For anyone interested, found following blog post on OP’s website, which is linked to from their HN profile:

_____

How to make DNA synthesis affordable

https://keonigandall.com/posts/affordable_dna_2.html

Having worked at the largest synthetic DNA manufacturer (at least they were, I think they still are)... a lot of his information is just wrong. There is a huge incentive to lowering the cost of producing oligos and synthetic genes. This is actually a very interesting time in the space (shoutout AnsaBio).

I encourage him to continue explore new ways of making DNA, but understanding the market is very different from building off an expired patent.

I’ve spoken to the CEO of Ansa bio about this topic and they aren’t focused on lowering prices, but increasing what can be built.

I would like to know what specifically you think I am wrong about, though. Always happy to improve my thinking.

(Digital) chip designer here: this is super cool. What tech node are you targeting? Have you checked out any of the free open-source tools and PDK from Skywater, Google, eFabless and co?

I'm planning on using the chip ignite program! They can build the chip I need - the harder bit is figuring out the coatings needed (sputter coating post-processing is needed to be compatible with the chemistry).

I am pretty new to chip design but know the DNA space quite well - I would love to do a call, if possible, because I have lots of noob questions about chip design and chip design tools. Happy to share anything about the biological side in exchange!

Is there a page, blog, twitter account, newsletter, Github repo or anything to follow this? I have no knowledge in this space so I'm of no help, but I'm very interested in the prospect of this stuff becoming more accessible!

Github here - https://github.com/koeng101/dnachips

It is a bit dead when it comes to a git, since I am trying to get the first machine needed, which is a DNA synthesizer (asked about that here https://groups.google.com/g/diybio/c/V3OYVBxaH04 for example).

The idea is that with a traditional DNA synthesizer I can have positive controls of the chemistry, and develop a chip that can fit inside the flow cell of the existing synthesizer. In biotech, everything goes wrong a bit more often than in computer science, so the focus lately has been getting my hands on a working synthesizer. This is a tried and true method of getting chip synthesis working.

If that works, I'd like to provide the chip at cost for integrators, as well as develop a functioning full product for integration with some bots I'm building for my official work.

Personal website is here - http://keonigandall.com

Likewise, piggybacking!

I'd just like to echo (verbally "vote") my concern. Every great step forward comes with the potential for an order of magnitude steps backward, i.e. destruction. The amount of man hours to e.g. blow up a building is far fewer than the amount needed to build it.

Will the output of your product add a suicide timer to a cell?

Will the output of your product prevent the cells from procreating/multiplying?

Will the output of your product prevent pathogen creation?

Will the output of your product require a specific, unnatural energy source that can only be man made?

Professionals take great care in thinking about those problems, and sometimes still fail. (IIRC, a synthesized breed of mosquitos that were released in Brazil failed to die off and are now a part of the biosystem).

[0] https://www.dw.com/en/genetically-modified-mosquitoes-breed-...

This is like asking people if they've properly guarded against a malicious AI before making hobbyist computers.

> Will the output of your product prevent the cells from procreating/multiplying?

Why would this matter? We have immortal cell lines like hela cells that have been alive for decades.

> Will the output of your product prevent pathogen creation?

No, but no one is going to "accidentally" create a new pathogen (you'd need this as well as some expensive labware and a lot of expertise), and the people with the incentive can already do so in labs.

> Will the output of your product require a specific, unnatural energy source that can only be man made?

What lol

I'm not an expert, but if it's a chip that just synthesizes DNA from a sequence of base pairs, isn't what you're asking similar to making a computer that can't be used to perform evil? I suspect that computing if a given sequence is usable in a pathogen is equivalent to the halting problem. And practically, it seems that a lot of computational resources are required to figure out what a protein does, even for common cases.

If we had really smart software engineers, well paid red-teams, and robust government policy collaboration with industry, I think we can make it at least 95% harder to create something dangerous. We have none of those, though.

It's super hard, but until novel bioweapons are discovered, it is at least a tractable problem.

> Will the output of your product add a suicide timer to a cell?

Absolutely not.

> Will the output of your product prevent the cells from procreating/multiplying?

Absolutely not.

> Will the output of your product prevent pathogen creation?

Strictly defined as the output being a chip, absolutely does not.

> Will the output of your product require a specific, unnatural energy source that can only be man made?

Absolutely not.

> Professionals take great care in thinking about those problems

I am a professional in this field, and have been thinking about these problems quite deeply (if you check on my website, my first time writing about my concern for these problems was back in 2014). I have developed opinions on this over the years, but roughly they come down to the fact that many folks have a gross misunderstanding of the field in general, but quite like to think that they understand what is going on.

For example, I mentioned I wanted to do oligo pool synthesis - how the hell would the output of an oligo pool synth run add a suicide timer? Or prevent replication? Or require a certain kind of energy source? In the context of the stated goal, these objections really don't make any sense. It is roughly equivalent to someone wanting to run a mining company and getting countered by "will the output of your product stop school shootings?". Perhaps better questions are along the lines of - how are oligos matching biohazard sequences prevented from being synthesized? Well, this is a question of both governmental policy (what IS a biohazardous sequence?) and of the integrated device (does it phone home for each synthesized sequence? What about hardware hacking?).

Cart is way before the horse. Also grad students doing this type of work are absolutely not taking great care in thinking about these problems.

I fail to see how considering the impacts of a tool before building a tool is putting the cart before the horse. How is that not a necessary step in building a thing?

I saw someone posted a reactive database just now on HN. I can't believe they didn't think about what child pornographers might do with that. There is literally no discussion of it on their web site. How could it not be a necessary step in building such a thing.

Perhaps part of the disconnect here is not realising how vast the applications are for synthesizing DNA oligos are. It's a very basic thing, and anybody can already basically order them online for a very affordable amount. It's like being worried about someone open sourcing a way to make printer ink.

I mean, at what point do stop and ask yourself if the thing you're making is going to cause bad things to happen? Do we only consider that when the thing is really obviously a weapon and ignore all the other creations?

> I fail to see how considering [all] the impacts of a tool before building a tool is putting the cart before the horse.

It’s interesting how people revise their arguments, or omit words from it, to make their interlocutor’s response appear more absurd.

I hereby vote for the establishment of a Regulatory and Executive Committee to Understand and Reconsider Special Impacts On Nature.

Err, wait, ummm, it looks like we first need a R.E.C.U.R.S.I.O.N. to establish the R.E.C.U.R.S.I.O.N.

> Will the output of your product prevent the cells from procreating/multiplying?

How would unicellular organisms procreate exactly?!

I am not being pedantic here but procreation usually entails sexual reproduction and I don't see how this is possible for these organisms.

I'm pretty sure procreation just refers to the process of reproduction, sexual and asexual inclusive.

My understanding of the pertinent terms in this specific context is as follows:

1) Multiplying: Asexual reproduction only.

2) Reproduction: Sexual and asexual reproduction.

3) Procreation: Sexual reproduction only.

I appreciate the way you understand the terminology. However, I'm not sure everyone else understands it the same way. Although, I do admit the terms can be confusing.

BTW: I don't see how 'multiplying' could refer to just asexual reproduction. People often use it in sentences like 'the deer population near here multiplied the last couple years'.

Well, I see how referring to reproduction in a herd of deer, as a collective, in everyday speech, by using the word "multiplying", but not on an individual level, which adds to my point.

As you can see, getting terminology right is challenging and not always straightforward.

> so I have been learning analog IC chip design to build an open source high-throughput DNA synthesis chip.

Any resources and books you'd recommend?

As a software engineer, verily and the like just didn't make as much sense to me as chisel. Got this book and have been very slowly working through it - https://www.amazon.com/Digital-Design-Chisel-Martin-Schoeber...

Efabless's chip ignite program is also great - check it out! https://efabless.com

This is not at all an area I know anything about, but a podcast I was listening to (Moore's Lobby) recently mentioned on chip design broadly:

https://www.zerotoasiccourse.com

And also:

https://www.udemy.com/user/anagha/

Thank you!

How will you prevent people from using this technology to create DIY pathogens? If the answer is "I won't" or "it'll be open source, I won't be able to", consider doing something less harmful instead.

How far down this road do you go? Someone engaged in bioweapons manufacturing probably uses laptops and chairs too.

The difference is that those already exist. I think concern about the development of new technology is valid.

Suppose nuclear weapons did not exist and someone was concerned about the Manhattan project — would you say that chairs enable people to build regular bombs, so we shouldn't worry about nuclear bombs?

Nuclear bombs have very few uses other than blowing up cities or threatening to do so. DNA synthesis is both of considerable use outside of bioweapons production and not really a critical bottleneck in bioweapons, which is why I'd consider it more like laptops or chairs than like, say ICBM guidance systems or weapons grade enrichment programs.

The technology already exist. The OP stated, patents are over, and that is why (s)he is working on it. Even if it not exist, security by obscurity is no security... if anybody can do the tech, the bad guys are going to be as fast, or faster than the good guys... So I hope the good guys do the tech for everybody...

You are severely underplaying how chaotic people can be, and how valuable a barrier to entry is at deterring that chaos from causing damage.

Synthesizing oligos is not the same thing as creating an infectious clone. This technology would be used to synthesize primers and custom promoter+gene fragments.

Presumably the answer is "do exactly what is done now", which is to say offer the tech as a service (i.e. don't sell the hardware) and screen the uploaded sequence requests for dangerous sequences.

How about “oligo pool synthesis chips” != “dna synthesis machines”

“Harmful” can also be seen the other way. From my view within the industry, it is harmful that the tech does not exist, and the idea of harmfulness is, largely, propaganda perpetuated by elites to maintain the status quo.

This specific attitude is something that I have capitalized on in many ways in my life to do well: ad tech, location data, trading. There is massive alpha in not being like this. And if this DNA synthesis thing had some value to me I would gladly do it and may the terrorists breed superbugs from it if they will. Even if you convince him, you won't convince me. I will become even more convinced that I should build the building blocks for extinction weapons. Every time you make this argument, I will move closer to doing it.

One day, I will do it just because I can and because you argued I shouldn't. Then your actions will be a proximate cause of the existence of the thing.

Ideally, I would not be so controllable but a deep part of me loves the transgressive nature of fighting a puritan.

All talk, no action

Hahaha! Fair fair :D

Upvotes for the bants

Not knowing anything about this field, what could someone do with such a chip?

Is it something like a 3D printer where you can get a rough but usable finished product, or is it more like a "if you want to make bacterium X produce Y product, you need to do X, Y, Z, W, etc." and the chip is used to do one of the steps.

It is more like the X Y Z W. However, the X Y Z W bits I am working on as well (https://github.com/TimothyStiles/poly , https://github.com/TimothyStiles/allbase , trilo.bio, freegenes.org). Going for fully automated "make bacterium X produce molecule Y", but still a while away (but surprisingly not THAT far off)

That's really cool! I was about to ask how to get started on that field, but I also noticed that you have that covered in https://github.com/TimothyStiles/how-to-synbio

Do you mean completely from scratch?

If so, why would one want to do that versus taking an existing cell and injecting custom DNA?

You can't jump over fitness troughs. For example, full tRNA recoding. Plus, it is neat to make life from chemicals.

I don't understand why, if it really worked, the org holding the patent didn't do anything of it.

kodak invented digital photography

They did. This runs genscript's high throughput DNA synthesis platform. They actively sell the result as their oligo pool product.

this sounds so cool! i wish you the best luck with it.

Sounds fascinating, what could possibly go wrong?

“Your scientists were so preoccupied with whether or not they could, they didn't stop to think if they should.” —Dr. Ian Malcolm (Jurassic Park).

That's an excellent question. Another of my faves is "what are the worst consequences and how do we reduce the risk of a negative outcome? Is it possible to entirely eliminate issues responsibly?"

The former tends to stop all progress, while the latter considers that negative outcomes are real, but that we can productively reduce risk.

Kind of like how OpenAI removed racist, sexist, and other troubling images from their AI training pool and then released it in pieces (to a small group of subjects) to remove as many issues as possible. With that said, they definitely still made mistakes.

I like the motto “safety is our number three priority” but I also think that people sharing info about their danger-spraying project should take a moment to say a line or two about how they think about the issues. Instead of just ignoring them.

Kind of an uncharitable quote, considering I have essays and presentations going back 8 years (and more recently) where I question potential harmfulness to the environment. I also previously worked for 3yr at a nonprofit specifically aimed at improving the world/society with biotech, where we considered these questions carefully and deeply.

In any case, blatant sarcasm is also out of the spirit of hackernew’s “ Be kind. Don't be snarky. Have curious conversation”

Responding to the first part of your comment, I’m glad to hear that!

“Possibly” is the crux of that question, as it requires knowledge and expertise to answer in any kind of real way.

It’s very easy to come up with answers to that question if you don’t know what is actually possible. Not very useful answers, though.

> “Possibly” is the crux of that question, as it requires knowledge and expertise to answer in any kind of real way.

That is untrue. If you mean by "...it requires knowledge and expertise to answer" domain knowledge.

It is possible to understand the implications of technology without mastering it.

The experts in the field have huge incentives to say it is safe.

If we are to make decisions about releasing novel self replicating organisms into the environment, we should not task the people who will profit (scientists) to decide if it is a good idea or not.

What's your point? The technology already exists and is being used.

Your name, password, and the names and addresses and phone numbers and emails of all your family members already exist and are being used. So, by your logic, you have no reason to share them to everyone?

The logic doesn’t hold up.

You can make the same argument for anything. It makes sense to think about the dangers, not pretend that bad logic is an excuse to do anything you want.

No, actually your first sentence's logic doesn't hold up as it isn't a fair comparison at all. You can already order custom oligos and synthesized genes for relatively cheap. The chip idea would just reduce the cost more.

Digging into personal information on people can be done for relatively cheap. I’m not sure it’s a good thing to make it cheaper.

But, in the concrete case in question (gene synthesising technology), what are those potencial dangers?

This is silly. Unix already existed, what's the point of linux?

I think you didn't understand what I was referring too. Read again.

Pretty cool. May I ask, what is your background? And, what resources are you using to learn about analog IC chip design?

~10yr of synthetic bio, did 4yr of mitochondrial engineering + directed evolution at UCI, then ran the FreeGenes Project for 3yr at Stanford.

Chisel for programming it (great little lang/project) https://www.amazon.com/Digital-Design-Chisel-Martin-Schoeber...

Efabless PDKs - https://efabless.com/

Other than that, lots of trial and error. Hardware people are brutal with their acronyms, so it really comes down to a lot of stumbling around and reading whatever I can.

Very cool. Best of luck!