364 lines
18 KiB
TeX
364 lines
18 KiB
TeX
\chapter{A Deal with Life}
|
||
\begin{refsection}[bib/sivanov-dblp-mod.bib,bib/sivanov-extra.bib,bib/dealb.bib]
|
||
|
||
Life is one of the most beautiful things in the universe. Arguably,
|
||
it is because we humans belong to the kingdom of Life that it
|
||
fascinates us so. Beyond its intrinsic beauty to which our sensory
|
||
organs are attuned, it also deeply attracts us because of the
|
||
self-referentiality of its contemplation: when thinking about Life, we
|
||
often think about our interactions with it, and ultimately
|
||
about ourselves.
|
||
|
||
Self-referentiality is also a hurdle: it is intrinsically difficult to
|
||
conceive of oneself. Even though theoretical computer science is no
|
||
substitute for philosophy, I enjoy taking Gödel's incompleteness
|
||
theorems\footnote{\url{https://en.wikipedia.org/wiki/Gödel's_incompleteness_theorems}}
|
||
and especially Hilbert's
|
||
\emph{Entscheidungsproblem}\footnote{\url{https://en.wikipedia.org/wiki/Entscheidungsproblem}}
|
||
and the halting
|
||
problem\footnote{\url{https://en.wikipedia.org/wiki/Halting_problem}}
|
||
as vivid examples: Turing's famous proof states that a Turing machine
|
||
cannot generally decide whether another Turing machine will ever halt.
|
||
Since abstract computing devices can be seen as distant
|
||
mathematizations of the human brain, this formal result hints that
|
||
entirely conceiving of our mind---and by extension of Life itself---is
|
||
borderline intractable.
|
||
|
||
The difficulty of self-referiantiality is also deeply disturbing,
|
||
especially because understanding how our bodies function within their
|
||
environments has so many essential implications: dealing with the
|
||
climate crisis, tackling diseases, improving the quality of life, to
|
||
only cite the foremost ones. To avoid the worry of looking into the
|
||
mirror for too long, one can brutally build a wall between oneself and
|
||
``the rest'' of Life, and adopt what may be called the Engineer's
|
||
position: a living organism is a machine constituted out of mechanical
|
||
pieces, whilst the human disassembles, adjusts, and reassembles them
|
||
again, improved.
|
||
|
||
Modern biology, medicine, biotechnology illustrate the high
|
||
performance of the Engineer's approach, and this text is not
|
||
a criticism of mechanicism per se. Nevertheless, its efficiency does
|
||
not entail total truthfulness, nor even exclusivity about truth.
|
||
In other words, mechanistic views allowing for impressive technical
|
||
achievements does not mean that these views fully reflect reality, nor
|
||
that mechanicism is the final stop on our journey to understanding
|
||
Life. In my research, I aim for exploring different approaches to
|
||
Life and tools supporting such approaches. I take particular
|
||
enthusiasm in thinking about striking \emph{a deal with Life}:
|
||
establishing \emph{mutually beneficial} interactions with living
|
||
systems.
|
||
|
||
Concluding deals as opposed to taking the Engineer's position resets
|
||
the power balance in our relationship with Life: instead of seeking to
|
||
control, hack, or otherwise dominate living organisms, the goal is to
|
||
further take into account their well-being. I believe that
|
||
approaching Life from this viewpoint is essential if we are after true
|
||
solutions to fundamental problems such as the climate crisis or
|
||
complex diseases. On a more philosophical note, the framework of
|
||
mutually beneficial interactions should remind us that our
|
||
intelligence in no way warrants an extraction of the human being into
|
||
an exceptional superior stance---we are part of Life, and we ought to
|
||
think and act accordingly.
|
||
|
||
\newpage
|
||
|
||
\section{Mechanicism: Where engineering meets biology}
|
||
\label{sec:mechanicism}
|
||
|
||
In the 20th century, biology was dramatically affected by physics and
|
||
engineering, and this has brought revolutionary advances in
|
||
understanding Life and interaction with
|
||
it~\cite{CornishBowdenCLSA2007,Glade22,Nicholson2019,Woese2004}.
|
||
Grounding the function of biological structures in the physical
|
||
reality allowed for convergence of worldview between physics and
|
||
biology, thereby conferring to the latter the gravitas of a ``real''
|
||
science. A remarkable tool physics and engineering brought to biology
|
||
is reductionism---to understand a system, decompose it into parts,
|
||
understand each of the parts, and understand the interactions between
|
||
the parts to get back to the big picture. Reductionism in turn
|
||
fostered the emergence of mechanicism, the modern proponents of which
|
||
``conceive of the cell as an intricate piece of machinery whose
|
||
organization reflects a pre-existing design, whose structure is wholly
|
||
intelligible in reductionistic terms, and whose operation is governed
|
||
by deterministic laws, rendering its behaviour predictable and
|
||
controllable—at least in principle.''\cite{Nicholson2019}
|
||
|
||
With all due recognition of the major advances yielded by reductionism
|
||
and mechanicism, it appears hard to believe that this is the final
|
||
stop on the way to understanding Life. I recall first of all the
|
||
discussion in~\cite[page~2]{Woese2004} of reductionism as an
|
||
operational tool allowing to tackle complexity (empirical
|
||
reductionism), as opposed to the belief that it actually corresponds
|
||
to the organization of the living matter (fundamental reductionism).
|
||
Fundamental reductionism makes therefore an additional strong
|
||
assumption, which impacts the ``sense of what is important'':
|
||
molecular biology established the molecular level as fundamental, and
|
||
demoted the status of larger structures---e.g. organisms, ecosystems,
|
||
etc. These are deemed emergent, and therefore less important,
|
||
secondary, directly derivable from more fundamental matters.
|
||
|
||
While the notion of emergence in natural sciences is fraught, and its
|
||
objective qualities can be debated (e.g.~\cite{RonaldSC99}), it has
|
||
the merit of putting in focus the hierarchy of scales. It is
|
||
a hierarchy in the sense that, while physics teaches us that the whole
|
||
is always necessarily the sum of its parts (plus the interactions), it
|
||
is often irrelevant to put the whole away, and only peer at the
|
||
components. It is therefore important to not always fall through to
|
||
the underlying levels, and specifically to avoid Laplace's daemon
|
||
abuse: the Laplace's daemon\footnote{Laplace's daemon is a thought
|
||
experiment introducing an imaginary creature which knows exactly the
|
||
positions and momenta of every atom in the universe. The original
|
||
conclusion conceived by of Pierre-Simon Laplace in 1814 is that this
|
||
absolute knowledge should entail full knowledge of past and future
|
||
positions of these particles~\cite{wikiLaplace}. In modern days,
|
||
Laplace's daemon is often used as a metaphor for absolute knowledge
|
||
of the minutae of a complex system, down to its elementary
|
||
particles.} cannot practically exist, but should it exist, it would
|
||
in no way have any influence on the fact that we as humans find it
|
||
extremely useful to operate with concepts situated at higher
|
||
scales\footnote{An informal inspiration for these observations comes
|
||
from~\cite{Carroll}.}. It is physics again, and statistical
|
||
mechanics in particular, that recalls this saliently by deeply relying
|
||
upon thinking about systems such as gasses in terms of macrostates
|
||
(volume, pressure, temperature) and microstates (positions and momenta
|
||
of all particles)~\cite{SusskindCourse,wikiEntropy}. In other words,
|
||
while one might argue that microstates are more ``fundamental'' in
|
||
some way, it is of little practical importance, and addressing
|
||
multiple scales is still pertinent.
|
||
|
||
Fundamental reductionism as a belief is strongly related to
|
||
engineering, and specifically the practice of constructing complex
|
||
structures and mechanisms out of simpler building blocks.
|
||
The multiple ways in which engineering has been durably changing our
|
||
lives and our surroundings naturally fuels extending its reach beyond
|
||
human creation, onto living matter. A spectacular manifestation is
|
||
the Machine Conception of the Cell (MCC) as introduced
|
||
in~\cite{Nicholson2019}: the cell is seen as an intricate machine,
|
||
somewhat similar to a computer, which makes it appropriate to use
|
||
engineering terms to designate the cellular components visible by
|
||
microscopy: molecular motors, Golgi apparatus, genetic program, pumps,
|
||
locks, keys, gates, circuitry, etc. The choice of terms is in
|
||
principle contingent, and it is natural to use words evoking familiar
|
||
structures, but in practice this reinforces the belief in the
|
||
truthfulness of the engineering approach. Indeed, scientific papers
|
||
ubiquitously summarize knowledge in the form of circuits or maps.
|
||
As stated in~\cite[page~6]{Mayer2009}, ``the typical ‘cartoons’ of
|
||
signaling pathways, with their reassuring arrows and limited number of
|
||
states [...] could be the real villain of the piece.'' The Wikipedia
|
||
page on molecular motors literally starts with the sentence
|
||
``Molecular motors are [...] molecular
|
||
\emph{machines}''\cite{wikiMotors} (the emphasis is mine), and
|
||
features several animations which would look appropriate in a book on
|
||
the construction of mechanical toys. The last illustration---and
|
||
probably the most verbose---of the relationship between reductionism
|
||
and the Engineer's work I bring here is the very term
|
||
``biological engineering''.
|
||
|
||
In fact, widely admitted considerations easily uncover some flaws in
|
||
the belief in the fundamental nature of the MCC~\cite{Nicholson2019}.
|
||
To cite two of the most salient ones, the cell is a milieu which is
|
||
better described as liquid, rather than solid. It is densely packed
|
||
with various molecules, which do not always strictly respect a certain
|
||
conformation, but rather continuously evolve across a spectrum of
|
||
shapes. It being impossible for a human to observe the cellular
|
||
processes with the naked eye, the researcher is tempted to follow the
|
||
mindset suggested by the available technology conceived for conceiving
|
||
of and observing microscopic machines~\cite{Glade22}, a mindset which
|
||
also happens to be mainstream. Unsurprisingly, if one looks for
|
||
machines, one finds machines, as the animation ``The Inner Life of the
|
||
Cell'' conveniently illustrates~\cite{lifeOfTheCell}.
|
||
|
||
Avoiding conceptual frameworks other than fundamental reductionism and
|
||
mechanicism not only forces our thinking into a certain box which
|
||
partially corresponds to reality, but also biases our methodology of
|
||
interactions with Life. When one imagines the cell as a machine, one
|
||
expects mechanistic explanations, building upon strong causality.
|
||
When the computer screen shows a picture or a car modifies its
|
||
trajectory, it is always possible to indicate a satisfactory set of
|
||
causes. This is because the engineers who built the device had
|
||
a specific intention in mind, which can be relatively easily unpacked.
|
||
Biological systems originated from spontaneous evolution, without
|
||
anyone human baking in specific goals, implying that causality is much
|
||
harder to establish convincingly. Yet, reductionism and mechanicism
|
||
tempt the researches to only look for correlations which may be
|
||
interpreted as causal: ``It is much easier to write and publish
|
||
a paper suggesting Protein X is necessary for transmitting a signal
|
||
from A to B, than one showing that Protein X is one of many potential
|
||
components of a heterogeneous ensemble of signaling complexes that
|
||
together couple A to B.''~\cite{Mayer2009}.
|
||
|
||
While the Machine Conception of the Cell and similar mechanistic
|
||
points of view are not oblivious to the intrinsic noise of the
|
||
respective biological systems, seeing them as machines invites to
|
||
treating noise as a nuisance which the biological systems manage to
|
||
successfully combat in every moment of their existence. However,
|
||
multiple indications exist that noise plays an essential role, as
|
||
a matter of fact making some processes possible. We cite as an
|
||
example the Brownian ratchet model of intracellular transport, which
|
||
has been gaining considerable traction recently~\cite{Nicholson2019},
|
||
and which essentially consists in hypothesising that molecular motors
|
||
feature two distinct conformations of the energy landscape---a flat
|
||
one and a saw-toothed one. By periodically switching between the two,
|
||
the motor buffeted by thermal fluctuations will tend to advance along
|
||
the cytoskeletal track it is attached to
|
||
(Figure~\ref{fig:ratchet-motor}).
|
||
|
||
\begin{figure}
|
||
\centering
|
||
|
||
\tikzstyle axis=[->]
|
||
\tikzstyle movement=[-{Latex[width=1.2mm]},semithick]
|
||
\tikzstyle landscape=[very thick,cap=round]
|
||
\tikzstyle motor=[draw,circle,thick,minimum size=3.5mm]
|
||
\tikzstyle motorFlip=[motor]
|
||
\tikzstyle motorFlop=[motor,fill=black!40]
|
||
\tikzstyle motorGhost=[motor,densely dotted]
|
||
\newcommand{\landscapeXOff}{.2mm}
|
||
\newcommand{\landscapeYOff}{1mm}
|
||
\newcommand{\xLength}{56mm}
|
||
\newcommand{\yLength}{11mm}
|
||
\newcommand{\graphSkip}{\vspace{-3mm}}
|
||
\newcommand{\stepLabOff}{-7mm}
|
||
\begin{tikzpicture}
|
||
\draw[axis] (0,0) --
|
||
node[midway,xshift=\stepLabOff,minimum width=7mm] {\small (1)}
|
||
(0,\yLength)
|
||
node[xshift=3mm] {$U$};
|
||
\draw[axis] (0,0) -- (\xLength, 0) node[yshift=-2mm,xshift=-1mm] {$x$};
|
||
\draw[landscape] (\landscapeXOff,\landscapeYOff) -- +(52mm,0);
|
||
|
||
\node[motorFlip] (motor) at (11mm,3mm) {};
|
||
\node[motorGhost] at ($(motor)-(3.5mm,0)$) {};
|
||
\node[motorGhost] at ($(motor)-(6mm,0)$) {};
|
||
\node[motorGhost] at ($(motor)+(3.5mm,0)$) {};
|
||
\node[motorGhost] at ($(motor)+(6mm,0)$) {};
|
||
|
||
\coordinate[above=2mm of motor] (arrowAnchor);
|
||
\draw[movement] ($(arrowAnchor)-(2mm,0)$) -- +(-6mm,0);
|
||
\draw[movement] ($(arrowAnchor)+(2mm,0)$) -- +(6mm,0);
|
||
\end{tikzpicture}
|
||
|
||
\graphSkip
|
||
|
||
\begin{tikzpicture}
|
||
\draw[axis] (0,0) --
|
||
node[midway,xshift=\stepLabOff,minimum width=7mm] {\small (2)}
|
||
(0,\yLength)
|
||
node[xshift=3mm] {$U$};
|
||
\draw[axis] (0,0) -- (\xLength, 0) node[yshift=-2mm,xshift=-1mm] {$x$};
|
||
\draw[landscape] (\landscapeXOff,\landscapeYOff)
|
||
-- ++(2mm,5mm) -- ++(11mm,-5mm)
|
||
-- ++(2mm,5mm) -- ++(11mm,-5mm)
|
||
-- ++(2mm,5mm) -- ++(11mm,-5mm)
|
||
-- ++(2mm,5mm) -- ++(11mm,-5mm);
|
||
|
||
\node[motorFlop] (motor) at (25.2mm,3.7mm) {};
|
||
\coordinate[above=2mm of motor] (arrowAnchor);
|
||
\draw[movement] ($(arrowAnchor)-(2mm,0)$) -- +(-4.5mm,0);
|
||
\draw[movement] ($(arrowAnchor)+(2mm,0)$) -- +(9mm,0);
|
||
\end{tikzpicture}
|
||
|
||
\graphSkip
|
||
|
||
\begin{tikzpicture}
|
||
\draw[axis] (0,0) --
|
||
node[midway,xshift=\stepLabOff,minimum width=7mm] {\small (3)}
|
||
(0,\yLength)
|
||
node[xshift=3mm] {$U$};
|
||
\draw[axis] (0,0) -- (\xLength, 0) node[yshift=-2mm,xshift=-1mm] {$x$};
|
||
\draw[landscape] (\landscapeXOff,\landscapeYOff) -- +(52mm,0);
|
||
|
||
\node[motorFlip] (motor) at (25.2mm,3mm) {};
|
||
\node[motorGhost] at ($(motor)-(3.5mm,0)$) {};
|
||
\node[motorGhost] at ($(motor)-(6mm,0)$) {};
|
||
\node[motorGhost] at ($(motor)+(3.5mm,0)$) {};
|
||
\node[motorGhost] at ($(motor)+(6mm,0)$) {};
|
||
|
||
\coordinate[above=2mm of motor] (arrowAnchor);
|
||
\draw[movement] ($(arrowAnchor)-(2mm,0)$) -- +(-6mm,0);
|
||
\draw[movement] ($(arrowAnchor)+(2mm,0)$) -- +(6mm,0);
|
||
\end{tikzpicture}
|
||
|
||
\graphSkip
|
||
|
||
\begin{tikzpicture}
|
||
\draw[axis] (0,0) --
|
||
node[midway,xshift=\stepLabOff,minimum width=7mm] {\small (4)}
|
||
(0,\yLength)
|
||
node[xshift=3mm] {$U$};
|
||
\draw[axis] (0,0) -- (\xLength, 0) node[yshift=-2mm,xshift=-1mm] {$x$};
|
||
\draw[landscape] (\landscapeXOff,\landscapeYOff)
|
||
-- ++(2mm,5mm) -- ++(11mm,-5mm)
|
||
-- ++(2mm,5mm) -- ++(11mm,-5mm)
|
||
-- ++(2mm,5mm) -- ++(11mm,-5mm)
|
||
-- ++(2mm,5mm) -- ++(11mm,-5mm);
|
||
|
||
\node[motorFlop] (motor) at (38.2mm,3.7mm) {};
|
||
\coordinate[above=2mm of motor] (arrowAnchor);
|
||
\draw[movement] ($(arrowAnchor)-(2mm,0)$) -- +(-4.5mm,0);
|
||
\draw[movement] ($(arrowAnchor)+(2mm,0)$) -- +(9mm,0);
|
||
\end{tikzpicture}
|
||
|
||
\caption{A schematic illustration of the Brownian ratchet model of
|
||
molecular motors. A motor is shown as a circle
|
||
(\protect\tikz[baseline,yshift=1.2mm]\protect\node[motorFlip,minimum
|
||
size=2.5mm]{}; or
|
||
\protect\tikz[baseline,yshift=1.2mm]\protect\node[motorFlop,minimum
|
||
size=2.5mm]{};), and its energy landscape is shown as a thick line
|
||
\protect\tikz[baseline,yshift=.2em]\protect\draw[landscape]
|
||
(0,0) -- (2ex,0);. The horizontal axis $x$ represents the motor's
|
||
position on the cytoskeletal track, while the vertical axis $U$
|
||
illustrates the motor's free energy. The motor is hypothesized to
|
||
feature two distinct potential energy landscapes, depending on its
|
||
conformational state. In the flip conformation
|
||
\protect\tikz[baseline,yshift=1.2mm]\protect\node[motorFlip,minimum
|
||
size=2.5mm]{};, the energy landscape is flat so the protein may
|
||
slide freely in one of the two directions, with equal probability
|
||
for both directions. In the flop conformation
|
||
\protect\tikz[baseline,yshift=1.2mm]\protect\node[motorFlop,minimum
|
||
size=2.5mm]{};, the saw-tooth shape of the landscape favors the
|
||
motor moving to the right, illustrated by a longer arrow pointing
|
||
to the right. When cycles of ATP hydrolysis make the motor
|
||
periodically switch between the two conformations, thermal
|
||
fluctuations will tend to push it to the right. (The original
|
||
figure is~\cite[Figure~4]{Nicholson2019}, itself a reproduction
|
||
from~\cite{Kurakin2006}.)}
|
||
\label{fig:ratchet-motor}
|
||
\end{figure}
|
||
|
||
\section{A Deal: Mutually beneficial interactions}
|
||
\label{sec:deals}
|
||
|
||
Seeing Life as an ensemble of machines biases how we expect to collect
|
||
profit from acting on it. Machine means control: we are constantly
|
||
looking for knobs which we could turn this or that way, and which
|
||
could modify the behavior of the system to fit our needs and
|
||
expectations. This can be seen both at the very practical level,
|
||
where bioengineers seek to modify bacteria to produce chemicals,
|
||
e.g.~\cite{berkleyBio}, and also at the theoretical level, where
|
||
researchers develop methodologies to support looking for the coveted
|
||
knobs, e.g.~\cite{PardoID21,Vogel2008,Zanudo2015}. If we admit that
|
||
the reductionistic and mechanistic approach is not globally true, we
|
||
must accept that these knobs may not necessarily have a definitive
|
||
shape, but rather be a complex assemblage of factors, affecting the
|
||
trajectory of the system in multiple non-trivial ways, and possibly
|
||
shifting in time. Finally, this control mindset introduces an
|
||
asymmetric relationship between the controller and the controlled,
|
||
which is unnatural biological context because both the controller and
|
||
the controlled are made out of the same kind of matter, and are
|
||
ultimately embedded in the same environment.
|
||
of a Deal with Life is to render the interactions \emph{mutually
|
||
beneficial}: ideally, both systems engaging in the interaction
|
||
should benefit from it. In practice, this should be translated into
|
||
joint maximization of a pair of functions measuring the utility of the
|
||
interaction for both parties, possibly with one of the two functions
|
||
being prioritized over the other.
|
||
|
||
\printbibliography[heading=subbibliography]
|
||
|
||
\end{refsection}
|
||
|
||
%%% Local Variables:
|
||
%%% TeX-engine: luatex
|
||
%%% TeX-master: "hdr"
|
||
%%% End:
|