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*Entropy*
**2016**,
*18*(2),
46;
doi:10.3390/e18020046

Review

Relative Entropy in Biological Systems

^{1}

Department of Mathematics, University of California, Riverside, CA 92521, USA

^{2}

Centre for Quantum Technologies, National University of Singapore, Singapore 117543, Singapore

^{3}

Department of Physics and Astronomy, University of California, Riverside, CA 92521, USA

*

Correspondence:

Academic Editor:
Kevin H. Knuth

Received: 9 December 2015 / Accepted: 21 January 2016 / Published: 2 February 2016

## Abstract

**:**In this paper we review various information-theoretic characterizations of the approach to equilibrium in biological systems. The replicator equation, evolutionary game theory, Markov processes and chemical reaction networks all describe the dynamics of a population or probability distribution. Under suitable assumptions, the distribution will approach an equilibrium with the passage of time. Relative entropy—that is, the Kullback–Leibler divergence, or various generalizations of this—provides a quantitative measure of how far from equilibrium the system is. We explain various theorems that give conditions under which relative entropy is nonincreasing. In biochemical applications these results can be seen as versions of the Second Law of Thermodynamics, stating that free energy can never increase with the passage of time. In ecological applications, they make precise the notion that a population gains information from its environment as it approaches equilibrium.

Keywords:

Second Law; relative entropy; relative information; Kullback–Leibler divergence; free energy; Markov process; reaction network; game theoryMSC:

94A17## 1. Introduction

Life relies on nonequilibrium thermodynamics, since in thermal equilibrium there are no flows of free energy. Biological systems are also open systems, in the sense that both matter and energy flow in and out of them. Nonetheless, it is important in biology that systems can sometimes be treated as approximately closed, and sometimes approach equilibrium before being disrupted in one way or another. This can occur on a wide range of scales, from large ecosystems to within a single cell or organelle. Examples include:

- a population approaching an evolutionarily stable state;
- random processes such as mutation, genetic drift, the diffusion of organisms in an environment or the diffusion of molecules in a liquid;
- a chemical reaction approaching equilibrium.

A common feature of these processes is that as they occur, quantities mathematically akin to entropy tend to increase. Closely related quantities such as free energy tend to decrease. In this review we explain some mathematical results that explain why this occurs.

Most of these results involve a quantity that is variously known as “relative information”, “relative entropy”, “information gain” or the “Kullback–Leibler divergence”. We shall use the first term. Given two probability distributions p and q on a finite set X, their
We use the word “information” instead of “entropy” because one expects entropy to increase with time, and the theorems we present will say that $I(p,q)$ decreases with time under various conditions. The reason is that the Shannon entropy
contains a minus sign that is missing from the definition of relative information.

**relative information**, or more precisely the**information of p relative to q**, is
$$I(p,q)=\sum _{i\in X}{p}_{i}ln\left(\frac{{p}_{i}}{{q}_{i}}\right).$$

$$S\left(p\right)=-\sum _{i\in X}{p}_{i}ln{p}_{i}$$

Intuitively, $I(p,q)$ is the amount of information gained when we start with a hypothesis given by some probability distribution q and then change our hypothesis, perhaps on the basis of some evidence, to some other distribution p. For example, if we start with the hypothesis that a coin is fair and then are told that it landed heads up, the relative information is $ln2$, so we have gained 1 bit of information. If however we started with the hypothesis that the coin always lands heads up, we would have gained no information.

Mathematically, relative information is a
and
but not necessarily the other axioms for a distance function, symmetry and the triangle inequality, which indeed fail for relative information. There are many other divergences besides relative information [1,2]. However, relative information can be singled out by a number of characterizations [3], including one based on ideas from Bayesian inference [4]. The relative information is also close to the expected number of extra bits required to code messages distributed according to the probability measure p using a code optimized for messages distributed according to q (Theorem 5.4.3 in [5]).

**divergence**: it obeys
$$I(p,q)\ge 0$$

$$I(p,q)=0\iff p=q,$$

In this review we describe various ways in which a population or probability distribution evolves continuously according to some differential equation. For all these differential equations, we describe conditions under which relative information decreases. Briefly, the results are as follows. We hasten to reassure the reader that our paper explains all the terminology involved, and the proofs of the claims are given in full:

- In Section 2 we consider a very general form of the Lotka–Volterra equations, which are a commonly used model of population dynamics. Starting from the population ${P}_{i}$ of each type of replicating entity, we can define a probability distribution$${p}_{i}=\frac{{P}_{i}}{{\displaystyle \sum _{i\in X}{P}_{i}}},$$
- In Section 3 we consider a special case of the replicator equation that is widely studied in evolutionary game theory. In this case we can think of probability distributions as mixed strategies in a two-player game. When q is a dominant strategy, $I(q,p(t\left)\right)$ can never increase when $p\left(t\right)$ evolves according to the replicator equation. We can think of $I(q,p(t\left)\right)$ as the information that the population has left to learn. Thus, evolution is analogous to a learning process—an analogy that in the field of artificial intelligence is exploited by evolutionary algorithms.
- In Section 4 we consider continuous-time, finite-state Markov processes. Here we have probability distributions on a finite set X evolving according to a linear equation called the master equation. In this case $I\left(p\right(t),q(t\left)\right)$ can never increase. Thus, if q is a steady state solution of the master equation, both $I\left(p\right(t),q)$ and $I(q,p(t\left)\right)$ are nonincreasing. We can always write q as the Boltzmann distribution for some energy function $E:X\to \mathbb{R}$, meaning that$${q}_{i}=\frac{exp(-{E}_{i}/kT)}{{\displaystyle \sum _{j\in X}exp(-{E}_{j}/kT)}},$$$$I(p\left(t\right),q)=\frac{F\left(p\right)-F\left(q\right)}{kT}.$$
- Finally, in Section 5 we consider chemical reactions and other processes described by reaction networks. In this context we have nonnegative real populations ${P}_{i}$ of entities of various kinds $i\in X$, and these population distributions evolve according to a nonlinear equation called the rate equation. We can generalize relative information from probability distributions to populations by setting$$I(P,Q)=\sum _{i\in X}{P}_{i}ln\left(\frac{{P}_{i}}{{Q}_{i}}\right)-\left({P}_{i}-{Q}_{i}\right).$$

## 2. The Replicator Equation

The replicator equation is a simplified model of how populations change with time. Suppose we have n different types of self-replicating entity. We will call these entities

**replicators**. We will call the types of replicators**species**, but they do not need to be species in the biological sense. For example, the replicators could be genes, and the types could be alleles. Or the replicators could be restaurants, and the types could be restaurant chains.Let ${P}_{i}\left(t\right),$ or just ${P}_{i}$ for short, be the population of the i-th species at time $t.$ Then a very general form of the
Thus the population ${P}_{i}$ changes at a rate proportional to ${P}_{i},$ but the “constant of proportionality” need not be constant: it can be any smooth function ${f}_{i}$ of the populations of all the species. We call ${f}_{i}$ the
This lets us write the Lotka–Volterra equations more concisely as
where the dot stands for a time derivative.

**Lotka–Volterra equations**says that
$$\frac{d{P}_{i}}{dt}={f}_{i}({P}_{1},\cdots ,{P}_{n})\phantom{\rule{0.166667em}{0ex}}{P}_{i}.$$

**fitness function**of the i-th species. We can create a vector whose components are all the populations:
$$P=({P}_{1},\cdots ,{P}_{n}).$$

$${\dot{P}}_{i}={f}_{i}\left(P\right){P}_{i},$$

Instead of considering the population ${P}_{i}$ of the i-th species, one often considers the probability ${p}_{i}$ that a randomly chosen replicator will belong to the i-th species. More precisely, this is the fraction of replicators belonging to that species:
As a mnemonic, remember that the

$${p}_{i}=\frac{{P}_{i}}{{\sum}_{j}{P}_{j}}.$$

**P**opulation ${P}_{i}$ is being normalized to give a**p**robability ${p}_{i}.$How do these probabilities ${p}_{i}$ change with time? The quotient rule gives
so the replicator equation gives
Using the definition of ${p}_{i},$ this simplifies to:

$${\dot{p}}_{i}=\frac{{\dot{P}}_{i}\left({\sum}_{j}{P}_{j}\right)-{P}_{i}\left({\sum}_{j}{\dot{P}}_{j}\right)}{{\left({\sum}_{j}{P}_{j}\right)}^{2}},$$

$${\dot{p}}_{i}=\frac{{f}_{i}\left(P\right){P}_{i}\phantom{\rule{0.277778em}{0ex}}\left({\sum}_{j}{P}_{j}\right)-{P}_{i}\left({\sum}_{j}{f}_{j}\left(P\right){P}_{j}\right)}{{\left({\sum}_{j}{P}_{j}\right)}^{2}}.$$

$${\dot{p}}_{i}={f}_{i}\left(P\right){p}_{i}-\left(\sum _{j}{f}_{j}\left(P\right){p}_{j}\right){p}_{i}.$$

The expression in parentheses here has a nice meaning: it is the
This gives the
where the dot stands for a time derivative. Thus, for the fraction of replicators of the i-th species to increase, their fitness must exceed the mean fitness.

**mean fitness**. In other words, it is the average, or expected, fitness of a replicator chosen at random from the whole population. Let us write it thus:
$$\langle f\left(P\right)\rangle =\sum _{j}{f}_{j}\left(P\right){p}_{j}.$$

**replicator equation**in its classic form:
$${\dot{p}}_{i}=\left({f}_{i}\left(P\right)-\langle f\left(P\right)\rangle \right)\phantom{\rule{0.166667em}{0ex}}{p}_{i},$$

So far, all this is classic material from population dynamics. At this point, Marc Harper considers what information theory has to say [7,8]. For example, consider the relative information $I(q,p)$ where q is some fixed probability distribution. How does this change with time? First, recall that
and we are assuming only ${p}_{i}$ depends on time, not ${q}_{i}$, so
By the replicator equation we obtain

$$I(q,p)=\sum _{i}{q}_{i}ln\left(\frac{{q}_{i}}{{p}_{i}}\right),$$

$$\frac{d}{dt}I(q,p\left(t\right))=-\sum _{i}\frac{{\dot{p}}_{i}}{{p}_{i}}\phantom{\rule{0.166667em}{0ex}}{q}_{i}.$$

$$\frac{d}{dt}I(q,p\left(t\right))=-\sum _{i}\left({f}_{i}\left(P\right)-\langle f\left(P\right)\rangle \right)\phantom{\rule{0.166667em}{0ex}}{q}_{i}.$$

This is nice, but we can massage this expression to get something more enlightening. Remember, the numbers ${q}_{i}$ sum to one. So:
This result looks even better if we treat the numbers ${f}_{i}\left(P\right)$ as the components of a vector $f\left(P\right),$ and similarly for the numbers ${p}_{i}$ and ${q}_{i}.$ Then we can use the dot product of vectors to write
whenever p evolves according to the replicator equation while q is fixed. It follows that the relative information $I(q,p(t\left)\right)$ will be nonincreasing if and only if
This nice result can be found in Marc Harper’s 2009 paper relating the replicator equation to Bayesian inference (Theorem 1 in [8]). He traces its origins to much earlier work by Akin [9,10], and also Hofbauer, Schuster and Sigmund [11], who worked with a certain function of $I(q,p(t\left)\right)$ rather than this function itself.

$$\begin{array}{ccc}{\displaystyle \frac{d}{dt}I(q,p\left(t\right))}& =& {\displaystyle \langle f\left(P\right)\rangle -\sum _{i}{f}_{i}\left(P\right){q}_{i}}\hfill \\ \phantom{\rule{0.277778em}{0ex}}\\ & =& {\displaystyle \sum _{i}{f}_{i}\left(P\right)({p}_{i}-{q}_{i}).}\hfill \end{array}$$

$$\frac{d}{dt}I(q,p\left(t\right))=f\left(P\left(t\right)\right)\xb7(p\left(t\right)-q),$$

$$f\left(P\right(t\left)\right)\xb7\left(p\right(t)-q)\le 0.$$

Next we turn to the question: how can we interpret the above inequality, and when does it hold?

## 3. Evolutionary Game Theory

To go further, evolutionary game theorists sometimes assume the fitness functions are linear in the probabilities ${p}_{j}$. Then
for some matrix A, called the

$$f}_{i}\left(P\right)=\sum _{j=1}^{n}{A}_{ij}{p}_{j$$

**fitness matrix**.In this situation the mathematics is connected to the usual von Neumann–Morgenstern theory of two-player games. In this approach to game theory, each player has the same finite set X of

**pure strategies**. The**payoff matrix**${A}_{ij}$ specifies the first player’s winnings if the first player chooses the pure strategy i and the second player chooses the pure strategy j. A probability distribution on the set of pure strategies is called a**mixed strategy**. The first player’s expected winnings will be $p\xb7Aq$ if they use the mixed strategy p and the second player uses the mixed strategy q.To apply this analogy to game theory, we assume that we have a well-mixed population of replicators. Each one randomly roams around, “plays games” with each other replicator it meets, and reproduces at a rate proportional to its expected winnings. A pure strategy is just what we have been calling a species. A mixed strategy is a probability distribution of species. The payoff matrix is the fitness matrix.

In this context, the vector of fitness functions is given by
Then, if $p\left(t\right)$ evolves according to the replicator equation while q is fixed, the time derivative of relative information, given in Equation (5), becomes
Thus, we define q to be a
for all mixed strategies p. If q is dominant, we have
whenever $p\left(t\right)$ obeys the replicator equation. Conversely, if the information of $p\left(t\right)$ relative to q is nonincreasing whenever $p\left(t\right)$ obeys the replicator equation, the mixed strategy q must be dominant.

$$f\left(P\right)=Ap.$$

$$\frac{d}{dt}I(q,p\left(t\right))=(p\left(t\right)-q)\xb7Ap\left(t\right).$$

**dominant mixed strategy**if
$$q\xb7Ap\ge p\xb7Ap$$

$$\frac{d}{dt}I(q,p\left(t\right))\le 0,$$

The question is then: what is the meaning of dominance? First of all, if q is dominant then it is a

**steady state**solution of the replicator equation, meaning one that does not depend on time. To see this, let $r\left(t\right)$ be the solution of the replicator equation with $r\left(0\right)=q$. Then $I(q,r(t\left)\right)$ is nonincreasing because q is dominant. Furthermore $I(q,r(t\left)\right)=0$ at $t=0$, since for any probability distribution we have $I(q,q)=0$. Thus we have $I(q,r(t\left)\right)\le 0$ for all $t\ge 0$. However, relative information is always non-negative, so we must have $I(q,r(t\left)\right)=0$ for all $t\ge 0$. This forces $r\left(t\right)=q$, since the relative information of two probability distributions can only vanish if they are equal.Thus, a dominant mixed strategy is a special kind of steady state solution of the replicator equation. But what is special about it? We can understand this if we think in game-theoretic terms. The inner product $q\xb7Ap$ will be my expected winnings if I use the mixed strategy q and you use the mixed strategy p. Similarly, $p\xb7Ap$ will be my expected winnings if we both use the mixed strategy p. So, the dominance of the mixed strategy q says that my expected winnings can never increase if I switch from q to whatever mixed strategy you are using.

It helps to set these ideas into the context of evolutionary game theory [12]. In 1975, John Maynard Smith, the founder of evolutionary game theory, defined a mixed strategy q to be an “evolutionarily stable state” if when we add a small population of “invaders” distributed according to any other probability distribution $p,$ the original population is more fit than the invaders [13]. He later wrote [14]: “A population is said to be in an evolutionarily stable state if its genetic composition is restored by selection after a disturbance, provided the disturbance is not too large.”

More precisely, Maynard Smith defined q to be an
for all mixed strategies $p\ne q$ and all sufficiently small $\u03f5>0.$ Here
is the population we get by replacing an ϵ-sized portion of our original population by invaders.

**evolutionarily stable state**if
$$q\xb7A\left(\right(1-\u03f5)q+\u03f5p)>p\xb7A\left(\right(1-\u03f5)q+\u03f5p)$$

$$(1-\u03f5)q+\u03f5p$$

Taking this inequality and separating out the terms of order ϵ, one can easily check that q is an evolutionarily stable state if and only if two conditions hold for all probability distributions $p\ne q$:
and
The first condition says that q is a

$$q\xb7Aq\ge p\xb7Aq$$

$$q\xb7Aq=p\xb7Aq\phantom{\rule{0.277778em}{0ex}}\Rightarrow \phantom{\rule{0.277778em}{0ex}}q\xb7Ap>p\xb7Ap.$$

**symmetric Nash equilibrium**. In other words, the invaders can’t on average do better playing against the original population than members of the original population are. The second says that if the invaders are just as good at playing against the original population, they must be worse at playing against each other! The combination of these conditions means the invaders won’t take over.Note, however, that the dominance condition (7), which guarantees nonincreasing relative information, is different from either Equation (9) or (10). Indeed, after Maynard Smith came up with his definition of “evolutionarily stable state”, Bernard Thomas [15] came up with a different definition. For him, q is an
This condition is stronger than Equation (10), so he renamed Maynard Smith’s evolutionarily stable states

**evolutionarily stable strategy**if Maynard Smith’s condition (9) holds along with
$$q\xb7Ap\ge p\xb7Ap.$$

**weakly evolutionarily stable strategies**.More importantly for us, Equation (11) is precisely the same as the condition we are calling “dominance”, which implies that the relative information $I(q,p(t\left)\right)$ can never increase as $p\left(t\right)$ evolves according to the replicator equation. We can interpret $I(q,p(t\left)\right)$ as the amount of information “left to learn” as the population approaches the dominant strategy.

This idea of evolution as a learning process is exploited by genetic algorithms in artificial intelligence [16]. Conversely, some neuroscientists have argued that individual organisms act to minimize “surprise”—that is, relative information: the information of perceptions relative to predictions [17]. As we shall see in the next section, relative information also has the physical interpretation of free energy. Thus, this hypothesis is known as the “free energy principle”. Another hypothesis, that neurons develop in a manner governed by natural selection, is known as “neural Darwinism” [18]. The connection between relative information decrease and evolutionary game theory shows that these two hypotheses are connected.

## 4. Markov Processes

One limitation of replicator equations is that in these models, when the population of some species is initially zero, it must remain so for all times. Thus, they cannot model mutation, horizontal gene transfer, or other sources of novelty.

The simplest model of mutation is a discrete-time Markov chain, where there is a fixed probability per time for a genome to change from one genotype to another each time it is copied [19]. The information-theoretic aspects of Markov models in genetics have been discussed by Sober and Steel [20]. To stay within our overall framework, here we instead consider continuous-time Markov chains, which we shall simply call Markov processes. These are a very general framework that can be used to describe any system with finite set X of states where the probability that the system is in its i-th state obeys a differential equation of this form:
with the matrix H chosen so that total probability is conserved.

$$\frac{d{p}_{i}}{dt}=\sum _{j\in X}{H}_{ij}{p}_{j}\left(t\right),$$

In what follows we shall explain a very general result saying that for any Markov process, relative information is nonincreasing [21,22,23]. It is a form of the Second Law of Thermodynamics. Some call this result the “H-theorem”, but this name goes back to Boltzmann, and strictly this name should be reserved for arguments like Boltzmann’s which seek to derive the Second Law from time-symmetric dynamics together with time-asymmetric initial conditions [24,25]. The above equation is not time-symmetric, and the relative information decrease holds for all initial conditions.

We can describe a Markov process starting with a directed graph whose nodes correspond to states of some system, and whose edges correspond to transitions between these states. The transitions are labelled by “rate constants”, like this:
The rate constant of a transition from $i\in X$ to $j\in X$ represents the probability per time that an item hops from the i-th state to the j-th state.

More precisely, we say a

**Markov process**M consists of:- a finite set X of
**states**, - a finite set T of
**transitions**, - maps $s,t:T\to X$ assigning to each transition its
**source**and**target**, - a map $r:T\to (0,\infty )$ assigning a
**rate constant**$r\left(\tau \right)$ to each transition $\tau \in T$.

From a Markov process we can construct a square matrix, or more precisely a function $H:X\phantom{\rule{3.33333pt}{0ex}}\times \phantom{\rule{3.33333pt}{0ex}}X\phantom{\rule{3.33333pt}{0ex}}\to \phantom{\rule{3.33333pt}{0ex}}\mathbb{R}$, called its
to be the sum of the rate constants of all transitions from j to i. We choose the diagonal entries in a more subtle way:

**Hamiltonian**. If $i\ne j$ we define
$${H}_{ij}=\sum _{\tau :j\to i}{r}_{\tau}$$

$${H}_{ii}=-\sum _{\begin{array}{c}\tau :i\to j\\ j\ne i\end{array}}r\left(\tau \right).$$

Given a Markov process, the
where H is the Hamiltonian. Thus, given a probability distribution p on X, for $i\ne j$ we interpret ${H}_{ij}{p}_{j}$ as the rate at which population flows from state j to state i, while the quantity ${H}_{ii}{p}_{i}$ is the outflow of population from state i. The diagonal entries ${H}_{ii}$ are chosen in a way that ensures total population is conserved.

**master equation**for a time-dependent probability distribution on X is:
$$\frac{d}{dt}p\left(t\right)=Hp\left(t\right),$$

More precisely, H is
This guarantees that if $p\left(t\right)$ obeys the master equation and if it is initially a probability distribution, it remains a probability distribution for all times $t\ge 0$.

**infinitesimal stochastic**, meaning that its off-diagonal entries are non-negative and the entries in each column sum to zero:
$${H}_{ij}\ge 0\phantom{\rule{0.277778em}{0ex}}\text{if}i\ne j\phantom{\rule{1.em}{0ex}}\text{and}\phantom{\rule{1.em}{0ex}}\sum _{i}{H}_{ij}=0.$$

Markov processes are an extremely general formalism for dealing with randomly evolving systems, and they are presented in many different ways in the literature. For example, besides the master equation one often sees the
where $G(t,s)$ is a square matrix depending on two times $s,t\in \mathbb{R}$ with $s\le t$. The idea here is that the matrix element ${G}_{ij}(t,s)$ is the probability that if the system is in the j-th state at time s, it will be in the i-th state at some later time t. We thus demand that $G(t,s)$ is the identity matrix when $s=t$, and we can show that
whenever $s\le t$. From this it is easy to see that $G(t,s)$ also obeys the
We should warn the reader that conventions differ and many, perhaps even most, authors multiply these matrices in the reverse order.

**Kolmogorov forward equation**:
$$\frac{d}{dt}G(t,s)=HG(t,s)$$

$$G(t,s)=exp\left(\right(t-s\left)H\right),$$

**Kolmogorov backward equation**:
$$\frac{d}{ds}G(t,s)=-G(t,s)H.$$

The master equation and Kolmogorov forward equation are related as follows. If $p\left(t\right)$ obeys the master equation and $G(t,s)$ solves the Kolmogorov forward equation, then
whenever $s\le t$. Thus, knowledge of $G(t,s)$ immediately tells us all solutions of the master equation.

$$p\left(t\right)=G(t,s)p\left(s\right),$$

Most of our discussion so far, and the results to follow, can be generalized to the case where X is an arbitrary measure space, for example ${\mathbb{R}}^{n}$. The Kolmogorov forward equation is often studied in this more general context, sometimes in the guise of the “Fokker–Planck equation”. This formulation is often used to study Brownian motion and other random walk processes in the continuum. A careful treatment of this generalization involves more analysis: sums become integrals, and one needs to worry about convergence and passing derivatives through integrals [26,27,28,29]. To keep things simple and focus on basic concepts, we only treat the case where X is a finite set.

As one evolves any two probability distributions p and q according to a Markov process, their relative information is nonincreasing:
This is a very nice result, because it applies regardless of the Markov process. It even applies to a master equation where the Hamiltonian depends on time, as long as it is always infinitesimal stochastic.

$$\frac{d}{dt}I(p\left(t\right),q\left(t\right))\le 0.$$

To prove this result, we start by computing the derivative:
where in the second line we used the master equation. We can rewrite this as
Note that the last two terms cancel when $i=j$. Thus, if we break the sum into an $i\ne j$ part and an $i=j$ part, we obtain
Next we use the infinitesimal stochastic property of H to write ${H}_{jj}$ as the sum of $-{H}_{ij}$ over i not equal to j:
Since ${H}_{ij}\ge 0$ when $i\ne j$ and $ln\left(s\right)+1-s\le 0$ for all $s>0$, we conclude that
as desired. To be precise, this derivation only applies when ${q}_{i}$ is nonzero for all $i\in X$. If this is true at any time, it will be true for all later times. If some probability ${q}_{i}$ vanishes, the relative entropy $I(p,q)$ can be infinite. As we evolve p and q in time according to the master equation, the relative entropy can drop from infinity to a finite value, but never increase.

$$\begin{array}{ccc}{\displaystyle \frac{d}{dt}I(p\left(t\right),q\left(t\right))}& =& {\displaystyle \frac{d}{dt}\sum _{i\in X}{p}_{i}ln(\frac{{p}_{i}}{{q}_{i}})}\hfill \\ \\ & =& {\displaystyle \sum _{i}{\dot{p}}_{i}ln(\frac{{p}_{i}}{{q}_{i}})+{p}_{i}\left(\frac{{\dot{p}}_{i}}{{p}_{i}}-\frac{{\dot{q}}_{i}}{{q}_{i}}\right)}\hfill \\ \\ & =& {\displaystyle \sum _{i,j}{H}_{ij}{p}_{j}ln(\frac{{p}_{i}}{{q}_{i}})+{p}_{i}\left(\frac{{H}_{ij}{p}_{j}}{{p}_{i}}-\frac{{H}_{ij}{q}_{j}}{{q}_{i}}\right),}\hfill \end{array}$$

$$\frac{d}{dt}I(p\left(t\right),q\left(t\right))=\sum _{i,j}{H}_{ij}{p}_{j}\left(ln(\frac{{p}_{i}}{{q}_{i}})+1-\frac{{p}_{i}{q}_{j}}{{p}_{j}{q}_{i}}\right).$$

$$\frac{d}{dt}I(p\left(t\right),q\left(t\right))=\sum _{i\ne j}{H}_{ij}{p}_{j}\left(ln(\frac{{p}_{i}}{{q}_{i}})+1-\frac{{p}_{i}{q}_{j}}{{p}_{j}{q}_{i}}\right)+\sum _{j}{H}_{jj}{p}_{j}ln(\frac{{p}_{j}}{{q}_{j}}).$$

$$\begin{array}{ccc}{\displaystyle \frac{d}{dt}I(p\left(t\right),q\left(t\right))}& =& {\displaystyle \sum _{i\ne j}{H}_{ij}{p}_{j}\left(ln(\frac{{p}_{i}}{{q}_{i}})+1-\frac{{p}_{i}{q}_{j}}{{p}_{j}{q}_{i}}\right)-\sum _{i\ne j}{H}_{ij}{p}_{j}ln(\frac{{p}_{j}}{{q}_{j}})}\hfill \\ \\ & =& {\displaystyle \sum _{i\ne j}{H}_{ij}{p}_{j}\left(ln(\frac{{p}_{i}{q}_{j}}{{p}_{j}{q}_{i}})+1-\frac{{p}_{i}{q}_{j}}{{p}_{j}{q}_{i}}\right).}\hfill \end{array}$$

$$\frac{d}{dt}I(p\left(t\right),q\left(t\right))\le 0$$

One of the nice features of working with a finite state space X is that in this case every Markov process admits one or more
and thus give solutions of the master equation that are constant in time [30]. If we fix any one of these, we can conclude
for any solution of the master equation. This is the same inequality we have already seen for the replicator Equation (8), when q is a dominant mixed strategy. But for a Markov process, we also have
and this, it turns out, has a nice meaning in terms of statistical mechanics.

**steady states**: probability distributions q that obey
$$Hq=0,$$

$$\frac{d}{dt}I(q,p\left(t\right))\le 0$$

$$\frac{d}{dt}I(p\left(t\right),q)\le 0,$$

In statistical mechanics we want to assign an
here β is a parameter which in physics is defined in terms of the temperature T by $\beta =1/kT$, where k is Boltzmann’s constant. The quantity $Z\left(\beta \right)$ is a normalizing constant called the
to ensure that the probabilities ${q}_{i}$ sum to one.

**energy**${E}_{i}$ to each state such that the steady state probabilities ${q}_{i}$ are given by the so-called**Boltzmann distribution**:
$${q}_{i}=\frac{{e}^{-\beta {E}_{i}}}{Z\left(\beta \right)},$$

**partition function**, defined by
$$Z\left(\beta \right)=\sum _{i\in X}{e}^{-\beta {E}_{i}}$$

However, whenever we have a probability distribution q on a finite set X, we can turn this process on its head. We start by arbitrarily choosing $\beta >0$. Then we define energy differences by
This determines the energies up to an additive constant. If we make a choice for these energies, we can define the partition function by Equation (17), and Boltzmann’s law, Equation (16), will follow.

$${E}_{i}-{E}_{j}=-{\beta}^{-1}ln(\frac{{q}_{i}}{{q}_{j}}).$$

We can thus apply ideas from statistical mechanics to any Markov process, for example the process of genetic drift. The concepts of “energy” and “temperature” play only a metaphorical role here; they are not the ordinary physical energy and temperature. However, the metaphor is a useful one.

So, let us fix a Markov process on a set X together with a steady state probability distribution q. Let us choose a value of β, choose energies obeying Equation (18), and define the partition function $Z\left(\beta \right)$ by Equation (17). To help the reader’s intuition we define a
and the
From these, we can construct the all-important
In applications to physics and chemistry this is, roughly speaking, the amount of “useful” energy, meaning energy not in the form of random “heat”, which gives the term $TS\left(p\right)$.

**temperature**$T=1/\beta $, setting Boltzmann’s constant to 1. Then, for any probability distribution p on X we can define the**expected energy**:
$${\langle E\rangle}_{p}=\sum _{i\in X}{p}_{i}{E}_{i}$$

**entropy**:
$$S\left(p\right)=-\sum _{i\in X}{p}_{i}ln\left({p}_{i}\right).$$

**free energy**
$$F\left(p\right)={\langle E\rangle}_{p}-TS\left(p\right).$$

We can prove that this free energy can never increase with time if we evolve p in time according to the master equation. This is a version of the Second Law of Thermodynamics. To prove this, note that
but by Boltzmann’s law, Equation (16), we have
so we obtain
or, using the definition of relative information and the fact that the ${p}_{i}$ sum to one:
In the special case where $p=q$ the relative information vanishes and we obtain
Substituting this into the previous equation, we reach an important result:
Relative information is proportional to a difference in free energies! Since relative entropy is nonnegative, we immediately see that any probability distribution p has at least as much free energy as the steady state q:
Moreover, if we evolve $p\left(t\right)$ according to the master equation, the decrease of relative entropy given by Equation (15) implies that
These two facts suggest, but do not imply, that $p\left(t\right)\to q$ as $t\to \infty $. This is in fact true when there is a unique steady state, but not necessarily otherwise. One can determine the number of linearly independent steady states from the topology of the graph associated to the Markov process (Section 22.2 in [30]).

$$\begin{array}{ccc}F\left(p\right)& =& {\displaystyle {\langle E\rangle}_{p}-TS\left(p\right)}\hfill \\ \\ & =& {\displaystyle \sum _{i\in X}{p}_{i}{E}_{i}+T\phantom{\rule{0.166667em}{0ex}}{p}_{i}ln\left({p}_{i}\right),}\hfill \end{array}$$

$${E}_{i}=-T\left(ln\left({q}_{i}\right)+ln\left(Z\right)\right),$$

$$F\left(p\right)=-T\sum _{i\in X}\left({p}_{i}ln\left({q}_{i}\right)-{p}_{i}ln\left({p}_{i}\right)+{p}_{i}ln\left(Z\right)\right),$$

$$F\left(p\right)=I(p,q)-Tln\left(Z\right).$$

$$F\left(q\right)=-Tln\left(Z\right).$$

$$\frac{F\left(p\right)-F\left(q\right)}{T}=I(p,q).$$

$$F\left(p\right)\ge F\left(q\right).$$

$$\frac{d}{dt}F\left(p\left(t\right)\right)\le 0.$$

## 5. Reaction Networks

Reaction networks are commonly used in chemistry, where they are called “chemical reaction networks”. An example is the Krebs cycle, important in the metabolism of aerobic organisms. A simpler example is the Michaelis–Menten model of an enzyme E binding to a substrate S to form an intermediate I, which in turn can break apart into a product P and the original enzyme:
Mathematically, this is a directed graph. The nodes of this graph, namely $E+S,I$, and $E+P$, are called “complexes”. Complexes are finite sums of “species”, which in this example are $E,S,I,$ and P. The edges of this graph are called “reactions”. Each reaction has a name, which may also serve as the “rate constant” of that reaction. In real-world chemistry, every reaction has a reverse reaction going the other way, but if the rate constant for the reverse reaction is low enough, we may simplify our model by omitting it. This is why the Michaelis–Menten model has no reaction going from $E+P$ back to I.

$$E+S\underset{\beta}{\overset{\alpha}{\rightleftharpoons}}I\stackrel{\gamma}{\to}E+P.$$

From a reaction network we can extract a differential equation called its “rate equation”, which describes how the population of each species changes with time. We treat these populations as functions of time, taking values in $[0,\infty )$. If we use ${P}_{E}$ as the name for the population of the species E, and so on, the rate equation for the above reaction network is:
We will give the general rules for extracting the rate equation from a reaction network, but the reader may enjoy guessing them from this example. It is worth noting that chemists usually deal with “concentrations” rather than populations: a concentration is a population per unit volume. This changes the meaning and the values of the rate constants, but the mathematical formalism is the same.

$$\begin{array}{ccc}{\displaystyle \phantom{\rule{6.0pt}{0ex}}\frac{d}{dt}{P}_{E}}& =& -\alpha {P}_{E}{P}_{S}+\beta {P}_{I}+\gamma {P}_{I}\hfill \\ {\displaystyle \phantom{\rule{6.0pt}{0ex}}\frac{d}{dt}{P}_{S}}& =& -\alpha {P}_{E}{P}_{S}+\beta {P}_{I}\hfill \\ {\displaystyle \phantom{\rule{6.0pt}{0ex}}\frac{d}{dt}{P}_{I}}& =& \alpha {P}_{E}{P}_{S}-\gamma {P}_{I}\hfill \\ {\displaystyle \phantom{\rule{6.0pt}{0ex}}\frac{d}{dt}{P}_{P}}& =& \gamma {P}_{I}\hfill \end{array}$$

More precisely, a

**reaction network**consists of:- a finite set S of
**species**, - a finite set X of
**complexes**with $X\subseteq {\mathbb{N}}^{S}$, - a finite set T of
**reactions**or**transitions**, - maps $s,t:T\to X$ assigning to each reaction its
**source**and**target**, - a map $r:T\to (0,\infty )$ assigning to each reaction a
**rate constant**.

For convenience we shall often write k for the number of species present in a reaction network, and identify the set S with the set $\{1,\cdots ,k\}$. This lets us write any complex as a k-tuple of natural numbers. In particular, we write the source and target of any reaction τ as

$$s\left(\tau \right)=({s}_{1}\left(\tau \right),\cdots ,{s}_{k}\left(\tau \right))\in {\mathbb{N}}^{k},$$

$$t\left(\tau \right)=({t}_{1}\left(\tau \right),\cdots ,{t}_{k}\left(\tau \right))\in {\mathbb{N}}^{k}.$$

The rate equation involves the
The rate equation says how this vector change with time. It says that each reaction τ contributes to the time derivative of P via the product of
where $P:\mathbb{R}\to {[0,\infty )}^{k}$ and we have used multi-index notation to define
Alternatively, in components, we can write the rate equation as
The reader can check that this rule gives the rate equations for the Michaelis–Menten model.

**population**${P}_{i}\in [0,\infty )$ of each species i. We can summarize these in a population vector
$$P=({P}_{1},\cdots ,{P}_{k}).$$

- the vector $t\left(\tau \right)-s\left(\tau \right)$ whose i-th component is the change in the number of items of the i-th species due to the reaction τ;
- the concentration of each input species i of τ raised to the power given by the number of times it appears as an input, namely ${s}_{i}\left(\tau \right)$;
- the rate constant $r\left(\tau \right)$ of τ.

**rate equations**are
$$\frac{d}{dt}P\left(t\right)=\sum _{\tau \in T}r\left(\tau \right)(t\left(\tau \right)-s\left(\tau \right))P{\left(t\right)}^{s\left(\tau \right)},$$

$${P}^{s\left(\tau \right)}={P}_{1}^{{s}_{1}\left(\tau \right)}\cdots {P}_{k}^{{s}_{k}\left(\tau \right)}.$$

$${\dot{P}}_{i}=\sum _{\tau \in T}r\left(\tau \right)({t}_{i}\left(\tau \right)-{s}_{i}\left(\tau \right)){P}^{s\left(\tau \right)}.$$

Reaction networks include Markov processes as a special case. A reaction network where every complex is just a single species—that is, a vector in ${\mathbb{N}}^{S}$ with one component being 1 and all the rest 0—can be viewed as a Markov process. For a reaction network that corresponds to a Markov process in this way, the rate equation is linear, and it matches the master equation for the corresponding Markov process. The goal of this section is to generalize results on relative information from Markov processes to other reaction networks. However, the nonlinearity of the rate equation introduces some subtleties.

The applications of reaction networks are not limited to chemistry. Here is an example that arose in work on HIV, the human immunodeficiency virus [31]:
Here we have three species:

$$\begin{array}{ccc}\hfill 0\stackrel{\alpha}{\to}H\stackrel{\beta}{\to}0& & H+V\stackrel{\gamma}{\to}I\stackrel{\delta}{\to}I+V\\ \hfill I\stackrel{\u03f5}{\to}0& & V\stackrel{\zeta}{\to}0.\end{array}$$

- H: healthy white blood cells,
- I: infected white blood cells,
- V: virions (that is, individual virus particles).

- α: the birth of one healthy cell, which has no input and one H as output.
- β: the death of a healthy cell, which has one H as input and no output.
- γ: the infection of a healthy cell, which has one H and one V as input, and one I as output.
- δ: the reproduction of the virus in an infected cell, which has one I as input, and one I and one V as output.
- ϵ: the death of an infected cell, which has one I as input and no output.
- ζ: the death of a virion, which has one V as input and no output.

$$\begin{array}{ccc}{\displaystyle \phantom{\rule{6.0pt}{0ex}}\frac{d}{dt}{P}_{H}}& =& \alpha -\beta {P}_{H}-\gamma {P}_{H}{P}_{V}\hfill \\ {\displaystyle \phantom{\rule{6.0pt}{0ex}}\frac{d}{dt}{P}_{I}}& =& \gamma {P}_{H}{P}_{V}-\u03f5{P}_{I}\hfill \\ {\displaystyle \phantom{\rule{6.0pt}{0ex}}\frac{d}{dt}{P}_{V}}& =& -\gamma {P}_{H}{P}_{V}+\delta {P}_{I}-\zeta {P}_{V}.\hfill \end{array}$$

The equations above are not of the Lotka–Volterra type shown in Equation (3), because the time derivative of ${P}_{H}$ contains a term with no factor of ${P}_{H}$, and similarly for ${P}_{I}$ and ${P}_{V}$. Thus, even when the population of one of these three species is initially zero, it can become nonzero. However, many examples of Lotka–Volterra equations do arise from reaction networks. For example, we could take two species:
Taken literally, this seems like a ludicrous model: rabbits reproduce asexually, a wolf can eat a rabbit and instantly give birth to another wolf, and wolves can also die. However, the resulting rate equations are a fairly respectable special case of the famous Lotka–Volterra predator-prey model:
It is probably best to think of this as saying no more than this: general results about reaction networks will also apply to Lotka–Volterra equations that can arise from this framework.

- R: rabbits,
- W: wolves,

$$\begin{array}{ccccc}R\stackrel{\alpha}{\to}2R& & R+W\stackrel{\beta}{\to}2W& & W\stackrel{\gamma}{\to}0.\end{array}$$

$$\begin{array}{ccc}{\displaystyle \phantom{\rule{6.0pt}{0ex}}\frac{d}{dt}{P}_{R}}& =& \alpha {P}_{R}-\beta {P}_{R}{P}_{W}\hfill \\ {\displaystyle \phantom{\rule{6.0pt}{0ex}}\frac{d}{dt}{P}_{W}}& =& \beta {P}_{R}{P}_{W}-\gamma {P}_{W}.\hfill \end{array}$$

In our discussion of the replicator equation, we converted populations to probability distributions by normalizing them, and defined relative information only for the resulting probability distributions. We can, however, define relative information for populations, and this is important for work on reaction networks. Given two populations $P,Q:X\to [0,\infty )$, we define
When P and Q are probability distributions on X this reduces to the relative information defined before in Equation (1). As before, one can prove that
To see this, note that a differentiable function $f:\mathbb{R}\to \mathbb{R}$ is convex precisely when its graph lies above any of its tangent lines:
This is true for the exponential function, so
and thus for any $p,q>0$ we have
or
Thus, each term in the sum Equation (21) is greater than or equal to zero, so $I(P,Q)\ge 0$. Furthermore since we have equalities above only when $x=y$, or in other words $p=q$, we also obtain
So, relative information has the properties of a divergence, but for arbitrary populations $P,Q:X\to [0,\infty ).$ A function very similar to $I(P,Q)$ was used by Friedrich Horn and Roy Jackson in their important early paper on reaction networks [32]. They showed that this function is nonincreasing when P evolves according to the rate equation and Q is a steady state of a special sort, called a “complex balanced equilibrium”. Later Martin Feinberg, another of the pioneers of reaction network theory, gave a shorter proof of this fact [33]. Our goal here is to explain this result and present Feinberg’s proof.

$$I(P,Q)=\sum _{i\in X}{P}_{i}ln(\frac{{P}_{i}}{{Q}_{i}})-({P}_{i}-{Q}_{i}).$$

$$I(P,Q)\ge 0.$$

$$f\left(y\right)\ge f\left(x\right)+{f}^{\prime}\left(x\right)(y-x).$$

$${e}^{y}\ge {e}^{x}+{e}^{x}(y-x),$$

$$q\ge p+p(ln(q)-ln(p\left)\right),$$

$$pln(\frac{p}{q})-(p-q)\ge 0.$$

$$I(P,Q)=0\iff P=Q.$$

We say that a population Q is
This says that each complex is being produced at the same rate at which it is being destroyed. This is stronger than saying Q is a steady state solution of the rate equation. On the other hand, it is weaker than the “detailed balance” condition saying that each reaction occurs at the same rate as the reverse reaction. The founders of chemical reaction theory discovered that many results about detailed balanced equilibria can just as easily be shown in the complex balanced case. The calculation below is an example.

**complex balanced**if for each complex $\kappa \in K$ we have
$$\sum _{\tau :s\left(\tau \right)=\kappa}r\left(\tau \right){Q}^{s\left(\tau \right)}=\sum _{\tau :t\left(\tau \right)=\kappa}r\left(\tau \right){Q}^{s\left(\tau \right)}.$$

We have
so, using the rate Equation (20), we obtain:
We can convert each sum over i of the logarithms into a logarithm of a product, and if we define a vector
we can use multi-index notation to write these products very concisely, obtaining
Then, using the fact that $(lnx-lny)y\le x-y$, we obtain
Next, we write the sum over reactions as a sum over complexes κ and then a sum over reactions having κ is their target (for the first term) or target (for the second):
We can pull out the factors involving $\frac{P}{Q}$:
but now the right side is zero by the complex balanced condition, Equation (22). Thus, we have
whenever $P\left(t\right)$ evolves according to the rate equation and Q is a complex balanced equilibrium.

$$\frac{d}{dt}I(P\left(t\right),Q)=\sum _{i\in X}{\dot{P}}_{i}ln(\frac{{P}_{i}}{{Q}_{i}}),$$

$$\begin{array}{ccc}{\displaystyle \frac{d}{dt}I(P\left(t\right),Q)}& =& {\displaystyle \sum _{i\in X}\sum _{\tau \in T}r\left(\tau \right)\left({t}_{i}\left(\tau \right)-{s}_{i}\left(\tau \right)\right)ln(\frac{{P}_{i}}{{Q}_{i}})\phantom{\rule{0.277778em}{0ex}}{P}^{s\left(\tau \right)}}\hfill \\ \\ & =& {\displaystyle \sum _{i\in X}\sum _{\tau \in T}r\left(\tau \right)\left[ln\left({\left(\frac{{P}_{i}}{{Q}_{i}}\right)}^{{t}_{i}\left(\tau \right)}\right)-ln\left({\left(\frac{{P}_{i}}{{Q}_{i}}\right)}^{{s}_{i}\left(\tau \right)}\right)\right]{P}^{s\left(\tau \right)}.}\hfill \end{array}$$

$$\frac{P}{Q}=(\frac{{P}_{1}}{{Q}_{1}},\cdots ,\frac{{P}_{k}}{{Q}_{k}}),$$

$$\begin{array}{ccc}{\displaystyle \frac{d}{dt}I(P\left(t\right),Q)}& =& {\displaystyle \sum _{\tau \in T}r\left(\tau \right)\left[ln\left({\left(\frac{P}{Q}\right)}^{t\left(\tau \right)}\right)-ln\left({\left(\frac{P}{Q}\right)}^{s\left(\tau \right)}\right)\right]{P}^{s\left(\tau \right)}}\hfill \\ \\ & =& {\displaystyle \sum _{\tau \in T}r\left(\tau \right)\left[ln\left({\left(\frac{P}{Q}\right)}^{t\left(\tau \right)}\right)-ln\left({\left(\frac{P}{Q}\right)}^{s\left(\tau \right)}\right)\right]{\left(\frac{P}{Q}\right)}^{s\left(\tau \right)}{Q}^{s\left(\tau \right)}.}\hfill \end{array}$$

$$\frac{d}{dt}I(P\left(t\right),Q)\le \sum _{\tau \in T}r\left(\tau \right)\left[{\left(\frac{P}{Q}\right)}^{t\left(\tau \right)}\phantom{\rule{-0.166667em}{0ex}}-{\left(\frac{P}{Q}\right)}^{s\left(\tau \right)}\right]{Q}^{s\left(\tau \right)}.$$

$$\frac{d}{dt}I(P\left(t\right),Q)\le \sum _{\kappa \in X}\left[\sum _{\tau :t\left(\tau \right)=\kappa}r\left(\tau \right){\left(\frac{P}{Q}\right)}^{t\left(\tau \right)}{Q}^{s\left(\tau \right)}-\sum _{\tau :s\left(\tau \right)=\kappa}r\left(\tau \right){\left(\frac{P}{Q}\right)}^{s\left(\tau \right)}{Q}^{s\left(\tau \right)}\right].$$

$$\frac{d}{dt}I(P\left(t\right),Q)\le \sum _{\kappa \in X}{\left(\frac{P}{Q}\right)}^{\kappa}\left[\sum _{\tau :t\left(\tau \right)=\kappa}r\left(\tau \right){Q}^{s\left(\tau \right)}-\sum _{\tau :s\left(\tau \right)=\kappa}r\left(\tau \right){Q}^{s\left(\tau \right)}\right],$$

$$\frac{d}{dt}I(P\left(t\right),Q)\le 0,$$

As noted above, a reaction network where every complex consists of a single species gives a linear rate equation. In this special case we can strengthen the above result: we have
whenever $P\left(t\right)$ and $Q\left(t\right)$ evolve according to the rate equation. The reason is in this case, the rate equation is also the master equation for a Markov process. Thus, we can reuse the argument leading up to inequality (13) for Markov processes, since nothing in this argument used the fact that the probability distributions were normalized.

$$\frac{d}{dt}I(P\left(t\right),Q\left(t\right))\le 0,$$

## 6. Conclusions

We have seen theorems guaranteeing that relative information cannot increase in three different situations: evolutionary games described by the replicator equation, Markov processes, and reaction networks. In all cases, the decrease of relative entropy is closely connected to the approach to equilibrium as $t\to \infty $. For the replicator equation, this equilibrium is a dominant mixed strategy. For a Markov process, whenever there is a unique steady state, all probability distributions approach this steady state as $t\to \infty $. For reaction networks, the appropriate notion of equilibrium is a complex balanced equilibrium, generalizing the more familiar concept of detailed balanced equilibrium.

It is natural to inquire about the mathematical relation between these results. Inequality (24) for Markov processes resembles inequality (23) for reaction networks. However, neither result subsumes the other. The master equation for a Markov process is a special case of the rate equation for a reaction network. However, the result for reaction networks says only that
when Q is a complex balanced equilibrium and $P\left(t\right)$ obeys the rate equation, while the result for Markov processes says that
whenever $P\left(t\right)$ and $Q\left(t\right)$ obey the master equation. Furthermore, neither of these inequalities subsume or are subsumed by the result for the replicator equation, inequality (8). Indeed, this result applies only to the probability distributions obtained by normalizing population distributions, not populations. Furthermore it is “turned around”, in that sense that q appears first:
whenever $p\left(t\right)$ obeys the replicator equation and q is a dominant strategy. We know of no results showing that $I\left(p\right(t),q)$ is nonincreasing when $p\left(t\right)$ obeys the replicator equations, nor results showing that $I\left(P\right(t),Q)$ or $I(Q,P(t\left)\right)$ is nonincreasing when $P\left(t\right)$ obeys the Lotka–Volterra equation.

$$\frac{d}{dt}I(P\left(t\right),Q)\le 0,$$

$$\frac{d}{dt}I(P\left(t\right),Q\left(t\right))\le 0,$$

$$\frac{d}{dt}I(q,p\left(t\right))\le 0,$$

In short, while relative entropy is nonincreasing in the approach to equilibrium in all three situations considered here, the details differ in significant ways. A challenging open problem is thus to find some “super-theorem” that has all three of these results as special cases. The work of Gorban [21] is especially interesting in this regard, since he tackles the challenge of finding new nonincreasing functions for reaction networks.

## Acknowledgments

We thank the referees for significant improvements to this paper. We thank Manoj Gopalkrishnan [34] for explaining his proof that I(P(t),Q) is nonincreasing when P(t) evolves according to the rate equation of a reaction network and Q is a complex balanced equilibrium. We thank David Anderson [35] for explaining Martin Feinberg’s proof of this result. We also thank NIMBioS, the National Institute for Mathematical and Biological Synthesis, for holding a workshop on Information and Entropy in Biological Systems at which we presented some of this work.

## Author Contributions

John C. Baez and Blake S. Pollard did the research, carried out the computations and wrote the paper. Both authors have read and approved the final manuscript.

## Conflicts of Interest

The authors declare no conflict of interest.

## References

- Crooks, G.E. On measures of entropy and information. Available online: http://threeplusone.com/info (accessed on 27 January 2016).
- Gorban, A.N.; Gorban, P.A.; Judge, G. Entropy: The Markov ordering approach. Entropy
**2010**, 12, 1145–1193. [Google Scholar] [CrossRef] - Hobson, A. Concepts in Statistical Mechanics; Gordon and Breach: New York, NY, USA, 1971. [Google Scholar]
- Baez, J.C.; Fritz, T. A Bayesian characterization of relative entropy. Theory Appl. Categories
**2014**, 29, 422–456. [Google Scholar] - Cover, T.M.; Thomas, J.A. Elements of Information Theory, 2nd ed.; Wiley: Hoboken, NJ, USA, 2006. [Google Scholar]
- Pollard, B. Open Markov processes: a compositional perspective on non-equilibrium steady states in biology.
**2016**. [Google Scholar] - Harper, M. Information geometry and evolutionary game Theory.
**2009**. [Google Scholar] - Harper, M. The replicator equation as an inference dynamic.
**2009**. [Google Scholar] - Akin, E. The Geometry of Population Genetics; Springer: Berlin/Heidelberg, Germany, 1979. [Google Scholar]
- Akin, E. The differential geometry of population genetics and evolutionary games. In Mathematical and Statistical Developments of Evolutionary Theory; Lessard, S., Ed.; Springer: Berlin/Heidelberg, Germany, 1990; pp. 1–93. [Google Scholar]
- Hofbauer, J.; Schuster, P.; Sigmund, K. A note on evolutionarily stable strategies and game dynamics. J. Theor. Biol.
**1979**, 81, 609–612. [Google Scholar] [CrossRef] - Sandholm, W.H. Evolutionary game theory. Available online: http://www.ssc.wisc.edu/~whs/research/egt.pdf (accessed on 27 January 2016).
- Smith, J.M. Game theory and the evolution of fighting. In On Evolution; Edinburgh University Press: Edinburgh, UK, 1972; pp. 8–28. [Google Scholar]
- Smith, J.M. Evolution and the Theory of Games; Cambridge University Press: Cambridge, UK, 1982. [Google Scholar]
- Thomas, B. On evolutionarily stable sets. J. Math. Biol.
**1985**, 22, 105–115. [Google Scholar] [CrossRef] - Mitchell, M. An Introduction to Genetic Algorithms; MIT Press: Cambridge, MA, USA, 1998. [Google Scholar]
- Friston, K.; Ao, P. Free energy, value, and attractors. Comput. Math. Methods Med.
**2012**, 2012, 937860. [Google Scholar] [CrossRef] [PubMed] - Edelman, G.M. Neural Darwinism: The Theory of Neuronal Group Selection; Basic Books: New York, NY, USA, 1987. [Google Scholar]
- Nielsen, R. Statistical Methods in Molecular Evolution; Springer: Berlin/Heidelberg, Germany, 2005. [Google Scholar]
- Sober, E.; Steel, M. Entropy increase and information loss in Markov models of evolution. Biol. Philos.
**2011**, 26, 223–250. [Google Scholar] [CrossRef] - Gorban, A.N. General H-theorem and entropies that violate the Second Law. Entropy
**2014**, 16, 2408–2432. [Google Scholar] [CrossRef] - Liese, F.; Vajda, I. Convex Statistical Distances; Teubner: Leipzig, Germany, 1987. [Google Scholar]
- Moran, P.A.P. Entropy, Markov processes and Boltzmann’s H-theorem. Math. Proc. Camb. Philos. Soc.
**1961**, 57, 833–842. [Google Scholar] [CrossRef] - Price, H. Time’s Arrow and Archimedes’ Point: New Directions for the Physics of Time; Oxford University Press: Oxford, UK, 1997. [Google Scholar]
- Zeh, H.D. The Physical Basis of the Direction of Time; Springer: Berlin/Heidelberg, Germany, 2001. [Google Scholar]
- Norris, J.R. Markov Processes; Cambridge University Press: Cambridge, UK, 1997. [Google Scholar]
- Rogers, L.C.G.; Williams, D. Diffusions, Markov Processes, and Martingales: Volume 1, Foundations, 2nd ed.; Cambridge University Press: Cambridge, UK, 2000. [Google Scholar]
- Rogers, L.C.G.; Williams, D. Diffusions, Markov Processes, and Martingales: Volume 2, Itô Calculus, 2nd ed.; Cambridge University Press: Cambridge, UK, 2000. [Google Scholar]
- Ethier, S.N.; Kurtz, T.G. Markov Processes: Characterization and Convergence; Wiley: Hoboken, NJ, USA, 2005. [Google Scholar]
- Baez, J.C.; Biamonte, J. Quantum Techniques for Stochastic Mechanics.
**2015**. [Google Scholar] - Korobeinikov, A. Global properties of basic virus dynamics models. Bull. Math. Biol.
**2004**, 66, 879–883. [Google Scholar] [CrossRef] [PubMed] - Horn, F.; Jackson, R. General mass action kinetics. Arch. Ration. Mech. Anal.
**1972**, 49, 81–116. [Google Scholar] [CrossRef] - Feinberg, M. Lectures on chemical reaction networks. Available online: https://crnt.osu.edu/LecturesOnReactionNetworks (accessed on 27 January 2016).
- Gopalkrishnan, M. Lyapunov functions for complex-balanced systems. Available online: https://johncarlosbaez.wordpress.com/2014/01/07/lyapunov-functions-for-complex-balanced-systems/ (accessed on 27 January 2016).
- Anderson, D. Comment on Azimuth Blog, 2014. Available online: https://johncarlosbaez.wordpress.com/2014/01/07/lyapunov-functions-for-complex-balanced-systems/#comment-35537 (accessed on 27 January 2016).

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