

Cofactor Genomics (YC S15) Pursues RNA Testing, Offers Better Diagnoses Than DNA - katm
http://techcrunch.com/2015/07/31/cofactor-genomics/

======
carbocation
The article has a DNA versus RNA spin that, scientifically, is more of a
distractor than anything when it comes to cancer. I understand that for
marketing, it's useful.

In blood cell cancers, Steve McCarroll's group has shown that oncogenic
somatic DNA changes are readily discovered through routine sequencing, and
these are prognostic of poor outcome.[1] If you do this on a pre-disease
schedule based on the risk estimates from your first round of sequencing, you
will be able to detect blood cell cancers at any stage you like.

In non-blood cell cancers (say, breast cancer), you don't expect to capture
any of the tissue-specific cell of interest from a blood draw to determine if
there are somatic mutations occurring. However, there is growing evidence that
there is often enough circulating tumor DNA in the blood that it can be of
diagnostic significance.[2]

In contrast, for diseases that do not involve somatic mutations (in other
words, for diseases aside from cancer), an RNA-based assay could be quite
interesting. For example, getting better characterization around non-dilated
cardiomyopathies would be of broad interest.

1 =
[http://www.nejm.org/doi/full/10.1056/NEJMoa1409405](http://www.nejm.org/doi/full/10.1056/NEJMoa1409405)

2 = [https://www.genome.gov/27556716](https://www.genome.gov/27556716)

~~~
davemessina
Thanks for your comments, and yes, you've got it exactly.

In cancer, both DNA and RNA can be effective diagnostics, and there's been a
lot of great work on the DNA side in cancer.

In essentially all other diseases, though, there are changes in RNA but not in
DNA.

~~~
jeffdavis
"In essentially all other diseases, though, there are changes in RNA but not
in DNA."

Is that true for autoimmune diseases like Type I Diabetes?

~~~
davemessina
Yes.

------
daemonk
Bioinformatician here. When you say RNA testing, you mean RNA-seq? Gene
expression? If yes, then do you think blood samples will be enough to make
these type of diagnosis? I imagine you will probably need tissue specific
samples to make some of these disease predictions.

~~~
davemessina
Hi,

Great question.

We're developing tests around a recently discovered type of RNA called
circular RNA. Tissue-specific circular RNAs are present in blood, and so
that's how it's possible to use a blood test instead of having to go to tissue
like you would with traditional mRNA-seq.

~~~
daemonk
I don't quite understand how just using circ. RNAs would give you better
predictions. From the little I've read about circ. RNAs is that they can form
from normal RNAs and possibly function in sequestering regulatory small-RNAs.

So you can detect circ. RNA that come from specific tissues and partition
those reads out as expression for those tissues? What kind of coverage do you
need to do that? Are mRNA circularization rates consistent among different
genes?

~~~
jarmstropreamp
Hi daemonk, Jon Armstrong from Cofactor Genomics here. You hit on some
excellent points.

So you can detect circ. RNA that come from specific tissues and partition
those reads out as expression for those tissues?

In reality, we are detecting circRNA that arises or predominates during a
specific disease state and then partition those reads out as a signal for the
disease state. On a related note, the circRNA molecule resists degradation
much more than linear RNA molecules, leading to a longer half-life and less
variability in signal from tissue, plasma, and exosomes.

What kind of coverage do you need to do that?

Currently, 100's of million of reads need to be generated to just detect the
highest expressed circRNAs. We have a patent pending circRNA enrichment
technology (supported by a large NIH phase II grant) that increases the ratio
of circRNA in the total RNA pool by logs, thus one could sequence logs less
reads for the same level of detection. The coverage cutoff for detection can
be "tuned" for assay sensitivity.

Are mRNA circularization rates consistent among different genes?

CircRNAs do not seem to be translated into proteins and probably perform
multiple regulatory functions. Also, the level of a linear form does not
correlate with the level of the circular form for the same gene. As with
linear mRNA production, which is not consistent from gene to gene or tissue to
tissue, we observe the same phenomenon with circRNA.

Hope this info helps.

~~~
niekmaas
Finally a topic on hackernews that I am getting my PhD in..! Anyway, do you
have any data indicating what percentage of circRNA is "free" in the plasma
versus inside of other entities like platelets or extracellular vesicles
(exosomes)?

~~~
jarmstropreamp
The work with these molecules is early enough, that to my knowledge, there are
no studies of this type that are published. And, in fact one could pose the
same question for linear mRNA and ncRNA in exosomes (or ESVs). Most of the
studies are on miRNA in ESVs, however we have done considerably work
internally on characterizing long- mRNA and ncRNA in exosomes. These vesicles
are fascinating!

------
mmaunder
Related: Check out Jorge Soto's talk on NPR's Ted Radio Hour:

[http://www.npr.org/programs/ted-radio-hour/](http://www.npr.org/programs/ted-
radio-hour/)

Soto is the CTO of Miroculus and they're using MicroRNA analysis to develop a
cost effective way to provide early diagnosis for a variety of cancers.

So far they've made progress with pancreatic, breast and IIRC two others. This
is huge because usually cancer is discovered when you become symptomatic which
is usually stage three or worse and it's much harder to treat then.

If they can make this cost effective enough to be included in a regular doctor
'check up', then we may catch a large proportion of cancers early which makes
treating them way easier.

------
davemessina
Hi everyone! Dave Messina from Cofactor Genomics here. I'd be happy to answer
any questions you might have. We're excited to launch!

~~~
Asparagirl
What kinds of disorders and diseases will you be testing for?

Will your tests be available direct-to-consumer, or will patients have to go
through health provider gatekeeping?

~~~
davemessina
We are looking at Parkinson's, heart disease, and cancer initially.

~~~
lucidrains
Hi, could you point us to some papers on this subject? I have never heard of
circular RNAs put into clinical use.

------
robbiep
So they're getting 20k from YC to get valley contacts, at the cost of a
percentage of the company, when they already have pharmaceutical and NIH
funding? Or is there a different deal in place for biotechs?

~~~
davemessina
Over half of the YC companies (us included) don't really need the money. The
$120k investment is only a small part of what YC does.

See [http://www.ycombinator.com/atyc/](http://www.ycombinator.com/atyc/)

------
jonlucc
If I find myself in the area, can I take a tour of your lab? I work in pharma
and this is interesting to me.

~~~
jarmstropreamp
Jonlucc, Shoot us an email through the website and I am sure we can set
something up.

------
_ihaque
How do circRNA-based biomarkers compare to miRNA-based approaches?

