Journal of Human Genetics

https://doi.org/10.1038/s10038-020-0813-z

REVIEW ARTICLE

Genes, the brain, and artificial intelligence in evolution

Naoyuki Kamatani1

Received: 3 June 2020 / Revised: 9 July 2020 / Accepted: 19 July 2020

© The Author(s), under exclusive licence to The Japan Society of Human Genetics 2020

Abstract
Three important systems, genes, the brain, and artificial intelligence (especially deep learning) have similar goals, namely,
the maximization of likelihood or minimization of cross-entropy. Animal brains have evolved through predator-prey
interactions in which maximizing survival probability and transmission of genes to offspring were the main objectives.
Coordinate transformation for a rigid body necessary to win predator-prey battles requires a huge amount of matrix
operations in the brain similar to those performed by a powerful GPU. Things (molecules), information (genes), and
energy (ATP) are essential for using Maxwell’s demon model to understand how a living system maintains a low level of
entropy. However, while the history of medicine and biology saw molecular biology and genetics disciplines flourish, the
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study of energy has been limited, despite estimates that >10% all human genes code energy-related proteins. Since there
are a large number of molecular and genetic diseases, many energy-related diseases must exist as well. In addition to
mitochondrial disease, common diseases such as neurodegenerative diseases, muscle diseases, cardiomyopathy, and
diabetes are candidates for diseases related to cellular energy shortage. We are developing ATP enhancer, a drug to treat
such diseases. I predict that in the future, the frontier of medicine and biology will involve energy and entropy, and the
frontier of science will be about the cognitive processes that scientists’ brains use to study mathematics and physics. That
will be understood by comparing the abilities that were necessary to survive battles between predators and prey during
evolutionary history.

Introduction The Big History of genes, the brain, and

Genes, the brain, and artificial intelligence (especially deep
learning) are important systems for understanding how
organisms developed, with differences as well as simila-
rities between them. What is clear, however, is the causal
relationship between the three. In other words, genes led
to development of the brain, and human brains created
artificial intelligence (Fig. 1). The order of development
in evolution also shows that genes emerged first, the brain
next, and finally artificial intelligence. Since artificial
intelligence was originally intended to mimic the brain,
there is an arbitrary component to the similarity between
the two.
* Naoyuki Kamatani
kamatani@msb.biglobe.ne.jp
1
StaGen Co., Ltd., 4-11-6 Kuramae, KUGA Bldg. 8F, Taito-ku,
Tokyo 111-0051, Japan
artificial intelligence
The Big History of genes, the brain, and artificial intelli-
gence, and their relationship to organismic evolution, began
with the formation of the Earth, which occurred about 4.6
billion years ago [1]. Life then started as bacterium or
archaea about 4 billion years ago, which was also when the
system of genes, perhaps using DNA, began [1]. Thereafter,
for about 2 billion years, little evolutionary improvement
occurred, but about 2 billion years ago, bacteria and archaea
underwent an internal symbiosis and acquired a huge
energy-generating ability that led to a rapid increase in the
sophistication of life [2]. Using that enormous energy-
generating capacity, organisms have become nucleated,
multicellular, and acquired sexual reproductive functions
[2]. Then, about 700 million years ago, they acquired sys-
tems of muscles powered by ATP, which efficiently con-
verted chemical energy into kinetic energy [3]. That is,
animals emerged [4]. That allowed organisms to move on
their own, enabling them to acquire food and reproduce
effectively. In order to achieve those movement related
goals, they needed sensory organs that allow for input of

Fig. 1 Three systems of genes, brain and AI have analogous structures
and the objectives are to maximize the probabilities of achieving the
objectives. An arrow indicates a causality and an arrowhead indicates
the direction of an activity
external data [5] and a nervous system that processes the
information obtained from the sensory organs and transmits
it to the muscles [6]. In other words, animals possessed
input devices (sensory organs), information-processing
devices (the brain and nervous system), and output devi-
ces (muscles). This system is, of course, very similar to the
deep-learning algorithm, which has input, an information-
processing system, and output (Fig. 1).
This system has evolved to be more and more efficient
by repeated interactions between predators and prey, which
have led animals to evolve in a direction that maximizes the
probability that the predator would capture the prey and the
probability that the prey would escape from the predator.
This is because components of the system that increase the
probability of success (survival) are selected for and passed
on to future generations. As a result, the brain has evolved
into an extremely sophisticated system in humans, and from
that, sciences such as mathematics and physics have
emerged. Humans subsequently went on to make prototypes
of artificial intelligence that mimicked the brain.
Considering the above steps, it is clear that the three
systems developed in the order of genetic system → brain
system → artificial intelligence, and there is a causal rela-
tionship between them (Fig. 1). The genetic system and the
brain system are likely to have evolved toward maximizing
the probabilities of individual survival and transmission of
the genetic data to offspring (Fig. 1). Then, what principles
are at the basis of the three systems?
Energy and entropy
Schrödinger, the founder of quantum theory, proposed in
his book “What is life?” that living matter evades the decay
to equilibrium by maintaining a low level of entropy [7]. He
considered entropy as representative of disorder and nega-
tive entropy as that of order, referring to concepts derived
from statistical physics. He thought of the organism as a
N. Kamatani
system that maintains order against disorder. However, the
origin of the negative entropy by which an organism
maintained decreased levels of entropy was not entirely
clear at the time.
Entropy was originally a concept defined in thermo-
dynamics by Clausius and others, but Boltzmann and others
added to its significance from the aspect of statistical phy-
sics. Entropy was associated with living organisms by
Schrödinger and then a meaning in information theory was
added by Shannon. Deep learning is designed as a system
that aims to minimize cross-entropy [8].
The cross-entropy is interpreted to be proportional to the
logarithm of the likelihood function multiplied by −1
(in general, the proportional constants are meaningless for
likelihood functions) as will be explained in the following
sentences [9].
Among a total of M different events, let Qi denote the
probability of the ith event. Imagine that an experiment was
performed a total of N times, and Ni denotes the number of
times the ith event was observed. Then the likelihood
function L for the observed events will be:
Y N
L¼ Qi i ; ð1Þ
and the logarithm of L is:
X X
log L ¼ Ni log Qi ¼ N Pi log Qi ; ð2Þ
where the proportion of the ith event is Pi ¼ NNi and
P
Pi ¼ 1. Note that the right side of Eq. (2) is proportional
to the cross-entropy:
X
 Pi log Qi ; ð3Þ
although the sign is different. If Pi is fixed and Qi can vary
in Eq. (3), the minimum value of this cross-entropy is
P
entropy, i.e.,  Pi log Pi . This is equivalent to the fact
that the maximum value of the likelihood function is the
maximum likelihood. Of course, the entropy itself can be
reduced even further by varying Pi. Although the least
squares method appears to be different from likelihood and
cross-entropy, it is, in fact, equivalent to the maximum-
likelihood method and the minimization of the cross-
entropy under the assumption of a normal distribution.
In the case of deep learning applied to supervised
learning tasks, Pi is given externally by the data from
supervisors, and the objective is to minimize the cross-
entropy by moving Qi. Qi is a function containing many
parameters, and the parameter changes change Qi. That is,
for the supervised learning task performed in deep learning,
we aim to change the cross-entropy to entropy. When there
Genes, the brain, and artificial intelligence in evolution
is no supervisor, only Pi is present, so the objective is to
minimize entropy.
The system of genes developed to allow organisms to
survive and produce offspring during the course of evolu-
tion [10]. Genes in an individual that has survived and been
able to leave offspring are passed to the next generation. In
other words, if we consider the probability of transmitting
genes to an offspring as a likelihood function and the genes
as parameters, they are considered to have evolved due to
the principle of maximum likelihood by which the prob-
ability is maximized by changes that occur in the genes.
This is also equivalent to the minimization of cross-entropy.
In the supervised state where the environment does not
change, Pi in Eq. (3) is fixed and only Qi changes, but
during real evolution both Pi and Qi change because the
environment can also change. When environmental change
is unpredictable, the goal is to minimize entropy since there
is no supervisor. In other words, both genetic systems and
deep-learning algorithms are based on the maximum-
likelihood method that is equivalent, in principle, to the
cross-entropy and entropy minimization. In this case, the
parameters that can be varied to maximize the likelihood are
genes in the case of heredity and weights and biases in the
case of deep learning. That is, the genetic and deep-learning
systems operate under similar principles of likelihood
maximization or entropy minimization.
However, the major difference between the two is that
the former uses predominantly linear functions, while the
latter uses predominantly nonlinear functions. This may be
related to the different update rates of the parameters. The
system of inheritance updates parameters about every 20
years in humans. In comparison, in the case of the brain and
deep learning, parameter updates are instantaneous. There-
fore, the former can process only a limited number of
parameters, while the latter can process a huge number of
parameters. The number of genes is about 20,000 in humans
and the number of nucleotides is about 3 billion [11]. In
comparison, the number of synapses in a human brain is
thought to be 150 trillion [12]. If a genetic system were to
process such a large number of parameters, the number of
updates would be so small that it would be difficult to
manage the system.
Principles of the brain and its evolution
It is unclear what principle drives brain evolution and
development, but it is likely that the maximum-likelihood
method is at work, especially in the cortex [13]. Animals
have survived through numerous battles between predators
and prey for about 700 million years. Therefore, those
interactions should have altered the synaptic plasticity of the
brain to maximize the probability that the predator catches
the prey and the probability that the prey escapes from the
predator. That refers, in other words, to the maximization of
the likelihood and the minimization of cross-entropy and
entropy. Such a system should have evolved through
repeated predator-prey battles, which are analogous to the
recent combination of reinforcement learning with deep
neural networks (deep reinforcement learning) that was
used to make a deep-learning algorithm more efficient at
playing Go by battling itself [14].
As described above, genes, the brain, and deep-learning
systems are very similar in that they are based on the
maximum-likelihood method, i.e., the minimization of
cross-entropy and entropy. It should be noted that these
three systems can be considered as sequential layers. I have
previously proposed a six-layer structure for genomics that
describes the entire scientific field for genomics [15]. In this
context, I proposed that looking for an element missing in
one of the two different layers with similar structures but
present in the other can lead to a new discovery [15]. In
many cases, the missing element is not absent but hidden
and not easily recognized. If one can recognize the hidden
element, that will lead to a major discovery. This method
can be applied to the three sequential layers (genes, brain,
and artificial intelligence) of the present study.
Then, what system in the predator’s brain makes it
effective at capturing the prey? It would not be an arithmetic
system like Newtonian mechanics, but a system similar to
Lagrangian mechanics or Hamiltonian mechanics [16] that
is adaptive to the generalized coordinates. The reason is that
not only the prey but also the predator moves, and thus, the
predator needs to catch the prey based on the images cap-
tured by the predator’s own moving retinas. The predator
can obtain data regarding angles and distances of objects at
a point in time, and therefore, the brains of predator and
prey are likely to be using the polar coordinate system to
which Lagrangian or Hamiltonian mechanics can be
applied, rather than Cartesian coordinates used in New-
tonian mechanics. When we see perspective drawings, we
understand that the polar but not the Cartesian coordinate
system is in accord with the natural visual system in ani-
mals. For example, the Lagrangian is a function of gen-
eralized coordinates, their time derivatives and time. The
most necessary data for the predator would be the position
at which the prey could be caught relative to their own
position. Their internal arithmetic systems need to be able to
handle coordinate transformation. Furthermore, the position
of the prey should also be recognized as a rigid body, not a
point. It is necessary to process information based on the
image data reflected in the retinas of the predator’s two eyes
and correctly transmit course changes to the muscles to
achieve the goal of acquiring the prey. The brain’s need for
massive matrix operations to describe a moving rigid body
can be understood by analogous needs of a GPU to perform

massive matrix operations on computer graphics [17, 18]. In
addition, when a rigid body moves and rotates, it is
necessary to calculate the Eigenvalues and Eigenvectors of
the matrix to determine its center of gravity. As described
above, to win the battle between predator and prey, the
brain must be equipped with a matrix arithmetic system that
performs enormous amounts of linear operations and ana-
lytical mechanics capable of coordinate axis transformation.
The function of differentiation is needed to find the speed,
and the function of integration is also needed to find the
time and distance to achieve the objective. Using these,
predator and prey perform operations to minimize cross-
entropy and entropy, which are equivalent to operations to
find maximum-likelihood points using the maximum-
likelihood method.
Things (molecules), information (genes), and
energy (ATP) are important for applying
Maxwell’s demon model to living organisms
When considering the relationship between entropy and
living organisms, the model of Maxwell’s demon works as
a good reference [19]. The elements that appear in the
model of Maxwell’s demon are molecules, the demon, and
energy as well as two rooms connected by a small window
[19] (Fig. 2). If, as Schrödinger said, an organism is a
system that maintains itself at a low level of entropy, then
the model of Maxwell’s demon is really helpful for dis-
cussing negative entropy and the necessary role that energy
plays in maintaining that low entropy level. Since the rooms
describe a closed system, one can imagine them to represent
the whole body of an individual organism. If we apply this
system to an organism, gas molecules are represented by
small molecules and macromolecules, the demon is
Fig. 2 Maxwell’s demon model. A demon (eye) controls a small door
between two rooms of gas. As individual gas molecules approach the
door, the demon quickly opens and shuts the door so that only fast
molecules are passed from the left room to the right room, while only
slow molecules are passed into the other. In this process, energy is
necessary because, otherwise, the second law of thermodynamics does
not hold. The elements necessary for generating negative entropy
(order) are “things (molecules),” “information (demon),” and
“energy (ATP)”
N. Kamatani
represented by genes because they are in charge of the
information system, and energy is represented by ATP.
Historically, a main focus of biological research has been
the components that make up living systems, and from such
investigations, the disciplines of biochemistry and mole-
cular biology emerged. Recently, a main focus has also
been on identifying the genes that encode those compo-
nents, and along with development of methods to under-
stand differences in those genes between individuals, the
field of genetics has taken center-stage. In other words,
biology has been actively studied from the two aspects of
“things” and “information.” However, research in terms of
energy has not yet been fully developed. In fact, at least in
humans, almost all molecules and genes (and genome
sequences) have already been identified. This may mean
that not much remains to be discovered in such research
fields as molecular biology and genetics, which have been
focusing on things and information. Of course, I understand
that various characteristics such as concentrations, dis-
tributions, relationships, roles, functions, and other aspects
of molecules and genes are still left to be elucidated, but it
seems obvious to me that we need a new broad and fun-
damental concept besides things and information. From that
foundation, I predict that bioenergetic research will develop
to take a position alongside molecular biology and genetic
research. Thereafter, I predict that the study of entropy in
the context of these three elements, namely, things, infor-
mation, and energy, will be the focus of future biology and
medicine.
The study of energy in biology and medicine
In Maxwell’s demon model, three elements are important to
maintain a decreased level of entropy: things (molecules),
information (genes), and energy (ATP). In that context,
molecular biology and genetics have been the focuses of
modern biology and medicine, but there have been very few
studies regarding the role of energy in biomedical research.
The critical importance of energy for living organisms is
also suggested by the number and proportion of genes
associated with ATP. The metabolic pathways involved in
ATP production are the glycolytic system and oxidative
phosphorylation in mitochondria. While the number of
genes involved in glycolysis is not large, mitochondria, on
the other hand, are intracellular organelles for ATP synth-
esis, and many genes coding for proteins in mitochondria,
including ATP synthase, are either directly or indirectly
involved in ATP production. Mitochondrial proteins are
thought to be encoded by about 1500 chromosomal genes
[20], and there are also many proteins associated with ATP
consumption, including kinases and ligases, both of which
require ATP. The former are enzymes that transfer the
Genes, the brain, and artificial intelligence in evolution
phosphate at the γ position of ATP to other compounds,
while the latter are enzymes that combine two compounds
together using the energy obtained from ATP degradation.
The targets of kinases are not limited to proteins, but even
limiting oneself to genes for protein kinases, their number
exceeds 500 [21]. Ligases are not limited to enzymes using
ubiquitin, but even if limited to genes for the E3 ubiquitin
ligases, the number is thought to be 600–700 in the human
genome [22]. Thus, there are about 1500 genes involved in
ATP production and at least 1100 genes involved in ATP
consumption; these values cannot simply be added to the
earlier value because some of the proteins involved in ATP
consumption are likely to be present in the mitochondria.
However, it is estimated that genes encoding ATP-related
proteins account for at least 10% of all human genes.
Energy deficiency and diseases
As described above, energy, along with things and infor-
mation, is important for living organisms. In addition, the
percentage of genes related to ATP in the entire human
genome is very large. That contrasts with the disease
situation, wherein a large number of diseases are known to
be related to things (molecular diseases) and information
(genetic diseases), but the number ascribed to energy
(energy diseases) are quite few. Taken together, that data
suggests the existence of many energy (ATP) related dis-
eases as well as many diseases related to molecules and
genes. However, with the exception of mitochondrial dis-
ease [23–25], there have not been many studies that actively
elucidate the mechanisms of diseases in terms of energy.
Mitochondria are essential organelles that use oxygen to
produce ATP from the chemical energy of carbon-bearing
small molecules. The energy possessed by these small
molecules can be used effectively in vivo only after it is
converted to ATP. Mitochondrial disease is a disease caused
by mutations in genes related to mitochondria that cause
mitochondrial dysfunction [23–25]. The resulting disorders
include brain, hearing, visual, muscle, and heart disorders as
well as diabetes. Therefore, diseases in which these organs
are impaired are candidates for energy-related diseases. For
example, we already know that some forms of diabetes and
cardiomyopathy are caused by mutations in mitochondrial
genes [26, 27]. One of the candidate energy-related diseases
of interest is neurodegenerative disease. In fact, many
researchers have proposed, based on a variety of evidence
including that from genetic diseases, that Alzheimer’s and
Parkinson’s diseases are due to mitochondrial dysfunction
[28–30]. Mitochondrial function declines by 8% for every
10 years increase of age [31]. Thus, neurodegenerative
diseases may be caused by reduced energy production in
aged people due to reduced neuronal mitochondrial
function. In that regard, a genetic disease caused by muta-
tions in the VCP gene is especially informative, as muta-
tions in that gene cause both neurodegenerative disease and
inclusion body myopathy [32]. The inclusion bodies of
inclusion body myositis, which is pretty common in the
elderly, contain the same proteins that accumulate in neu-
rodegenerative diseases: amyloid-β, α-synuclein, tau, and
TDP-43 [33]. The VCP gene encodes a AAA-ATPase,
which is involved in ubiquitin-dependent proteolysis [34],
but degradation of a single protein molecule by the
ubiquitin-based proteasome system requires a large energy
expenditure: on the order of 300–400 ATP molecules [35].
Taken together, one can easily envision a situation wherein
decreased ATP production due to mitochondrial dysfunc-
tion could lead to decreased proteolytic function by the
proteasome system, and consequently, to increased protein
deposition and manifestation of neurodegenerative diseases
such as Alzheimer’s disease and Parkinson’s disease [36].
Based on such a hypothesis, we are developing an ATP
enhancer, i.e. a combination of a xanthine oxidase inhibitor
and inosine. By the administration of the ATP enhancer,
increased ATP has already been shown in healthy indivi-
duals [37], and dramatic improvements in biomarkers in
two patients with mitochondrial disease were demonstrated
[38]. We also showed that MDS-UPDRS Part III score was
significantly improved by the ATP enhancer in Parkinson’s
disease [39].
The future frontier of medicine and biology
I have already mentioned that the important concepts for
describing the world are things, information, and energy.
These are represented in the industrial world, for example,
by the manufacturing, information, and energy industries. In
biology, great progress has been made in molecular biology
(for things) and genetics (for information), but not much
progress has been made on energy. ATP-related genes are
estimated to account for more than 10% of human genes,
and the energy industry accounts for about 8% of the global
industry. Overall, I predict that the next frontier of biology
and medicine will be energy. This is because all three
concepts: things, information, and energy, are essential for
decreasing entropy, and the ability to maintain a decreased
level of entropy is the basic principle upon which living
things depend.
These three concepts are also important for describing
diseases. First, many molecular diseases exist, with exam-
ples being diabetes, which is a disease of sugar and insulin,
and hyperlipidemia, which is a disease of fat. Even if the
disease is not directly linked to a molecule, indirect con-
nections may exist. For example, hypertension is thought to
indirectly involve a variety of molecules, including sodium,

adrenaline, renin, and angiotensin, and neurodegenerative
disorders such as Alzheimer’s disease are thought to involve
molecules called amyloid-β and tau. Second, there are many
diseases of genes, which represent information. Thus, many
genetic diseases as well as common diseases are considered
to be related to genetic information. While there are many
diseases related to molecules, which are things, and genes,
which are information, there are lesser known diseases
related to ATP, which is energy. I predict that, in addition to
molecules and genes, ATP will be the next frontier, and life
will be understood as a system that uses things, information,
and energy to maintain a low level of entropy.
The future frontier of science
Until now, science has disregarded how scientists’ brains
themselves are involved in the scientific process. That
situation occurred because we did not know the details
underlying the brain’s cognitive mechanisms. However,
with the advent of deep learning, it is now possible to build
systems that mimic, albeit partially, the brain. I predict that,
in the future, we will begin to understand the mechanisms
by which the brain performs the thought processes that
occur during scientific endeavors. Specifically, I expect that
the systems of mathematics and physics that scientists have
conceived of as plausible will be deemed to have originated
in cognitive systems that are embedded in scientists’ brains.
In order to investigate that we need to understand what the
brain’s purpose has been in evolution and what systems it
has built to achieve that purpose. This is because the brain
has not developed suddenly, but has been built up over
about 700 million years of evolutionary history. In parti-
cular, I speculate that the struggle between predator and
prey played a major role in the construction of the brain’s
systems. Of course, the process of mating has also con-
tributed to its development. That also means that by using
brains constructed in such a fashion, scientists have devel-
oped their understanding of mathematics and physics.
For example, Einstein’s theory of relativity has as its
principles that physical laws are equivalent and that the speed
of light is the same for all moving observers. Such principles
may be inevitable outputs from a cognitive system that
evolved based on whether a predator pursues a prey effi-
ciently. The input to the eyes, which is a sensory organ, is
light, and it is necessary to use this information to perform
calculations in the brain and capture the prey efficiently. The
optimal arithmetic system for this purpose is not Newtonian
mechanics with a fixed coordinate axis, but preferably
Lagrangian or Hamiltonian mechanics, which are robust to
coordinate system transformations. The fact that these
mechanics fit into Einstein’s theory of relativity and Max-
well’s equations on electromagnetism may mean that the
N. Kamatani
cognitive systems that make up the scientists’ brains are an
inevitable result of evolution and are simply the structure best
suited to chasing and catching prey or escaping from pre-
dators. Predator and prey are likely to be using the same ever-
changing polar coordinate system. Even when considering
quantum theory and looking at the Schrödinger equation,
scientists may be using the Hamiltonian because it is a system
optimized for predator-prey combat. Certainly, the Hamilto-
nian represents energy of a system that has been fully
incorporated into physics but not into the study of brain or AI
systems. It is clear from the example of computer graphics
that a huge number of matrix operations are required to draw
the movement of an object, which is not a point but a rigid
body that moves and rotates. An equivalent ability should
have been required and implemented in the brain for a pre-
dator to chase and catch a prey. We all know that efficient
implementation of deep-learning algorithms requires GPUs
that have been developed to perform a huge amount of matrix
operations for computer graphics. Thus, a huge amount of
linear arithmetic should also be needed to win the battle
between predator and prey. Brains with such built-in func-
tions were also used by the scientists who developed the fields
of mathematics and physics and those who evaluate their
validity. In the future, studies will be performed about how
the algebraic structure that constitutes the basis of mathema-
tical thinking is related to the evolution of the brain.
In summary, I predict that, in the future, we will study
how cognitive processes in mathematics and physics relate
to the evolution of the brain, especially how they have been
enhanced by reinforcement learning through predator-prey
interactions. Research on artificial intelligence, which
mimics the human brain, will contribute to this research.
Although I focused on the battle between predator and prey
as one representative example, struggles between different
animals with equivalent strength as well as for mating
activities should have also played important roles.
Acknowledgements I thank Dr. Todd A. Johnson for correcting
English in the present paper.
Compliance with ethical standards
Conflict of interest NK is employed and paid by StaGen Co. Ltd.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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