
Biology needs a Grothendieck (or at least a Hilbert) - thanatosmin
http://thebench.mit.edu/?p=155
======
alevskaya
I came to biology from physics over a decade ago thinking that theory would
matter. But modern biology is not waiting for a Grothendieck. We are not
wanting for a deep theoretical view to reinterpret our data with. We are
wanting for cheap, high quality data about cells and organisms in the first
place.

Those of you who have not done biology can't realize how primitive things
still are. A CS analogy is that we're trying to reverse engineer a non-
deterministic alien architecture from the future via a remote debugger over a
noisy line that has no error correction and runs at a fraction of a millibaud,
where every peek or poke costs hundreds to thousands of dollars. With the
advent of high-throughput sequencing we just figured out how to get noisy
ROM/RAM dumps (genotype), but still have precious little ability to quickly
interact with the biological systems under study (phenotype). Biology is much
more like hacking and reverse engineering than it is like physics or
mathematics.

A working exploit is worth much more than general pontification. The
transformative events in biology these days are the clever hacks that enable
whole new classes of fast experiments to be done: quick homologous
recombination induced by CRISPR, optical interrogation of neural systems using
light-sensitive ion channels, the development of adeno-associated viruses for
rapid introduction of genetic material, etc. In the coming decades the
combination of such clever hacks with cheaper automation and sensors will
hopefully bring a flood of new data that will make a predictive, quantitative
science of biology possible.

With cheap and plentiful data, perhaps clever minds might discover general
quantitative principles that we can't see yet. But the data is what's lacking,
not cleverness.

~~~
TisButMe
While I absolutely agree with the need for cheaper way to obtain data, I don't
think this is the major problem we're going to face.

We now have ways of obtaining mountains of data (RNA-chIP comes to mind, but
high-speed sequencing is a big one as well), but we don't know how to process
it. We end up with thousands of candidate proteins, but then someone has to go
through them one by one. Things are incredibly primitive. The huge pain point
coming up is our ability to process information, which is very limited. How do
you deal with machine generating TBs of data/day ?

I think what's lacking is a culture of automation. Physicists do it, chemists
do it, but biologists still do everything "by hand", and not only is that
imprecise, is also slow and costly. We also need better ways of obtaining
information about other's work. When there are 1000 paper a year published on
your subject, how do you filter ? How do you even find the time to read papers
in other subjects, which could be interesting in their methods, or just for
general intuition and knowledge ?

What we need is good algorithms, able to replace curate our sources of
information well, and machines able to do the bulk-processing now needed in
biology. Some things are coming up (I'm co-founding a start-up to do exactly
this), but it should have happened 10 years ago.

~~~
daemonk
We have ways of obtaining mountains of sequencing data that represents only a
single dimension of an unknown system. While, it is a step in the right
direction, this data by itself is still lacking. It's like trying to model the
trajectory of a bouncing ball with extremely high resolution X coordinates,
but horrible Y and Z coordinate data.

I've been working with sequencing data for the past 5 years. The problem
really isn't with how to interpret the data, it is that the data itself sucks
because it's extremely myopic.

And yes, there are people who are trying to analyze the various *-seq methods
holistically. But I haven't really seen anything substantial coming out of it.

------
tokenadult
In what sense is Charles Darwin not that person for biology? (I looked up the
author of the short essay post submitted here, and it appears that his career
has been devoted to nonbiological technology. I wonder what analogies from
mathematics and electronics he is using to think about biology, perhaps
without having looked at what the theoreticians of biology have had to explain
in biological data?)

~~~
danieltillett
Darwin is that person since he discovered the only universal principle in
biology. There is no more universal biological concepts to discover since
evolution by natural selection makes universal properties impossible.

~~~
pvaldes
Of course not, the fact that all known living things have DNA or RNA (and that
this translates to proteins) is another universal biological concept for
example.

Another is that the live is carbon based

Concepts like ecosystem or the nature of predation are also universal.

~~~
danieltillett
These things are not universals. Let's take the fact that all living things
have DNA or RNA. We know that the first living thing did not have DNA and RNA.
The only reason that it is believed that all living things have DNA/RNA is
that this is how we look for new life - we say that something is alive if it
has RNA/DNA. For example, if some of the early life that did not use RNA/DNA
was still around we would not know since we would not recognise it as life.

~~~
pvaldes
A chemical reaction is not a life form, by definition. You can found sodium or
gold atoms in a lot of life forms playing essential roles to keep this things
alive for some more time; but if you dissolve salt in water you are not
killing some salt people.

There is not a single exception known until today by the human race so, do not
lie to yourself, those concepts are absolutely universal (right now).

Moreover if any slime or rock was really a early life form we should be able
to recognised as that, since many years ago, for sure. A gold necklace that
will create more gold or gain mass with time would not have gone unnoticed,
neither a limestone rock growing and taking the form of the drawer that
contains it.

Finally, an early form of life that did not use RNA/DNA in earth will be
contaminated with RNA/DNA of its parasites or symbionts after a few thousands
of years. The ecology predict this.

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thinkpad20
I'm wondering why the "at least a Hilbert" is thrown in there. His name
doesn't appear anywhere else in the article, and the wording suggests that
Hilbert is some sort of poor-man's Grothendieck, which is an association I'm
failing to make.

~~~
jeffreyrogers
Hilbert wanted to establish mathematics on a firm foundation because a number
of paradoxes suggested that the current foundations was faulty (Russell's
paradox being one, there are others that I can't remember as well).

Basically Hilbert wanted to find a list of axioms from which all of
mathematics could be derived and then prove that these axioms were consistent,
i.e., that you can't create two contradicting statements from them.

But then Gödel showed with his incompleteness theorems that this wasn't
possible.

So I guess the author was suggesting that biology have a firm, axiomatic
basis?

~~~
Retra
The reference to Grothendieck and Hilbert don't seem to be about establishing
something like an 'axiomatic basis', but about having a leader who can
organize a platform of modernization in the field. They both lead programs.
That's about as far as the thinking goes on that one, I suspect.

------
kevin_thibedeau
Biology is based on complex interactions among proteins and genetic material.
There is no way to construct generalities about such systems that bypass
careful observation of their inner workings. Just look at how long it took to
discover DNA after the discovery of heritable traits. You can't hand wave your
way around knowing how these molecules are assembled and transcribed.

Mathematics is an invented tool that can be arbitrarily defined to suit a
problem space. There will never be a Grothendieck of biology because the
mechanisms of life aren't so neat and ordered that they can reduced to first
principles.

~~~
zxcdw
> There will never be a Grothendieck of biology because the mechanisms of life
> aren't so neat and ordered that they can reduced to first principles.

Let us simulate the universe and let that simulation be the ruleset for the
first principles.

Not saying it's going to be neat and ordered, but on the other hand, the idea
of it surely is. Whether or not it is ever feasible (or even theoretically
possible) to do so doesn't take away from the merits of the _idea_ , I think.

------
danieltillett
Such a person in biology is impossible. Biology does not have any underlying
common principles other than evolution by natural selection.

~~~
dnautics
Actually it does, and that principle is called chemistry.

~~~
ajcarpy2005
And feedback loops. Actually feedback loops are arguably more important for
living organisms than DNA because life could conceivably store its
'blueprints' in some other fashion but in order to survive in changing
environments through adaptations, it's crucial that there be feedback loops.

------
orf
What gets me about this is that a single misplaced bomb during WW2 would have
stopped these discoveries, and he would have just been another casualty
statistic. It makes you think about what advances other misplaced (or well
placed) bombs have prevented.

------
akulesa
Original author here - I just discovered this thread. Thanks so much for all
the comments!

Some context behind why I wrote this post: as a researcher and technologist in
biology, I've realized that it's unclear to me what the real questions are;
that this lack of clarity is not due to my immaturity; and the field seems
dangerously aimless.

>99% of the time, work is justified (and finished) with some application to
health and medicine, with little regard for theory building or true
understanding of a system. Bringing up this point usually solicits two
responses: 1) we don't have enough data yet 2) there's little use for theory
in biology. I hope I can give more in depth responses where I see these themes
in other comments, but I'll generalize my thoughts here.

First, how do we judge what questions are worth asking and researching, vs
trivial details? How do we even know whether we understand whether a question
has been adequately answered? The current state of research to me often seems
like John Searle's Chinese Room: we just generate a huge dictionary of
perturbation-responses and call this "understanding". This might be effective
to find drug targets, but is it real understanding? It might be the first
step, but it seems to me that we're swimming in plenty of data already and
it's worth it to step back and try to figure out what what it is we are
actually trying to do. I'm comfortable with the fact that answers to our
questions might be a long ways off, but it's scary that no one seems to care
that we don't even know what the questions are.

Second, I'd argue biology has historically been very theoretical. We developed
a whole quantitative theory of genetics (Fisher, Wright, Haldane, ...) before
we had identified what a gene actually was. Hell, it was still debated what
matter even looked like at that the microscale (where we knew genes must
exist)! In the advent of molecular biology, Watson, Crick, Brenner, Gamow,
Delbruck, et al, predicted through (some) experiments but mostly reasoning and
conjecture much of what was later found to be true about
transcription/translation. There are countless other examples of where theory
has driven the study of the origin of life, molecular biology, ecology, et
cetera. Only recently, when health science started to dominate biological
research, did biology become less theoretical and more focused on individual
instances of problems.

tl;dr - What's most scary is that we don't even know what the foundational
questions are anymore for modern biology, and no one seems to even care.
Rather than focusing on clearly stated foundations, the field is guided by the
latest trends in glamour journals, which tend to obfuscate questions rather
than answer them.

------
graycat
I nominate Eric Lander.

~~~
graycat
Gee, Lander was first a mathematician.

His lectures on biology at MIT are on YouTube and are a lot of fun. He's
really charging ahead.

------
reasonattlm
Missing the trees for the forest. We already have exactly what the article is
calling for in biology, and it is called chemistry.

~~~
dnautics
I sympathize with the sentiment, but biology is not a _simple_ reduction to
chemistry (although chemical principles do undergird it, and it is useful to
describe biology in terms of chemistry as often as possible)

Nonetheless it is appalling how little chemistry biologists know. We were
having a dna shearing issue in our lab, and I once asked, "what is the
chemical mechanism of shearing" and no one could provide a convincing
mechanism, which meant their solutions to the problem were not much better
than shamanism.

It's even worse with the faddish worship of interdisciplinary-ism... Basically
chemical biology (versus the more classical field of biochemistry, which is
deep) is littered with dilettantes who were neither good enough to do straight
chemistry nor deeply knowledgeable about biology.

If there will be a grothendieck or a Hilbert in biology, that person will
almost certainly have to have some amount real chemistry training, and also
deep chemistry knowledge. Probably training in information theory is important
too.

In my view, physics is the study of the universe focused through the lens on
energetic state functions, with a reductionist bent, chemistry is the study of
the universe focused mostly on the diversity of matter with a passing nod to
path dependence, and biology is the study of self-organizing information
propagation with a strong acknowldgement of path dependence.

~~~
akulesa
Totally agreed - I might steal your last paragraph there!

Chemistry is "the details" of biology, but it tells us next to nothing about
what we actually care about, probably what you called "self-organizing
information propagation" .

I think good definition for life shouldn't include any dependence on the
chemistry used to manifest it. Agreed?

~~~
dnautics
yeah, it is just a broad stroke characterization of the feels of each field.
Some types of particle physicists would be probably be reclassified as
chemists under my scheme, which they would bristle at, although in all honesty
they are inheritors of a long line of tradition that goes through the
indisputably chemist lavoisier, berzelius, and curie - more than they are
newton or maxwell, planck, or einstein.

