Comment by theptip | Hacker News Reader

Comment by theptip | Hacker News Reader

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Passed this on to some biochem buddies and got the following response:

"There are plenty of constructs I'd love to have but don't have the time or expertise to make them. However, could this tool make them? There's so much expertise that goes into "if i hang this tag here, will the protein still traffic to where it needs to go/will it interfere with other domains/will it hang on the right side of the membrane/if I change literally one other amino acid the new tag will work but not if I leave it normal." The experts can already design proteins, but if this tool democratizes that, who's going to do QC?

AFAIK the real way people make substantive changes to proteins is to make 10 variants, test them all, and iterate the designs that worked best. Feels like we're miles away from being able to drag and drop functions."

And "In principle proteins are modular but I can give you ten examples where that principle ruined someone's life. The QC is hard and is case-by-case."

What is your editor aiming to help with? Is QC still the rate-limiting factor to innovating new protein designs with your tool? Does your tool help with QC in any way?

Thanks for sharing, I'm always interested to see new tech in this area.

That is exactly what we aim to do:

- We keep track of how domains have been used before (so as to mitigate if not entirely predict that QC). We are trying to encode that expertise in a way that is intuitive and frictionlessly sharable. The more people use it the more helpful it becomes. We help encode biological institutional knowledge.

- We collaborate with DNA synthesizers so that you just do the designing, and we help get you the designed DNA to your bench at a reasonable cost. You get exactly the sequence that you want, not what someone gave your neighboring lab's buddy sometime ago, or what some restriction enzyme/quick-change let you that's probably good enough. We alleviate the pain of cloning.

- We help you build entire sets by dragging and dropping: "I want these three fluorophores upstream, these 4 linkers on these proteins of interest" - Boom! Buy! Done! (in literally as much time). We make efficient high-throughput design.

- It is true, there are many proteins that are note entirely modular. But there are many more than 10 examples of proteins designed exactly that way (see Addgene's database). Biology is hard. We help you prevent failure buy being able to see how other successes have been achieved, prevent stupid mistakes, and get you your material to you as quickly and cheaply as possible. If your design does fail, it has failed faster and with less sunk cost than if you had to do all the construction yourself.

- Finally, because combinatorial design and purchasing is reasonably priced (and you don't have to do the construction work), you can order an entire logical set of proteins to actually figure out which would work and which would not. When I cloned I made some tiny fraction of what I expected to work purely because cloning was so painful - and if that small fraction failed I didn't even bother to figure out why or what would have worked.

I'd appreciate any feedback you might have.

As someone who is really interested in DNA programming but not am expert in biology, how approachable is the editing.

If I'd like to make trees that have a firefly glow at night, is this something that can be done by an amateur?

How about creating plants with higher efficiency of photosynthesis than 4-5% in most plants.

At the end of the day (century) it should be as straightforward as making beer, an espresso shot, bread or using a fertilizer. The end-products and techniques are quite simple, even ancient.

However the search-space to get to those solutions is enormous, and getting to those very simple conditions is still a significant (if no longer herculean) undertaking. If you're given the correct tools and a good protocol it's really pretty easy to accomplish useful and interesting biological tasks (again you already do this when you make beer/bread/yoghurt/kimchi). But for the time being engineering an entirely novel biological function would require a fairly sophisticated understanding of the context you're trying to fiddle with.

Why doesn't my FRT site logo invert when I reverse complement it? (not a serious complaint..) Signed up and played around a bit tonight. Really great concept. I think a couple of features will probably be helpful to your target audience, though some are a bit tricky to implement:

-User designed sequences (maybe I just couldn't find it). Everyone wants to drop their primer of interest in, their unique tag, their CRISPR site, etc. Also, some well-balanced GC spacers would be helpful, even make them unique so people could PCR off them if needed.

-Barcoded sequences. This will ruin / complicate the auto IDT pricing, but a nice drop-in feature would be a degenerate barcode sequence. This is all the range with MPRAs or other high-throughput methods, and could be really helpful

-Architectures. Say I want to design a lentivirus construct. Give the user the scaffold to drop their payload in, with set LTRs, etc. Screen for no polyA signals in their design, etc. An easier way to walk novice users into design (maybe best not to start with lenti...)

Anyway, keep up the good work, it's a cool product!

My friends didn't seem to be convinced by this response for their own areas of inquiry, but I'm not really qualified to hold a discussion here; happy to try to arrange a conversation if you're interested in going to the source. (PhDs and postdocs FWIW).

Hard to hold a conversation on HN. If you ever see this comment - I'd love to hear their skepticism :)

Email is my first name at my company's domain.

-justin

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