daemonk

TXTL systems already works. And there are antibodies (not many) that can only be produced cell free.

The problem is really scale.

Cell-free synthesis is the next step. Theres slow progress, but very interesting operational models if it works.

Nanopore spits out data as dna goes through the pores. And depending on the flowcell you are using, you can load or top up the flow cell in smaller amounts. So you can potentially have quick turn around time without having to wait for enough samples to pile up before you batch sequence on a larger illumina machine.

Illumina machines are cost efficient in terms of cost per basepair, but only at large batches. They are trying to rectify this after seeing other benchtop sequencing machines (Element Biosci) moving into the mid-throughout niche and doing well. Their solution is the miseq i100 that they just announced.

But at the end of the day, these are all still constrained by having to think in terms of multiplexed batches which has a lot of operational complexity involved (equi-molar pooling, barcoding, etc).

Ultimately, for commercial sequencing labs, one of the more difficult problem to solve is the operational complexity of how to optimally load the sequencer for lowest cost while balancing failure rates/low coverage rates rather than the technicalities of dna prep/lib prep. Given unlimited and consistent intake samples, the problem gets easier. But most labs have some kind of seasonality or project cycle built in which means it’s not about maximizing a yearly capacity, it’s more about how many samples max you can pump through within a few days.

Productionizing and scaling nanopore sequencing is definitely an achievement. With that operational obstacle out of the way, you get to think about sequencing in terms of “streams” of data rather than “batches” of huge amounts of data (illumina). That confers a huge operational and commercial benefit.

For most instruments, it's an interplay between resolution and consistency. There isn't a "true" reading in any sense of the word. There is just how much resolution you are measuring and how consistent the measurement is between independent readings of the same event.

The overwhelming amount of pre-existing clinical data gathered by cuff-monitors means that any novel measurement methods benefit from tying/correlating their output to the existing data for compatibility. It's a bit unfortunate in some sense as cuff-monitor data lacks resolution and sometimes can be a bit of a drag on novelty.

I think it is entirely fair to say that there probably isnt just one primary way to run a large organization. That’s really the main takeaway I found useful from Paul Graham’s blog post.

He obviously didnt specify at all what other ways are and what this nebulous “founder mode” means. But I think just pointing out hiring an army of consultants and mbas might not be the only way to do it is an important statement to make that I don’t think most people in the corporate world would readily admit to.

I am not a writer/novelist by any means, so please forgive my ignorance. Does the act of creative writing tend to lead to mental drift? So much so that minor distractions are so detrimental to the process?

I’ve always wondered if the hollywood stereotype of the reclusive writer typing away on a low tech typewriter is based in reality.

As an exited founder who left 2 years after acquisition, this really put into words thoughts that I’ve had leading up to me leaving.

Founders can sometimes be walking contradictions of being hyper self critical and also have supreme confidence. Going from a 50 employee startup to being a part of a multinational corporation is a “corporate shock” that makes a founder think they are out of their depths and should just follow the corporate’s lead.

The founder vs manager mode definitely resonates with me. However, the lack of concrete success stories of “founder mode” (whatever that may mean) leads to most founders giving up their reigns to the horde of corporate MBAs and quietly quitting after their holdback period is over.

Why exert so much effort trying to paddle a canoe and steering against the giant cruiseship that is the mothership corporation, when you should just go start another company and reap your potential reward.

Practically, learn linux if you’ll actually use it to its full potential. Most webdev work where you just need to plumb together components don’t.

For personal development and satisfaction, it’s always fulfilling to learn something new.

I enjoy my apple products and am perfectly fine within their ecosystem. I also appreciate naysayers who shit on their products whether with good reason or not. I think counterculture or contrarianism is a necessary force.

The louder they are, the quicker the progress towards something better. Keep up the good work.

The problem of non-selective cleavage of all terminators, whether they have been incorporated or not seems to be the most significant one. Is engineering a selective polymerase really the best solution here? If you don't top-up the reaction with un-cleaved terminators, won't the reaction become slower and slower as you go? The ideal solution is somehow have terminators that will only get cleaved after incorporation (maybe due to conformational changes); but I can see how that's probably even harder to engineer than a selective polymerase.

I can see that the complex microfluidics and reagent cycling can be a big added complexity/cost. The continuous process is definitely more elegant, but also seems really difficult to get right for longer read lengths and I wonder if it is really worth it.

What would be the potential benefits of the continuous process? I guess cheaper reagents since it is a one-pot process and faster sequencing speed since you don't need to cycle reagents?

Instead of killing and starting a new process for every input, it will keep re-using the same coproc'ed process. I guess it's almost like daemonizing the process into several daemons and then feeding inputs through the daemons as one becomes available.

I can see this being useful for extremely short-lived high paralleled jobs where the overhead of the killing/starting a new process is significant relative to the job itself.

I tend to agree. I see databases as a type of file system with more strict constraints in terms of reading/writing.

One can maybe argue that file systems are just an address book and databases are a more much complicated address book.

I wrote this one a long while back with react and d3.js: https://damiankao.github.io/life/

How well does it work with sklearn/scipy/pytorch?

“I had depended on the idea that scientific research is a sacred trust”

And that is part of the problem. Having gone through a phd, this unspoken religiosity that underlies scientific research where you are expected to be monks for science contributes to stuff like this.

I appreciate the perspective. There appears to be a lot of commonalities between your viewpoint and themes of classic Russian literature.

While I get that states is frustrating for share-ability and communicating your work, it is extremely useful for prototyping. Perhaps there just needs to be an explicit toggle for stateful vs non-stateful for notebooks

I would pay a monthly subscription for an app on my phone where I can take a picture of the doc and it will just immediately upload to the cloud without any bullshit. And I can go back and re-sort these document later with an intuitive UI.

What I have to do currently is use one of those document scanner apps on my phone to take a picture. It will give me a reasonably good pdf doc from that picture, but then I got to press multiple buttons to eventually email the doc to myself. Then I have to go into my mailbox and sort the doc into my google drive. Ultimately, it works, but also very annoying.

This is relevant also: https://hazyresearch.stanford.edu/blog/2023-03-07-hyena

I actually would not mind a ceiling mounted design where the headset is counterweighted so it is essentially "floating" and you pull it down to put on your head. I know it will take away from the mobility of the headset, but I am okay with being stuck to a 6ft radius while working. It could also charge through the ceiling.

None of the existing headsets I've tried has worked out in terms of working setup replacement. If it can replace a desk/monitor and lead to better ergonomics and flexibility, I would pay upwards of 5k for it. I really want Apple to succeed.

Here is a game of life simulation I built almost a decade ago when I was learning react.js

http://damiankao.github.io/life/

The best storage format for genomics data is DNA. At some point in the future, it might actually be cheaper to just re-sequence than to store the fastq. Instead of optimizing the digital infrastructure, it might be better to just optimize the lab infrastructure for storing the physical DNA.

It's difficult, but not impossible. There are plenty of whole genome amplification methods out there for single cell DNA-seq.

Idle games are the perfect distillation of what some people want from video games. Seeing numbers go up from low effort actions gives you that artificial sense of achievement that can be missing from real life.

I guess the viscosity of the resin prevents structures of certain size from sinking? I assume you would still need to try to print it in a way where "heavier" structures are done first on the bottom and work your way up?

I've gone through many sleep apnea oral appliances. The best one is this one: https://www.smlglobal.com/zyppah-k

It might look a bit flimsy with the dental rubber bands, but that's actually the best feature. Most other oral appliances have a hook or solid point where both halves of the top/bottom mouth pieces are locked in place. What happens is that after 6-12 months of usage, the stress points will eventually break and you are left with a useless device. This has happened to me with 3 previous "solid locked" devices. The zyppah device requires you to change out the dental rubber bands every few weeks, but the flex it gives and longevity is worth it.

If you have moderate-severe apnea, just go to a dentist who also specialize in sleep apnea and get it taken care of. You would be amazed at the difference it makes.

I think this is cool. But at some point in my career/life in the tech space, I stopped caring as much about my tools as long as it works to a reasonable degree. I am fine with whatever Dell/Apple/Asus/etc laptop that's out there. Will my productivity increase if I switch to Framework? Maybe? I am not sure how to convince people like me. Obviously, I am not the target audience for this. I wonder what is their addressable market?

Nice. I read about these cool new systems all the time, but have to end up waiting for some reagent company to start producing them after they resolve all the IP stuff. A lot of commercial and academic labs don't have access to the facilities/resources needed to produce the enzymes.