BionAlexHoward11.

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The fractal network information systems theory of molecular biology
Bion Howard, Russell Hanson, and Zihai Li
Life and death are one thread, the same line viewed from different sides. - Lao Tzu
My goal in this essay is to describe the name and mental image I use when thinking about
the clear interconnectedness we all feel upon considering the Life on Earth, and show that this
viewpoint could be useful for the future of medicine. What happens when a node in a network is
not a node, but a network in itself? What do we see when we zoom into the tree of Life, deeper
than the organism-scale network proposed by Darwin? (1) We see that Life is a
fractal network of
information systems
. What is a
fractal network
? Networks are simply understood as webs of
things that interact, and information systems are networks of the combinatorial probabilities of
causes and effects. Even if the Universe is fully deterministic, we have no choice but to account for
our uncertainties with probability: we are agents with limited knowledge. As described by Benoit
Mandelbrot, (2) fractal geometry shows the complex emergent results of simpler processes,
endlessly iterated. A key property of fractals is
self-similarity
; fractal objects appear the same
regardless of the scale on which they are viewed. So, a fractal system or fractal network is a group
of interconnected pieces, where each piece is a network of sub-pieces which is a network of
sub-sub-pieces in turn, and so on. A long-winded explanation of biology shows the
communication of information (a procession of causality) on many scales of space and time:
ecosystems involve sets of interacting, evolving populations which are made of organisms which
are made of organs which are made of cells which have organelles which are made of molecules
which are networks of atoms which are made of particles. Life must be a fractal process, because it
exemplifies self-similarity. For example, feedforward and feedback control motifs are found in
political dynamics, macroscale neural and microscale cellular networks. Life is not just a set of
individuals;
it is a singular, multi-scale, whirring,
LIFE
,
vastly spread across space and time
.
We
think we rule the world as powerful individuals, and yet we are the intermediate products of a
single [stochastic] biochemical reaction, if you zoom out far enough. We feel innately connected to
trees we are trees; trees, cells, brains, and social structures are all networks, and they are
networked together in turn.
There is a practicality to fracticality: it helps explains why biology and medicine can be so frustratingly
[over]complicated:
emergent linguistic complexity. Each human is a single tree on the beautiful tree of trees of trees, and we
are trying to name and categorize and remember the countless components of numerous networks on several scales. We are
the leaves memorizing the tree. True fractals have essentially infinite complexity; why try to fit into one leaf the labels of every
leaf in a tree with infinite branches? Lets make Medicine and Life less about Proper Nouns and more about Mechanisms. No
wonder a multiscale fractal naming process results in a dizzying array of names and acronyms! Good luck getting that to fit
entirely in your brain. Perhaps instead,
simplicity can cure our medical complexity problem. Combination therapies are
clearly important to investigate, but we might use fewer nanobiotech tools to modularly treat diverse diseases. I wish the
answer was, DIAMONDOID NANOROBOTS! as described by Freitas, (3) but nanomanufacturing remains difficult, and
Illness doesnt wait around for our inventions. Viruses, if armed and conditionally functional, will be very useful, but are
nonmotile and built of
immunogenic proteins, potentially causing reduced duration and effect. Nanoparticles have huge
potential for safety and computation
in vivo
, (24, 25) but are also nonmotile and dont replicate. [Yet.] Bacteria move around
and replicate, but have immunogenic proteins, just like viruses. Therefore, the ideal treatment for many human diseases is
probably human cells: they move, exist, and replicate, they can be patient-specific and thus less likely to be rejected, and they
can perform complicated functions and persist for decades, moving to specific places in the body and conditionally producing
viruses, enzymes, antibodies, etc in exactly the right place at the right time. We need not limit ourselves to natural cell types;
we should combine the useful traits of different cell types and build swiss-army-knife cells. A cell is a cell is a cell, despite
details of differentiation. My personal favorite cell type for medical use is the Macrophage, the big eater, because
phagocytosis, or eating, of cells and debris feels like a useful phenotype to engineer for medical purposes. How many diseases
could we cure with precisely targeted cell killing? Regardless of the chassis, mobile cellular factories might enable new and
precise diagnosis and treatment of numerous diseases like cancer, autoimmunity, chronic pain, amyloidosis, and others.


BionAlexHoward11.14

We can enhance our therapies with careful use of the powerful tools of synthetic biology, such as engineered
receptors, (4, 5) genome editing, (6) and conditional production of biomacromolecules. (7) Chimeric antigen receptors
(CARs) represent a clear example of the power of receptor engineering, and have shown great success in directing T cell
activity in liquid cancers like leukemia. Interestingly, similar intracellular activation motifs called ITAMs are present on
both T cell and macrophage receptors. (8, 9)


BionAlexHoward11.14
We might also find great use for ensembles of synthetic
inhibitory receptors to block unwanted attacks on cells
bearing stop antigens which demarcate crucial bystander organs like brain, heart, liver, kidneys, blood vessels, etc. (10)
Another useful engineered receptor would be
homing receptors directing therapeutic cell movement to specific disease sites.
If the receptors on our cell therapy can be designed properly, the only objects to be phagocytosed should be those expressing
a combination of target-specific antigens and lacking stop antigens. By combining various types of engineered receptors, we
can more precisely control the location and activation of cell therapies.
Genome editing is taking the world by storm
because it enables us to turn on, turn off, and edit
genes. The most advanced such tool is called
CRISPR/Cas9. This bacterial antiviral defense system
is
powerful because it is modular: a protein binds a
target-DNA-specific guide RNA (gRNA), which guides
the
protein to the matching sequence of DNA, and then
makes a double-stranded nuclease cut or a
single-stranded nickase cut. A double-strand cut will
induce a targeted insertion-deletion (indel) mutation
when
it is repaired via the process of
non-homologous end
joining
, leading to a disabling frameshift of the codons
of
desired genes. The nickase enzyme, with a deactivation of one of the RuvC or HNH active sites, has the advantage that a full
double-strand cut requires a pair of gRNAs binding close together, thus preventing off-target mutations; however this nickase
technique is slightly more difficult and expensive because of the requirement for multiple gRNA to direct multiple nicks in the
genome. To turn ON a gene, we can mutate both of the cutting sites to create a defective enzyme, and then fuse the activation
domain from a transcription factor to the Cas9 protein to create a CRISPR-ON. If we give this CRISPR-ON a gRNA
corresponding to the promoter sequence upstream of a desired gene, it will activate the gene by functioning as a synthetic
transcription factor. Finally, to specifically insert into (or edit) genomes, we can use
homology directed repair whereby, in
addition to CRISPR, we also insert a template DNA sequence with flanking sequences matching the ends of the
double-stranded break. (11, 12) This template enables the cell to repair the cut by inserting the template DNA between the
flanking sequences instead of causing an indel mutation. Another good method for inserting genes is to use a stable episome
vector called an
S/MAR minicircle
, (13) which is sort of like a bacterial plasmid except we use the CRE recombinase system to
chop out all of the bacterial bits and increase its compatibility with human cells, and we include a sequence called the S/MAR
which helps hold the vector in a safe place within the nucleus over long timescales. We might use cas9 systems to activate
stemness genes (so therapies last longer) and deactivate genes of tumor immunosuppression (so therapies keep working
within an immunosuppressive solid tumor microenvironment).
Since we can make cells move around and specifically grab onto targets with receptors and edit their genomes with
cas9, the next big goal should be to turn cells into factories producing therapeutics in exactly the right places. One option is to
program cells to secrete [multiple] soluble antibodies linking target antigens to macrophage Fc receptors, enabling cell
therapies which programmably devour many different pathogenic materials in many different diseases (cancer cells,
extracellular junk, autoimmune T-cells, etc). Besides antibodies, it should also be possible to secrete enzymes metabolizing
-8
pathogenic molecules only in areas where the pathogen concentration is high enough to activate low-affinity (k
)
d<
10
synthetic receptors. (14) One of the most powerful possible payloads is the virus: by hiding them within patients cells, we
can enable viruses to evade immune destruction in the bloodstream. (15) By implementing this carrier idea alongside
combinatorial logic by both carrier receptors and viral DNA, we might solve the vector problem of gene therapy and enable
genetic engineering for a wide range of situations...chronic pain, obesity, ageing, regeneration, photosynthesis, even tentacles.
Considering these epic bio/nano possibilities in light of simultaneous revolutions in 3D printing, neurotech, aerospace,
electronics, materials, energy, statistics, A.I., and botany, the future will clearly be interesting. I vote we ought to
open-source
advanced medical technology,
to reduce suffering, and that cell therapy is one of many damn good ways to do it. Immense
change is possible--so lets build the world we want. Lets focus on ambitious translational research and work together to
improve peoples lives and solve medical cost problems with cheaper, more powerful, more precise treatments.
Dedicated to lost friends and big thinkers!


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