
Show HN: Pinecone – Build your own genetically-encoded tools - jfarlow
https://serotiny.bio/notes/pinecone/
======
jfarlow
Justin here, cofounder of Serotiny. We've built a web-app to make the design
and organization of synthetic genetic constructs efficient, cheap and
effective. We've built an abstraction layer to enable scientists to build
novel genetic designs from functional units without worrying about the actual
underlying DNA sequence or how the sequence gets manufactured. Once designed,
we help you place an order for DNA from a synthesizer of your choice. The app
is free to use - go ahead and register. We charge 15% of the manufacturing
cost once an order is placed. Design single protein constructs, or high-
throughput combinatorial sets of proteins or mutation sets. [1] Our genetic
management infrastructure makes it straightforward to see where particular
designs came from and how they've been used. It straightforwardly keeps track
of the functions and restrictions of each design. For groups/labs we have an
API that can respond to queries relating various protein constructs by things
like function, sequence, or usage. [2]

Check it out, I'd be curious your thoughts. I'm happy to answer any questions.

We built it all with Go and Ember - a huge thanks to those in the community
working on those tools.

[1]
[https://serotiny.bio/notes/support/tutorials/](https://serotiny.bio/notes/support/tutorials/)
[2]
[https://serotiny.bio/notes/applications/](https://serotiny.bio/notes/applications/)

And a few write-ups/dissections of proteins of interest to HN:
[https://serotiny.bio/notes/proteins/](https://serotiny.bio/notes/proteins/)

~~~
atemerev
Whoa, cool!

Do you have any biosecurity-related protection mechanisms in place?

~~~
jfarlow
Yes. We have a curated database of protein functions - so we have some idea of
the function of new designs. Any designs submitted for manufacture are further
screened - both the customer and the design - by both us and the DNA
synthesizer.

------
ChicagoBoy11
What's the ELI5 for this in terms of who customers are and what kinds of
problems it is solving? Sounds terribly interesting but I have absolutely no
knowledge of this space :-/

~~~
jfarlow
Customers: Researchers and those they communicate with. Specifically those
doing early development of novel proteins - antibodies, biologics, CARs,
CRISPR, enzymes, bio-materials, bio-sensors, optogenetics, or basic research.
We help them organize and intelligently manage their libraries of constructs
based on the constructs' capabilities.

Problem: Communicating genetic designs to yourself, to others in your field,
to others in your company - your boss or your technicians, to manufacturers
and suppliers. And communicate without error, with higher-level abstraction,
and with functional rather than technical detail. High-throughput design and
analysis of designs naturally falls out of those capabilities.

DNA is the 'blueprint' for the "protein" machines. If you want to build a new
or novel biological machine, you must construct a DNA blueprint for it, that
blueprint is ingested, and the machine is built to spec. Our software is
essentially a 1-dimensional CAD program that lets you focus on, manipulate and
organize the material properties of the biological nanomachines you are
building, rather than focus on the manufacturing process. Think the difference
between producing a high-level CAD file vs G-code for the design of a sub-10nm
3d object.

Historically, you have to build the blueprint by hand. The challenges of
building the DNA blueprint itself were immense, and have slowly become more
and more routine. Simply obtaining a close-enough blueprint to what you wanted
was sufficient to develop synthetic insulin, synthetic HGH and a host of other
billion-dollar biologic therapies you see on TV commercials every night. This
tool is a break-point - it allows you to build biological machines based on
what you want the machine to do, and leave the construction of the blue-print
itself entirely behind the scenes. It compiles down the high-level design into
a synthesizable blueprint without the user needing to intervene. Construction
of DNA is fraught with all sorts of syntax rules that this helps to entirely
obviate. With this software a researcher can focus on the properties of their
desired product 'fluoresces green', 'binds to Gold', 'more soluble' rather
than nuanced genetic construction rules.

Many useful protein machines can be deconstructed into component parts (each
part itself encoded by DNA). Pinecone lets you drag and drop those component
parts together, press buy, and get shipped the DNA that encodes those parts.
Historically you'd have to parse a string of thousands of A, T, G and Cs
(literally in Excel or Word) - where a single error would result in failure of
the machine.

These proteins are useful therapeutically, economically, and socially - they
are biology's nanotechnology. They are a few orders of magnitude more precise
than Intel's new i9 processor's features, are 3D in nature, and work in wet,
room-temperature environments.

~~~
mikeash
Great comment. Once one has the DNA, what does one do with it? I know how to
spell "DNA" but that's about the extent of my knowledge in this area.

~~~
jfarlow
DNA needs to be compiled into a protein in order to 'do' anything. DNA is the
source code, proteins are the molecular machines built by the code. And every
organism uses a similar compiler. So the DNA has to be put inside an organism
before the DNA source code can be 'compiled' into a biological machine (a
protein). Interestingly at the level of the compiler, almost every organism on
Earth is capable of compiling most others' particular DNA into a protein (with
a lot of exceptions).

Most purchased DNA that encodes a protein comes in the form of a bacterial
'virus' called a plasmid that can very easily be given to e coli - and it
makes billions of copies of that DNA with very high fidelity in a few hours
([https://en.wikipedia.org/wiki/Plasmid](https://en.wikipedia.org/wiki/Plasmid)).
This DNA can then be purified from that e coli in physically appreciable
amounts and then be put into other organisms for ultimate usage. If you're
purifying a chemical or a therapeutic the DNA is often put into yeast or e
coli. If you're doing research, there are a number of 'model organisms' the
DNA can be put into to supplement the genes already in the organism you're
studying - including human cancer cells.

There are certain kinds of 'gene therapies' where the DNA is actually put into
living human cells, often that have been harvested, and then put back into the
person. This enables the genetic code for the new tools/proteins to be
incorporated as a therapy.

The physical insertion of DNA into an organism is called "Transfection"
[https://en.wikipedia.org/wiki/Transfection](https://en.wikipedia.org/wiki/Transfection)
(or transduction, or transformation for various particulars).

The general concept when applied to human health is called "Gene Therapy".
[https://en.wikipedia.org/wiki/Gene_therapy](https://en.wikipedia.org/wiki/Gene_therapy)

The manipulation of DNA as a tool to understand the mechanisms of biology can
be termed "Molecular Biology".
[https://en.wikipedia.org/wiki/Molecular_biology](https://en.wikipedia.org/wiki/Molecular_biology)

~~~
mikeash
Wonderful, thanks so much for the explanation. I think I knew that you had to
get the DNA into an organism, but I had no idea how that could be done. The
fact that the purchased DNA comes in the form of a virus that's ready to make
lots more of that DNA is amazing.

------
rrggrr
This sounds ripe for DEA and FDA regulation. If you cannot account for
possibly dangerous synthesys or mutations, and im not reading that you fully
can, then you have to ensure the end users can. Are you screening customers?
Can anyone order? Is it possible for the synthesis to alter the plasmid, or am
I not understanding the DNA packaging mechanism?

------
folli
Looks cool! Can you link to any experimental data/publications that show the
functionality of enzymes that were designed this way? It would be very
interesting to get a feel for the success rate of such an approach. You
mention several research groups that use your tool, so I assume there is some
in vitro/vivo data available.

~~~
jfarlow
As it's a 'ShowHN' \- we've only had the software public for a short time.
Biology takes a while, so many of our clients who have used the software have
chosen to not yet make their designs public - they're still working with them.

What we can do is reverse engineer already published data into our system to
see how it would work. If you're logged in you can see a synthetic Knoevenagel
Catalyst like KN.1:
[https://serotiny.bio/pinecone/part/11291](https://serotiny.bio/pinecone/part/11291)

or the Retroaldolase RA95.5-8:
[https://serotiny.bio/pinecone/part/11290](https://serotiny.bio/pinecone/part/11290)

And from that page you can see the mutations that were made to create that new
enzyme, as well as trace the history of the synthetic design from its current
sequence all the way back to its wild-type ancestor through years of research.

Our background is not in computational design of proteins from their atomic
structure (like Rosetta). We enable someone who does have that expertise - who
has such a design in mind, to actually go about producing their libraries,
getting the material delivered, evaluating the effectiveness of what they've
produced, and sharing that information with their colleagues in a
straightforward and actionable way. And if they're picking variants by a
screen or directed evolution, Pinecone would be useful in describing the
results of the screen in order to either move forward, or put the results to
work.

Similarly, some of the fluorophores have great 'histories' to them - and with
our software you can see how various fluorophores were designed, where they
came from, and how they've been used. See Dronpa:
[https://serotiny.bio/pinecone/part/9036](https://serotiny.bio/pinecone/part/9036)
or some of the pH-sensitive fluorophores like ArcLight:
[https://serotiny.bio/pinecone/part/10533](https://serotiny.bio/pinecone/part/10533)

We'd like to think this enables a more straightforward 'porting' of existing
designs into new scaffolds - if the mutations to GFP made it pH-sensitive,
similar mutations to YFP will likely make it pH-sensitive. Swap the
fluorophore entirely, or pull in a natural variant of Cas9 and likely the same
sites that produced a nickase from spCas9 will work on other cas9 constructs.

------
jszymborski
Hiring programmers with extensive wet lab experience? Asking for a friend who
might be me :P

~~~
jfarlow
I'd be happy to chat. Email me at my first name at serotiny.bio.

-Justin

------
saulrh
So, did script kiddies just achieve a whole new level of scary?

~~~
jfarlow
I don't think so. But we are certainly trying to lower the barrier to entry
for building useful biological tools. We hope to help 'smaller than billion-
dollar-blockbuster drugs' be built by companies and researchers who are
inventing all sorts of socially useful biological technologies. We are working
with scientists to enable novel uses of biotechnologies for things like
genetically targeted immunotherapies, synthetic biosensors, spider silk
clothing, vegan gelatins meats and milks, oil-free biofuel production, and of
course just much more rapid biological research.

Some of the uses for these proteins we've talked about already here on HN:
[https://serotiny.bio/notes/proteins/](https://serotiny.bio/notes/proteins/)

------
theprop
This looks really cool!! Are there similar tools or equipment available today?
How does Serotiny compare to them in pricing, speed and effectiveness?

~~~
jfarlow
We have a lot of friends building genetic design software. Each have slightly
different focuses. Ours is primarily, and I think uniquely, focused on an
abstraction above the DNA itself (protein construct design). We focus on
biological function of the output of the DNA rather than the 'assembly code'
of DNA itself. For better or worse, we're a 'C IDE' rather than an assembly
editor. If you are skilled enough to read the genetic matrix, some of the
other software permits more direct manipulation of DNA. Pinecone is useful if
you need to work or communicate your designs at a higher level of abstraction.

If you want cheap and dirty way to manipulate DNA, APE is great:
[http://biologylabs.utah.edu/jorgensen/wayned/ape/](http://biologylabs.utah.edu/jorgensen/wayned/ape/)

And YC's own Benchling has fantastic web-based software for designing, sharing
and keeping track of plasmids:
[https://benchling.com/](https://benchling.com/)

Genome Compiler is impressive as well:
[http://www.genomecompiler.com/](http://www.genomecompiler.com/)

SnapGene is another widely-liked native app for working with plasmid DNA:
[http://www.snapgene.com/](http://www.snapgene.com/)

Pinecone chooses to focus on guiding designs in order to produce genetic tools
that have particular functions rather than focusing on how to construct DNA.
We leave the construction details to the DNA synthesizers.

Pricing: design and individual use is free, we charge a percentage of the
manufacturing cost for designs submitted through us. We also make money
building custom infrastructure (of which Pinecone is an example) for companies
needing to keep track and analyze their genetic designs at a functional level.

Speed: The idea is because we use an abstraction above the DNA, certain kinds
of high-throughput designs becomes VERY fast with Pinecone. "I want all
proteins made with these 5 things up front, these 7 linkers, these 4
fluorescent probes - and all 140 combinations" \- would take about 2 minutes
to design with Pinecone, but would be days of error-prone work if done
manually.

Reliability: We can't guarantee novel designs will work - biology is hard. But
we can help give novel designs the best chance of working. Pinecone showcases
what has worked - and makes it easy to riff off of well-worn designs. And
because you're buying de-novo synthesized DNA (not copy/pasting other's code),
your sequences are exactly what you asked for, not just 'good enough'.

~~~
theprop
I want to genetically engineer extremely intelligent mice...what tools should
I use? Is this possible?

~~~
jfarlow
You still have to figure out what "intelligence" is, and how to transfer,
manipulate, or otherwise encode for it. I don't think we have the tools to
actually transplant intelligence yet. We are in the early stages of
understanding it at all. The field of "optogenetics"
[https://en.wikipedia.org/wiki/Optogenetics](https://en.wikipedia.org/wiki/Optogenetics)
has been a powerful genetic way to help start along that path to understanding
how brains work, to what extent a mouse is intelligent, and how to affect
neural processes.

------
an27
What does "zero-knowledge design"[0] mean? I don't understand the link between
"zero-knowledge proofs" and the storage of genetic data.

[0]:
[https://serotiny.bio/notes/applications/car/](https://serotiny.bio/notes/applications/car/)

