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A Clonal Selection Algorithm and Extensions

JASON BROWNLEE
Technical Report 070521A
Complex Intelligent Systems Laboratory, Centre for Information Technology Research,
Faculty of Information and Communication Technologies, Swinburne University of Technology
Melbourne, Australia
jbrownlee@ict.swin.edu.au

Abstract-The clonal selection theory suggests an information maturation of response


processing principle of the selection and proliferation of
The immune system is envisaged as being situated in
temporally useful information. The proliferation strategy
an environment where the task to perform is pattern
promotes maturation of response via blind mutation and
recognition. This pattern recognition task is achieved
anticipation of selection through adjusted information densities.
using an oracle function to which system patterns are
This work explores the clonal selection principle as an
submitted, and amorphous affinity scorings returned. In
information-processing algorithm and proposes (1) a minimal
this regard, affinity is an extrinsic property of the
approach, (2) an elaborated approach, and (3) implications and
system; it is assigned externally, and implies the
extensions of the proposed system.
temporal usefulness of a pattern for an unknown reason.
Keywords-Clonal Selection Theory, Algorithm, Artificial
The application of the oracle function may be
Immune System conceptualised as the pointing out of some system
patterns that are currently meaningful, to which the
I. INTRODUCTION system must respond.
The clonal selection principle is an abstraction of the Principle: Affinity is inherently extrinsic and only has
clonal selection theory an describes a stimulus response meaning for a given antigen, and a give receptor, at a
adaptive plan in which antigen select cell receptors given time
based on affinity resulting in clonal expansion, The system is allocated limited resources in which to
maturation by hypermutation and cell differentiation. store the repertoire of receptors, thus the resources
This work proposes a simple clonal selection algorithm allocated (space complexity) must be used effectively in
based on this adaptive plan. Natural extensions to this the context of the problem. Further, the direct evaluation
simple algorithm are enumerated and fundamental of patterns is also a moderated resource that must be
concerns with the approach are addressed such that the used sparingly (time complexity), such that the system is
result is a class of information-processing algorithms. capable of adaptation in the absence of additional
Section II summarises some design principles in external pattern evaluation.
devising a clonal selection algorithm. Section III Principle: Space and time complexity are limited
proposes a minimal clonal selection algorithm that resources (cost more than the internal operations of the
considers the clonal selection principle and the outlined system), thus must be used efficiently to promote the
design principles. Section IV elaborates on the minimal efficacy of the system in the domain
algorithm by expanding some of the algorithm steps into
sub-tasks and in adding an additional algorithm step. A binary encoding for pattern representation provides
Section V discusses the implication of emergent cells a flexible basis for investigating the clonal selection
classes in the elaborated algorithm, and proposes a principle. A bit string facilitates genetic-like operators
number of natural extensions of the approach. such as copying errors during duplication and
transformation via transcription for mapping into
II.SOME DESIGN PRINCIPLES domains. In addition, pattern recognition properties are
easily realised such as genetic similarity (binary
This section provides an ensemble of design distance), binding (matching function), and generation of
principles that influence the proposal and extension of na ve patterns (random bit strings).
the clonal selection algorithm.
Principle: Use of a binary representation for pattern
The clonal selection principle is (1) the external recognition
identification of useful patterns, (2) the internal
duplication, and modification of identified internal An effective realisation of the clonal selection
patterns. The system is concerned with providing the principle is a system in which relevant cognitive
best possible response to an antigenic query and properties of pattern recognition are self-regulating in
internally responding to the query through a process of response to the regularities of the domain. Concerns
blind adaptation. such as memory, acceptance of novelty, clonal
dominance, receptor densities, and maturation of
Principle: External stimulation which results in response are emergent properties of an effective
internal activation that takes the form of blind realisation.

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Principle: A self-regulating system with emergent selection principle to the simplest possible instantiation
cognitive properties as an algorithm. The central theme of this algorithm is
Some adaptive tools available to the clonal selection iterative selection and mutation upon a population. The
principle include competition between receptors for algorithm is important because it demonstrates some
recognition by antigen, attrition in the death and removal fundamental induction characterises of the principle, and
of unused receptors, and the proliferation and blind starkly highlights some problems with such an
maturation of useful receptors. Information available to minimalist realisation.
these tools include temporal usefulness of receptors Step1: Initialise the repertoire with a set of randomly generated bit strings
(both current and past) and the genetic similarity of Step2: Expose the system to a randomly selected antigen
receptors. Step3: Select the highest affinity bit string from the evaluated repertoire
Step4: Clone the best matching cell with genetic copying errors
Principle: Tools include competition, attrition, and Step5: Replace the best matching cell with the clone
maturation in proliferation, available information Step6: Repeat steps 2-5 until a stopping condition is triggered
includes temporal usefulness and genetic similarity of Figure 1 - A minimal clonal selection algorithm
receptors
The algorithm presumes the existence of a set of
The effective use of these tools and information will antigen patterns and a repertoire of receptor patterns. It
result in pressures in the system that the guide
behaviour. The effective tuning and application of these also presumes an affinity mapping function for an
pressures define the behaviour (efficacy) of the system antigen and receptor, and genetic operators for cloning
in a domain as well as the performance of the system of a receptor.
(space and time complexity). Perhaps the most important Antigenic Set: A set of antigen patterns that are exposed to the system. May
pressure in the system is competition, which includes be static or dynamic, known or unknown, binary or some other representation.
The order in which they are exposed to the system is presumed random,
competition for clonal selection, competition for although may be any distribution over the antigenic set. Further, the algorithm
survival, and competition for replacement into the only performs a cycle on the availability of antigen.
repertoire. Antigen: A single pattern to which the system is exposed. This external
pattern is not directly observable by the system, rather it is interacted with
Principle: Competition is the guiding pressure of the indirectly by the receptors in the repertoire via the affinity mapping function.
system Repertoire: Set of internal system patterns that encapsulate the information
induced by the system processes. Receptors do not interact directly with the
The system is anticipatory in principle. The outcome environment, thus input patterns never leave the system. They are created,
of the proliferation and maturation is the assumption that used, and destroyed in the repertoire.
patterns that are currently and temporally useful, will be Receptor: A single pattern in the system. Receptor patterns interact with
useful in the future. Thus, the economy of this antigen patterns indirectly via an affinity mapping function, although they
anticipation is payoff, the exploitation of patterns that may interact with each other directly based on intrinsically available
heuristics.
are most likely to payoff (be useful) in the systems Affinity Mapping Function: The Antigenic set and the repertoire are
future exposures to antigen. decoupled and interact indirectly via the affinity mapping function which acts
as mediator. The mapping function may or may not transform receptor
Principle: The system anticipates useful patterns patterns and antigen patterns such that an affinity may be assigned. The
guided by the pursuit of expected payoff affinity assigned has meaning for a given antigen, and a given receptor at a
A given receptor is redundant, such that it may be given time.
Genetic Operators: The genetic operators are used in the cloning of high
lost without major detriment to the systems performance. affinity receptors. They are responsible for the duplication of genetic material
In addition to this information redundancy, the cells do of a given receptor with copying errors. These errors may include insertions,
not live forever; rather they are continually turned over. deletions, inversions, and point mutations.
Unused cells are removed in a form of attrition, active Figure 2 - Summary of the principle characteristics of the minimal clonal
cells are employed in the response, and there is a selection algorithm
constant stream of new cells created as a function of
exposure. Na ve cells are also continually introduced
into the system. Initialise

Principle: A given receptor is redundant and the


Expose
repertoire is in state of constant flux
The clonal selection principles describe a combined Select
anticipatory learning scheme that is coupled with a
defensive response mechanism. Learning, adaptation, Clone
and memory formation occur online (as opposed to
offline) at the same time as the system must neutralise Replace
pathogen. Thus, the scheme embodies the efficiency and
efficacy tradeoffs associated with online learning. No
Stop?
Principle: The clonal selection scheme describes an Yes
online learning and response system End

III.A MINIMAL CLONAL SELECTION ALGORITHM


Figure 3 Flow chart of the minimal clonal selection algorithm
This first algorithm represents an exercise in
reduction, specifically the reduction of the clonal

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The repertoire of receptors will rapidly stabilise in all receptors in the repertoire
response to exposed antigen. The winner-take-all Figure 5 - Summary of four base measures in which to compare extensions of
selection of receptors by antigen will result in the the minimal clonal selection algorithm
specialisation of receptors in the repertoire for antigen.
The default acceptance of clones may result in the
IV.ELABORATIONS ON THE ALGORITHM
receptors not becoming too specific to the antigen
(maintaining some generality), further the acceptance This section proposes four different ways of changing
regardless of improvement will influence the systems the minimal clonal selection algorithm to address the
speed of convergence with a chronic antigen. principle concern of the approach: improve resource
utilisation by addressing a given antigen from multiple
Best Response: The winner-take-all (WTA) principle employed in responding perspectives.
to antigen ensures that the system provides its best possible response for a
given exposure.
Stable: The WTA principle will likely cause the system to stabilise with A. Elaborate Selection
regard to consistency of response. This stabilisation process will be rapid, The algorithm may be rephrased in between the
reinforced by the specialisation of receptors for antigen.
Specialisation: The repertoire will self-organize such that receptors specialise
Step3 (selection), and Step4 (cloning). The selection step
for a given antigen. This specialisation will be reinforced resulting in the implies (at least) three tasks, which may be elaborated:
stabilisation of the repertoire and the continuous iterative adjustment of
receptors for their associated receptor.
1. The evaluation of the repertoire of receptors
Moderated Convergence: The acceptance of clones irrespective of their within the context of a given antigen (calculate
affinity to the antigen as replacements for the highest matching affinity will affinity)
result in a convergence that is moderated by random jumps. The system will
converge (stabilise), but will do so in the context of a continual local search 2. The returning of the highest affinity receptor to
around best matching receptors. meet the needs that the antigen represents (a
Figure 4 - Summary of some properties of a minimal clonal selection
query, a threat, etcetera)
algorithm 3. The identification of a high-affinity set of
receptors that are currently useful and may be
A consequence of the pattern-exploitative properties made more useful (via cloning)
of the winner-take-all principle is that some receptors in
the repertoire may never win. The effect of not winning Thus the minimum clonal selection algorithm may be
is that a portion of the limited resources employed by the redefined as follows:
system are unused. For some domains, this may be an Step3a: Evaluate the repertoire in the context of the selected antigen
efficient side effect, and those receptors that are not used Step3b: Return the highest-affinity antigen to meet the needs of the antigen
for a time may be removed, leaving a repertoire of useful Step3c: Select a high-affinity set of activated receptors
receptors. Taken to an extreme, a particularly general Figure 6 - Modified clonal selection algorithm with an activated set
receptor may always win. The effect is that the receptor
(or small set of receptors) will indirectly (directed The change to the algorithm presumes the presence
random) seek an average of the patterns to which they of an activated set, which in the minimal clonal selection
respond. These general receptors will handicap the algorithm consists of a single receptor: the highest
system, and prevent the specialisation of receptors to affinity receptor for the exposed antigen.
differing patterns. The required replacement means that
Activation Set: A collection of receptors that have high affinity for a given
untested clones (with errors) supplant tested patterns antigen at a specific exposure time, which are subjected to cloning.
(which we know something about).
Figure 7 - Summary of the principle components of the change to the selection
Concern: Winner take all will create dominant set in the minimal clonal selection algorithm
winners resulting in ineffective application of available
resources and handicapped performance The winner-take-all principle is defined by the
highest affinity receptor addressing an antigen, but also
The implied solution is to raise a set of receptors for being the subject of adaptation (getting it all). In
each receptor, to address a given antigen from multiple
enlarging the activation set, the winner does not get all,
and (likely) different perspectives. This solution is but instead, gets most (of the computation). Further, the
facilitated by the underutilised resources of the winner- activation set may or may not possess the highest
take-all principle. These resources may be considered affinity receptor, thus the winner may only get half of
holes in activity (inactivity), and may be plugged with the outcome of the exposure. The increased size
these so-called different perspective receptors. The


activation set changes the algorithm from monoclonal


obvious effect of such a behavioural modification is the activation to polyclonal clonal activation, allowing the
slowing of system convergence, and system instability. repertoire to address a given antigen from multiple
The intended benefit is the increased utilisation of perspectives (runners up or competitors). A further step
resources and increased performance. All of these in addressing the concern with the minimal algorithm, is
factors may be measured and compared. that the activation schedule is likely to ensure that the
Convergence: A measure of time (algorithm cycles, epochs of the antigenic algorithm utilises more resources. The following
set) until major changes to the repertoire (receptor genetic composition) and outlines some schemes for selecting an activation set:
system response (affinity to antigen) stabilise
Stability: Amount of variation in repertoire composition (receptor genetic Winner-take-all: (WTA), the baseline for comparison as employed in the
composition) and system response (affinity to antigen) after convergence minimal clonal selection algorithm. The activation set contains only the
Performance: The systems ability to respond to an antigenic set (affinity) highest-affinity receptor.
Utilisation: The frequency of use (time in algorithm cycles since last use) of Greedy: The set is selected as a collection of the highest affinity receptors

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Probabilistic: The set is selected probabilistically with a bias towards higher function, which is applied in the creation of members of
affinity receptors (such as with a ranking, tournament or biased roulette wheel the clonal set (copying errors), and the selection of
method). members of each activated receptors clonal set which in
Random: The set is selected using a uniformly random distribution function.
aggregation becomes the replacement set.
Figure 8 - Proposal of some activation set selection schemes
Clonal Set: A set of cloned receptors with a common genetic ancestor, which
is a member of the current activated set. The clone is created as duplicates
The three proposed selection schemes require a user (clones) of the activated progenitor with copying errors.
parameter, which defines the size of the set. Given the Mutation Function: Employed to create genetic duplicates of a given
cloning step, a given receptor may not enter the set more activated receptor, which may introduce copying errors such as additions,
than once (no reselection). If the best matching receptor deletions, inversions, and point mutations of the binary string
is not added to the activation set, it will not be replaced Replacement Set: A set of clones selected from each activated receptors
clonal set. This set replaces each of the members of the activated set, thus
and the information it defines is retained. A further must contain the same number of receptors.
implication is that there is also no chance that that
specific piece information (winner) may be improved Figure 10 - Summary of the components of the elaborated cloning procedure
upon. Activation is a reward it is the verification that a
piece of information (receptor) is presently useful, thus, In the case of the minimal algorithm, the activate set
the activation set must be small (unless everything is contains the highest affinity receptor. The clonal set
useful). created for this receptor contains a single clone created
with copying errors, which is in turn selected into the
Oligoclonal Principle: The number of receptors replacement set.
selected in the active set is small relative to the size of
the repertoire. A single activated receptor may fill the clonal set
with an arbitrary number of clones (parameterised), each
Another concern is that the activation set may (likely) with a different genetic composition given
possess receptors that are not relevant to the antigen. coping errors. The number of clones could be a function
This may be a desirable effect in that receptors that are of the relative affinity of the progenitor to other
not used often may be adjusted such that they become receptors facilitating a higher the affinity, the more
useful, and the system may become more responsive clones created principle which may be useful in


(increased performance) for a novel antigenic pattern. distinguishing the clonal rate of receptors in an activated
Alternatively, a consequence is that information that is set larger than one.
desirable for other purposes (such as for another antigen)
Parameterised: The number of clones created for an activated receptor is
may be lost at that time. defined by an arbitrary parameter.
Concern: An alternative selection scheme of the Affinity Proportional: The number of clones created for an activated
activation set may result in the right information not receptor is proportional to the affinity of the receptor to other receptors. For
an activation set of one WTA), the rate may be a function of the receptors
been maturated, and the wrong information being affinity delta to the second highest affinity receptor. For an activation set of
maturated >1 or non WTA principle, the clonal rate may be a proportionate function of
the receptors affinity rank in the repertoire or activated set.
The cloning and maturation process is antigen
invariant, so it is possible that the maturation of Figure 11 - Summary of some cloning schemes for defining the size of an
irrelevant antigen may have a beneficial outcome. The activated receptors clonal set
concern from a computational perspective is that
computational resources may be employed Copying errors occur during the cloning of a receptor
unnecessarily. the effect of which are changes to the clones genetic
composition compared to its progenitor. Although the
B. Elaborate Cloning composition is changed, the clonal selection principle
suggests that progeny are within a neighbourhood of the
The cloning step (Step4) may be rephrased, and progenitor. Thus, the copying errors made during
elaborated into the following set of sub-tasks for each cloning have a high probability of creating a receptor
member of the activated receptor set: similar (duplicate) to the progenitor, and a low
1. Create a clone of genetically duplicate receptors probability of creating a receptor vastly different from
the progenitor. A copying error may not define the
2. Impose copying errors and mutations on the amount of conformation difference, but rather the
clone of receptors amount of genetic difference: mistakes in replicating
3. Select a clonal set of clones which may replace genetic material. Making multiple clones increasing the
members of the activated set chance of a copying error, but dramatically increases the
chance of making a receptor without a copying error.
Thus, the minimal clonal selection algorithm may be
redefined as the following: Cloning Principle: The more clones created, the
more chance of a copying error, and the much larger
Step4a: Clone each receptor in the activated set to create a clonal set
Step4b: Mutate each receptor in the clonal set for a given activated receptor chance of creating duplicates of the original receptor.
Step4c: Select a subset of each clonal set to compose a replacement set A duplicate receptor represents retention of
Figure 9 Modified clonal selection algorithm with elaborated cloning information, the small modification of a receptor
represent the gain (improvement) or loss (noise) of
The modified algorithm presumes the construction of existing information, and large modification of a
a clonal set for each member of activated set, a mutation receptor represents the loss of specific information and
the potential gain of new information.

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Parameterised: The amount of mutation may be defined by an arbitrary Supplant Set: A set of receptors from the repertoire, which are replaced by
parameter (such as a mutation probability). In the case of affinity- the replacement set which is composed of clones of activated receptors.
proportionate clonal set size, the affinity would also influence the number of Receptors the supplant set are kill, deleted from the system.
total mutations and number of duplicates and close-to-duplicate receptors are
created. Figure 15 - Summary of the principle components of the elaborated
Affinity Proportionate: The same relative affinity heuristics may be replacement mechanism
employed on the amount of copying errors. An inverse relationship may be
used such that the higher affinity of a receptor to an antigen, the less likely The default supplant set is the activated set of
copying errors are to occur in creating the receptors clonal set. receptors, the progenitors of the clones to which they are
Figure 12 - Summary of the mutation schemes being supplanted. The elaboration of the replacement
step allows the selection of receptors from the repertoire
The selection of a replacement set is the selection of to be replaced by clones of the activated set.
receptor clones that will replace the activation set. In the Activate Set: The active set (progenitors) are selected as the supplant set
case of each activated receptors clonal set holding a Random: Random receptors may be drawn from the repertoire such that the
single clone, no selection process is required, it is only size of the supplant set matches the replacement set.
when the aggregation of clonal sets is larger than the Figure 16 - Supplant set selection schemes
activated set that reduction of the union is required. It is
not the task of this selection task to replace the activated The capability to choose to not replace progenitor
set, but rather to propose a clonal set, which may be used receptors, the repertoire is provided with the ability to
in the replacement step. The default action for this both retain demonstrated high-affinity receptors, and
selection step, is thus to provide the union of clonal sets potentially higher-affinity clones of the receptor. In
as the replacement set. replacing repertoire members that have not been
Select All: The union of the clonal sets is taken as the replacement set, and the activated for a time (underutilised), this amendment to
size difference between the replacement set and the active set is reconciled (or replacement directly addresses the concern of the
not) by the replacement steps integration into the replacement set in the minimal clonal selection algorithm. A consequence of
repertoire this behaviour, is that receptors for other antigen (that
Similarity: The genetically most similar receptor of each clonal set to its
progenitor is selected into the replacement set
are useful) may also be replaced.
Probabilistic: Receptors may be selected probabilistically from each clonal Concern: In clones not replacing progenitors it is
set with a bias towards genetic similarity (or dissimilarity) to each clonal sets possible for information presently unrelated (to the
activated receptor. Alternatively, receptors may be drawn from clonal sets
proportional to the relative affinity of each clonal sets active receptor.
current antigen) to be replaced
Random: Receptors may be drawn randomly from the union of the clonal sets The supplant set defines the members of the
Figure 13 - Summary of the receptor set selection schemes repertoire that the replacement set compete with for a
position in the repertoire. The default form of
Cloning, mutation, and replacement set selection do competition is no competition the replacement set
not naturally impact on the primary concern of the always wins against the activation set. Alternatively,
minimal clonal selection algorithm. In replacing with a competition perspective, a potential supplant set
receptors with high approximations (duplications or near may be selected for each member of the replacement set.
duplications) will assist the WTA principle by Similarity: A replacement receptor may compete with a supplant set based on
maintaining a stable repertoire. Replacing the active set genetic similarity. The clones progenitor is likely to be the genetically most
with low receptor approximations will dampen the WTA similar receptor in the repertoire, and if the supplant set is drawn per-
principle and promote the utilisation of the broader replacement receptor, clonal siblings (if there are any) are also likely to be the
repertoire, without any adaptive capability. most similar receptors in the repertoire.
Affinity: A replacement receptor may assume the affinity of its parent
The fidelity of active receptor clones does directly activated receptor, and thus may compete based on affinity. Affinity similarity
influence information retention, and the acquisition and may be used to select receptors in the receptor set that that have a similar
rate of acquisition of new information (learning). present utility, although potentially different genetic basis. Affinity may be
used as a discriminator in which clones are rejected after the application of
another heuristic such as genetic similarity (assuming something other than
C. Elaborate Replacement WTA is used to prepare the active set)
The replacement step (Step5) may be rephrased, and Utilisation: Replacement receptors may compete with members of the
supplant set based upon the utilisation of receptors in that set. A default policy
elaborated into the following tasks: of replace poorly utilised receptors may be used.
1. The selection of a replacement (supplant) set Figure 17 - Summary of competition schemes for the replacement and
from the repertoire to complement the replacer supplant set of receptors
set (derived from clonal sets)
2. Replace the supplant set with the replacement set Ideally, the replacement scheme will be biased
toward replacing (1) genetically similar (2) underutilised
Thus, the minimal clonal selection algorithm may be receptors with (3) lower affinity than the replacer
redefined as follows: receptor s progenitor. Each of the three concerns support


Step5a: Select a subset of the repertoire to compose the supplant set each other, thus, this may be defined as a multiple
Step5b: Replace the supplant set with the replacement set objective problem.
Figure 14 Modified clonal selection algorithm with elaborated replacement
D. Add Na ve Receptors
The modified algorithm presumes the construction of A step may be added into the minimal clonal
a supplant set. selection algorithm after replacement (Step5) that inserts

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na ve (random) receptors into the repertoire. This step algorithm as an elaborated clonal selection algorithm.
involves the following tasks as follows: Step1: Initialise the repertoire with a set of randomly generated bit strings
1. Generation a na ve receptor set Step2: Expose the system to a randomly select an antigen
Step3a: Evaluate the repertoire in the context of the selected antigen
2. Selection of a supplant set Step3b: Return the highest-affinity antigen to meet the needs of the antigen
Step3c: Select a high-affinity set of activated receptors
3. Replacement of supplant set by the replacement Step4a: Clone each receptor in the activated set to create a clonal set
set Step4b: Mutate each receptor in the clonal set for a given activated receptor
Step4c: Select a subset of each clonal set to compose a replacement set
Thus, the minimal clonal selection algorithm may be Step5a: Select a subset of the repertoire to compose the supplant set
redefined as follows: Step5b: Replace the supplant set with the replacement set
Step6a: Generate a naive set of randomly generated bit strings
Step6a: Generate a naive set of randomly generated bit strings
Step6b: Select a subset of the repertoire to compose the supplant set
Step6b: Select a subset of the repertoire to compose the supplant set
Step6c: Replace the supplant set with the naive set
Step6c: Replace the supplant set with the naive set
Step7: Repeat steps 2-6 until a stopping condition is triggered
Figure 18 Modified clonal selection algorithm with added na ve replacement Figure 20 - Elaborated Clonal Selection Algorithm

The amendment to the algorithm presumes the The elaborated clonal selection contains the same
generation of a na ve receptor set, the selection of primary tasks of the minimal clonal selection algorithm
supplant set and competition for replacement. (initialisation, exposure, selection, cloning, and
replacement), with specific tasks of each step expanded
Na ve Set: A set of randomly generated receptors to insert into the repertoire upon. The elaborated algorithm also has an added na ve
Supplant Set: A set of receptors selected form the repertoire to replace with cell replacement step.
the na ve receptor set

Figure 19 - Summary of the principle components of the naive receptor Evaluate


amendment
Initialise Return

The preparation and replacement of a supplant set has Select


many of the same concerns to that of the selection and Expose
replacement of a supplant set to be replaced by the
replacement set after cloning. Two important differences Select
Clone

include the lack of parental affinity associated with the Mutate

generated na ve receptors, and the knowledge that Select


receptors in the repertoire are na ve. The lack of parent Clone

affinity limits the heuristics that may be used in the


preparation of the supplant set and in the competition for Replace Select

replacement between the supplant set and the na ve set. Replace

The knowledge that a receptor is na ve allows additional Naive


features such as the replacement of older unused na ve Generate
cell by newer na ve cells. This step may address the
concerns of the minimal clonal selection algorithm by no
Stop?
Select

replacing those receptors that are underutilised with Replace

na ve receptors. This strategy may permit new receptor yes


lines to be investigated for a given antigen, if the na ve End
receptor lines are able to take root . A concern with this


approach is that the utility of na ve receptors may be less


than that of the receptors that they are replacing, and the Figure 21 - Elaborated Clonal Selection Algorithm
likelihood of a na ve receptor having a higher affinity
than a matured affinity is low. V.SOME IMPLICATIONS AND EXTENSIONS
This mechanism may be suited to replace those This section discusses some implications and
underutilised receptors that fall through the cracks of extensions to the elaborated clonal selection model and


the replacement scheme employed by the clonal set elaborations proposed above. In particular, this section is
based replacement set. In the scenario in which the concerned with the broader concerns when the system is
replacement set performs replacement based on genetic considered holistically with all elaborations enacted.
similarity, it is likely that the repertoire may reach a
stable point of genetic-similarity-based replacement that A. Emergent Cell Types (Classes)
leaves genetically dissimilar receptors untouched in the It is proposed that the system can evolve emergent
repertoire. In this case, the benefits of a genetic-invariant cell types through the effective application of selection
(utility based) na ve receptor replacement scheme are and replacement heuristics. These cell types are not
apparent. delineated by anything other than level of maturation for
their antigen (affinity) and their usefulness through time
E. Elaborated Clonal Selection Algorithm (activation count). The result is a continuum of receptors
Given all the elaborations of this section, we may with the following (arbitrarily) defined classes.
now define a rephrased minimal clonal selection
Memory Cell: Relatively high affinity for a given antigen, with many

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activations in its lifetime, not likely to be replaced by anything other than a antigen (low affinity), assuming the present antigen is
competing effector cell on its ascension to memory cell chronic, they will be supplanted. If effectors are useful
Effector Cell: Moderate to high affinity receptor for a given antigen with few
activations, likely to be replaced by other competing effectors
to the present antigen (high affinity), they take residence
Naive Cell: A low to moderate affinity receptor for most antigen with none or in the repertoire. If their usefulness persists (multiple
very few activations, likely to be replaced by an effector cell or another naive activations), they ascend to memory status (emergent).
cell
Memory Types: Memory cells (long lifetime of useful
Figure 22 - Propose cell types delineated by amount of activation and affinity activation) represent long-term memory that is difficult
for their antigen
to dislodge. Effector cells (short lifetime of moderate to
The desire is for the system to be configured such low useful activation) represent short and medium term
that competition is between receptors of the same cell memory that is relatively easy to dislodge.
type. Memory cells should be useful when competing for This has interesting implications in that the repertoire
their antigen (step3). Effector cells should also be useful and replacement scheme must facilitate the retention of
in competing for their antigen, although should be the effectors for long enough to allow them to take root if


fodder that is replaced by other effector cells for the an antigen exposure is moderately infrequent. A natural
same antigen, including clones of memory cells. Na ve inclination of the system will be for effector cells to be
cells (as well as low affinity effector cells) should be supplanted by effectors in the context of other antigen (if
useful in step3 in addressing novel antigen, and provide there are other antigen in the intervening interval), or to
fodder for low affinity clones, and randomly generated be replaced by na ve cells (in the absence of antigen in
receptors. the interval). The pressures must be finely balanced. The
Competition Principle: Competition at the various replacement pressures must be such that there is a
levels should be biased to be between information of the graceful fall-off in the survivability of useful effectors in
same context, the same level of usefulness, and the same the presence of infrequent antigen exposures.
age. Alternatively, cell lines created and matured for Effector Principle: Effectors are effectors because
differing antigen should cooperate (at the system level) they are created as needed for an antigen, and likely are
rather than compete. supplanted by other effectors for the antigen, and after
Memory cells for another antigen (low affinity) still some time, effectors for other antigen, and na ve cells
look like memory cells given a history of activations, (graceful falloff in that order).
thus discriminative pressure for memory is durability A chronic infection will result (eventually) in a
and usefulness. Effector cells for another antigen (low biased repertoire for that infection (takeover). Antigen
affinity) are difficult to distinguish between na ve cells. may not last forever, and novel antigen may arrive.
This difficulty implies that clones (new potential There are many reasons for na ve cells, although the
effectors) should only compete with other effectors for selection of a suitable time for their arrival may be
the same antigen (genetically similar, affinity similar difficult to determine a priori. Na ve cells are those
receptors). Thus the supplant selection and replacement receptors from an untested cell line, thus they
scheme (Step5a/b) should be biased toward similar themselves are untested, and most likely useless in
genetic composition, lower affinity, and low activation normal circumstances. In this regard, they are similar to
count. The pressure for effector-effector competition, large mutations of high affinity receptors (likely
although biased, will not preclude the replacement of an useless), underutilised cells that have not seen activation
effector for a different antigen, or a na ve cell, or even a in a long time (temporally useless), and receptors
memory cell for the same antigen that has not been used without activation in their lifetime such as unused
for some time. Further, the stabilising effects of winner- effectors and other na ve cells (temporally useless).
take-all (and variations) in conjunction with the genetic Thus, cell types may be delineated by their lifespan
clustering will result in the formation of genetically in the repertoire. Memory cells remain through long-
disparate memory cell lines. term usefulness, effector cells linger briefly to address
Memory is perhaps the most critical emergent temporal needs, and na ve cells fill in the gaps with a
property, facilitated by the ongoing self-organization of relatively short lifespan.
the repertoire into the other two types of memory (short Lifespan Principle: Cell types delineate relative
term and long term). The emergent memory must be receptor lifespan in the repertoire
robust enough such that if information that should
become memory is discovered, that it very likely for it to B. Extensions
become memory. Further, if memory is lost (damage), or
becomes irrelevant (pathogen is exterminated) the The elaborated clonal selection algorithm is a pattern
mechanisms are such that this self-organized repertoire recognition system in which input patterns are not only
cell hierarchy will adapt. recognized, but their existence recorded and organized
within the repertoire of receptors. This section briefly
Memory Principle: Cells are memory cells because describes some natural extensions to the proposed
they are consistently (multiple activations) demonstrated algorithm.
to be useful (high affinity)
Automatic Configuration
Effectors are variations on relatively and presently
high affinity receptors that are proposed to address an It is proposed that through effective configuration
immediate concern. If they are not useful to the present many of the aspects of the algorithm that lend
themselves to be parameterised may be addressed

CIS Technical Report 070521A May 2007 page 7 of 9


automatically by the processes of the algorithm. which a given receptor may match onto many different
Examples include (1) the size of the activated set, (2) the antigen that exhibit the same general pattern (cross-
number of clones created and resultant modification of reactivity).
knowledge, and (3) the amount of na ve cells inserted. Decoupled Representation: A more elaborate
The first two examples may be addressed through the receptor genetic representation facilitates variable
effective use of genetic composition and affinity deltas receptor size, recessive receptor information, and
as heuristics (a diverse and high affinity response). The higher-order (macro) changes resultant receptors
third example may be addressed through effective use of
activation history and last activation time as heurists for A decoupled genetic representation and pattern
replacement (unused, non-memory). recognition allows mutations to occur without effect to
the receptor (conformation), and receptors to change
Automatic Heuristics: Parameterisation assumes the without changes to the genetic material (mapping). It
meaningful tuning of behaviour, which implies also facilitates the storage of receptor information
underlying heuristics that govern that tuning. These without use (in the unmapped genetic representation),
heuristics may be applied automatically, and and high-order changes to receptors during clonal
dynamically. expansion.
The intent of such automatic configuration is that the Cell-Cell Recognition
system may allocate resources proportional to their
assessed requirement. Thus, hyper-activation and or Receptors are pattern recognition devices, and a
hyper-cloning may occur to address novel antigen or repertoire of them represents a pattern recognition
other reasons for poor affinity of response. Clonal machine. Receptors themselves are patterns of bit
dominance (takeover of the repertoire) may occur in a strings, thus a natural extension to explore is the
mono-antigenic environment, and hyper-naivety (many recognition of receptors by other receptors (a concept
na ve receptor replacements) may occur in high noise that is reminiscent of the network theory of
antigenic environments. A final seminal example is the immunology). A natural interpretation of cell-cell
automatic resizing of the repertoire in response to the recognition and interaction is the genetic-based
diversity of antigenic signals the system is exposed. This replacement heuristics involved in consolidating
would allow the repertoire to expand (bloat) in times of genetically similar groups of receptors, providing a
diverse exposures, and to contract via mass-attrition in regulation mechanism.
times of mono-antigenicity. Antigen-Independent Information Processing:
Elaborated Genetics Pattern recognition facilitates information longevity (via
increased activation counts and replication), thus
Variation is introduced via copying errors in receptor antigen-independent processing via intra-repertoire
duplication via insertions, deletions, inversions, and pattern recognition allows the repertoire to reinforce
point mutations. This mechanism may be elaborated previously acquired information.
through the use of a common genetic basis from which
receptors are drawn. The genetic basis used by each Cell-cell recognition may be used for information
receptor would still be subjected to variation, although processing in the absence of antigen, where the activated
the genetic basis is remapped by the receptor. This receptors themselves are promoted to antigen-like status
remapping decouples the affinity scoring from the in the repertoire. Interaction based on genetic similarity
genetic material and assigns it to the receptors mapping would not be suitable for this mechanism, as related
of portions of the genetic material in the form of its clones would continually activate each other. Instead, a
conformation. A simple example1 of this remapping is a mapping is required, that facilitates the activation of
simple masking scheme as follows: chains of receptors. Such chains would facilitate the
ongoing maintenance (via proliferation) and processing
[01111]
Receptor:
Conformation: [_01_1_1_1_]
(maturation) of information in the absence of antigen. A
Mapping: [#__#_#_#_#] simple example uses the elaborated genetic scheme,
Genetic: [1010101010] where the receptor represents a complement (negative)
Figure 23 - Example of a more elaborate genetic representation scheme
image of an input pattern. After activation and the
resultant cloning and replacement, the activated receptor
The base genetic material is mutated by whatever set is taken as an exposure to the repertoire (given its
means. The mapping may represent the genes


current activity). Thus, an activated receptor becomes


(collections of alleles) in the genome or perhaps a string the focus of the receptor repertoire, which will attempt to
of amino acids for the protein. The conformation may bind to it. This binding may be attempted in a number of
represent the string of amino acids, or the folded protein, ways such as: (1) on the activated receptors receptor
and finally the receptor represents the part of the protein pattern , (2) on the conformation, or (3) on the receptors


that does the pattern recognition. This scheme facilitates genetic composition (the first and second options
variable length receptors, and mutation of the mapping provide a natural interpretation of the metaphor). If
function, which inturn may also be defined in the genetic receptors are applied to a combination of the activated
material. Variable receptor lengths provides and receptors conformation and mapping (a trinary bit string,
promotes a mechanism of polyclonal recognition, in with # representing anything ) such a configuration
 

would promote the reinforcement of inverse-blocks of


1
This is just a trivial example scheme, one may use any suitable
contiguous antigen matching.
mapping scheme off-the-shelf or of their own devising Integrating Feedback

CIS Technical Report 070521A May 2007 page 8 of 9


Presently, the system is provided with information as organization, thus replacement tournaments may be
to its general performance for each input signal (which based on affinity for a current antigen, and activation
or may not be external). Additional holistic feedback history.
may be perceived by the system, perhaps as an analogy Spatial Competition: An arbitrary spatial structure
to the amount of tissue damage the system has currently (such as a toroidal lattice) for the repertoire may impose
endured (much like the danger theory of immunology). a neighbourhood-based (spatial) competition between
This perceived feedback may take the form of positive receptors that may supplant genetic composition-based
(reinforcement), neutral (nothing), and negative competition.
(discouragement) of the current receptors in the
repertoire. The feedback may be apportioned in different The underlying spatial structure manifests meaning
ways to the receptors, for example (1) the currently for the limitations on repertoire size, and the self-
active set of receptors is allocated a portion of the organisation qualities of receptors apportion
feedback, or (2) receptors in the repertoire are allocated responsibility for antigen to spatial regions. The spatial
feedback based on their relative recency of activation, structure further reinforces concerns of take-over of
and activation history. receptor families as a spatial concept, and (after
repertoire stabilisation) improves the efficiency of intra-
Feedback Principle: Provides an additional cell class competition. The spatial-based competition
information layer to receptors regarding the present promotes diversity as a spatial concept (on the lattice)
holistic performance of the system rather than a genetic concept (through genetic
Feedback is additional information about the systems comparisons), thus in addition to the efficiency
performance, thus the system requires some way of offerings, may provide a more natural fit with the
using this information after it is allocated. Feedback metaphor.
provides an additional information layer that may T-Cell Mediation
influence the algorithm, for example:
A second population of receptors may be introduced
1) Selection of high-affinity receptors: Those receptors (T cells) that mediate which of those receptors that are
that have high-affinity to a given antigen, and low activated may clone (reminiscent of the two-signal
feedback may not be suited to the antigen. Feedback theory of mediated clonal activation). This mediation
provides a way of ignoring the specificity of receptor requires the insertion of an additional step in the
for antigen facilitating corrective behaviour. algorithm between the selection of the activation set
2) Cloning and maturation of selected receptors: (Step3) and the cloning of the activation set (Step4). It
Feedback may provide a way of differentiating high- may be implemented as an additional selection step, in
affinity receptors such that the amount of resources which those receptors that are selected from the
allocated (number of clones), or amount of maturation activation set may proliferate, and those that are not
(mutation) may be tuned. selected are not secondarily activated, and do not
3) Replacement of receptors: Feedback provides an
proliferate.
additional information layer over the repertoire at Mediated Recognition: Mediated recognition allows
replacement time (for those receptors around during input signals to be remapped that applies a second level
the feedback). Thus, feedback may dominant the of meaning to input signals and facilitates the
replacement probability (when feedback is available) development of high-order information complexes
such that low-feedback receptors are more likely to be (signals can be remixed and ignored)
replaced, and the converse for high-feedback The two-signal approach to activation and cloning
receptors. allows high-affinity input signals to be ignored. In using
Feedback provides system-level performance a second population of receptors, it allows input signals
information to individual receptors, thus that receptor- to be re-mapped and thus reinterpreted, applying
antigen interactions that employ the feedback meaning. The second population, in effect determines
information must promote the global system interests what to do with each input signal based on the context
rather than the local receptor-antigen (affinity) interests. (receptors) that recognised it. High-order information
Spatial Structure complexes result from the mapping of the internal
context of an input signal onto the second population,
The repertoire may be made spatial by assigning which may in turn enact an effector mechanism such as
receptors positions in a lattice structure (such as one or proliferation of matched first-tier (B cell) receptors.
two-dimensional). Clones of an activated set compete
and may be allocated positions in close proximity (the ACKNOWLEDGMENTS
neighbourhood) of the activated receptors. This Tim Hendtlass for his patience and for providing
behaviour allows neighbourhoods of the lattice to self- useful feedback on drafts of this paper
organize based upon the initial distribution of receptors.
The localised competition may presuppose that
neighbours are genetically similar to foster the self-

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