosantilli. Fees: 0% for individuals, up to 6% for organizations[ref]
- Patreon: www.patreon.com/cirosantilli. Fees: 8% pro plan + 1% PayPal withdrawal capped at 20 USD[ref]. We are waiting to reach the cap to withdraw!
- larger grants/contracts from filthy rich individuals or organizations: contact Ciro as mentioned at: Section "How to contact Ciro Santilli" to discuss.Ciro is interested in contracts/voluntary work that would be compatible/synergic with the OurBigBook.com project. Some possibilities include:
- interacting directly with classes of university students to help them learn the class subject, while at the same time spreading the university knowledge outside of the university walls
- one-to-one mentoring of individuals of any age that are looking to make an impact in the world, and not just pass their exams
- fixing specific bugs in related projects Ciro has experience in. These could be either via one-off contracts, or on platforms such as:
Ciro's current ambitions require him to remain in developed countries, because Ciro wants to document advanced science and technology by liaising with top universities, and there is not nearly as much high technology in poor countries. Remaining in developed countries is also a required due to family reasons.
If you would like public acknowledgement for your support, Ciro will very gladly give it, just let Ciro know how you'd prefer it. Due to Ciro Santilli's campaign for freedom of speech in China, many supporters have chosen to be anonymous, and that is totally fine, not everyone is interested in politics, or has a situation where going public is acceptable, so we don't have a standard setup yet, let's build it together. A acknowledgement section at the bottom of this page would be a minimum, but I for larger donations we could add a your advertisement in a locations such as:
- near the top of of the accounts controlled by Ciro Santilli, e.g. one of Ciro Santilli's Twitter accounts, github.com/cirosantilli or stackoverflow.com/users/895245
- near the top of cirosantilli.com
100k USD/year is a semi arbitrary amount that sounds nice. My last day job total compensation as of 2024 was about 150k USD/year.
Intro to the OurBigBook Project
. Source. 
Maybe if he ever gets enough credibility, such opportunities would actually materialize. It could be a bit like Periodic Videos, but for molecular biology and physics, and backed by OurBigBook text/tree with minimal openly licensed videos. The fact that such opportunities are essentially impossible outside of the boredom of the university system is something we should really change about education.
So that he can work full time on OurBigBook.com and revolutionize advanced university-level science, technology, engineering, and mathematics eduction for all ages.
Donating to Ciro is the most effective donation per dollar that you can make to:
- improve hardcore university-level STEM education for all ages
- help make every child into the next Nobel Prize/Fields Medal/deep tech unicorn co-founder
Ciro's goal in life is to help kids as young as possible to reach, and the push, the frontiers of natural sciences human knowledge, linking it to applications that might be the the next big thing as early as possible. Because nothing is more motivating to students than that feeling of:rather than repeating the same crap that everyone is already learning.
Hey, I can actually do something in this area that has never been done before!
To do this, Ciro wants to work in parallel both on:
- the multi-user website e-learning platform of OurBigBook.com
- creating amazing teaching content that motivates that platform, and that deeply interests Ciro, notably quantum mechanics and its related applications:
- quantum computing
- molecular biology
- condensed matter physics and chemistry
- slightly more theoretical stuff in somewhat related fields of:
- continue to dump his brain/research in areas Ciro has expertise in: software engineering and open source software
Ciro believes that this rare combination of both:produces a virtuous circle, because Ciro:
- proven passion and capability to learn and teach science, technology, engineering, and mathematics subjects
- proven programming skills, including web development
- wants to learn and teach, so he starts to create content
- then he notices the teaching tools are crap
- and since he has the ability to actually improve them, he does
As explained at OurBigBook.com and high flying bird scientist, Ciro is most excited to make contributions at the "missing middle level of specialization" that lies around later undergrad and lower grad education:But on that middle sweet spot, Ciro believes that something can be done, in such as way that delivers:in a way that is:
- at lower undergrad level, there is already a lot of free material out there to learn stuff
- at upper graduate level and beyond, too few people know about each specific subject, that it becomes hard to factor things out
- beauty
- power
- in your face, without requiring you to study for a year
- but also giving enough precision to allow you to truly appreciate the beauty of the subjectCiro's programming skills can also be used to create educational, or actually more production-like, simulations and illustrations.
Ciro believes that today's society just keep saying over and over: "STEM is good", "STEM is good", "STEM is good" as a religious mantra, but fails miserably at providing free learning material and interaction opportunities for people to actually learn it at a deep enough level to truly appreciate why "STEM is good". This is what he wants to fix.
The following quote is ripped from Gwern Branwen's Patreon page, and it perfectly synthesizes how Ciro feels as well:
Quote 1.
Omar Khayyam's chill out quote
. Omar Khayyam also came to the Vizier... but not to ask for title or office. 'The greatest boon you can confer on me,' he said, 'is to let me live in a corner under the shadow of your fortune, to spread wide the advantages of Science, and pray for your long life and prosperity.'
In addition to all of this, financial support also helps Ciro continue his general community support activities:
- writing and updating his amazing Stack Overflow answers: Section "Ciro Santilli's Stack Overflow contributions"
- saving the world from the CCP: Section "Ciro Santilli's campaign for freedom of speech in China"
Naming taxonomic ranks like genus, domain, etc. is a fucking waste of time, only useful before we developed molecular biology.
All that matters is the tree of clades with examples of species in each clade, and common characteristics shared by the clade.
And with molecular biology, we can build those trees incredibly well for extant species. When extinct species are involved however, things get more complicated.
Has some good mentions, but often leaves you wanting more details of how certain things happened, especially the early days stuff.
Does however paint a good picture of several notable employees, and non-search projects from the early 2000's including:
- the cook dude
- porn cookie guy
- the unusual IPO process
Paints a very positive picture of the founders. It is likely true. They gave shares generously to early employees. Tried to allow the more general public to buy from IPO, by using a bidding scheme, rather than focusing on the big bankers as was usual.
The introduction mentions that Google is very interested in molecular biology and mining genetics data, much like Ciro Santilli! Can't find external references however...
Two of the most compelling areas that Google and its founders are quietly working on are the promising fields of molecular biology and genetics. Millions of genes in combination with massive amounts of biological and scientific data are an excellent match for the Google search engine, the tremendous database the company has in place, and its immense computing power. Already, Google has downloaded a map of the human genome and is working closely with biologist Dr. Craig Venter and other leaders in genetics on scientific projects that may lead to important breakthroughs in science, medicine, and health. In other words, we may be heading toward a time when people can google their own genes.
The book gives good highlight as to why Google became big: search was just an incredibly computationally intensive task. From very early days, Largey were already making up their own somewhat custom compute systems from very early days, which naturally led into Google custom hardware later on. Google just managed to pull ahead on the reinvest revenue into hardware loop, and no one ever caught them back. This feels more the case than e.g. with Amazon, which notoriously had to buy off dozens of competitors to clear the way.
Cover of The Google Story
. Ciro Santilli started taking some notes at: github.com/cirosantilli/awesome-whole-cell-simulation. but they are going to be all migrated here.
It is interesting to note how one talks about single cell analysis, in contrast to whole cell simulation: experimentally it is hard to analyse a single cell. But theoretically, it is hard to simulate a single cell. This mismatch is perhaps the ultimate frontier of molecular biology.
A Computational Whole-Cell Model Predicts Genotype From Phenotype by Markus Covert (2013)
Source.