Biological	Information,	causality	and	specificity	–	an	intimate relationship Karola	Stotz1	and	Paul	Griffiths2 In	this	chapter	we	examine	the	relationship	between	biological	information,	the	key biological	concept	of	specificity,	and	recent	philosophical	work	on	causation.	We	begin by	showing	how	talk	of	information	in	the	molecular	biosciences	grew	out	of	efforts	to understand	the	sources	of	biological	specificity.	We	then	introduce	the	idea	of	'causal specificity'	from	recent	work	on	causation	in	philosophy,	and	our	own,	information theoretic	measure	of	causal	specificity.	Biological	specificity,	we	argue,	is	simple	the causal	specificity	of	certain	biological	processes.	This,	we	suggest,	means	that	causal relationships	in	biology	are	'informational'	relationships	simply	when	they	are	highly specific	relationships.	Biological	information	can	be	identified	with	the	storage, transmission	and	exercise	of	biological	specificity.	It	has	been	argued	that	causal relationships	should	not	be	regarded	as	informational	relationship	unless	they	are 'arbitrary'.	We	argue	that,	whilst	arbitrariness	is	an	important	feature	of	many	causal relationships	in	living	systems,	it	should	not	be	used	in	this	way	to	delimit	biological information.	Finally,	we	argue	that	biological	specificity,	and	hence	biological information,	is	not	confined	to	nucleic	acids	but	distributed	among	a	wide	range	of entities	and	processes. 1.	Introduction 1	Corresponding	author;	Department	of	Philosophy,	Macquarie	University,	Sydney, NSW	2109,	Australia.	Email:	karola.stotz@mq.edu.au 2	Department	of	Philosophy,	University	of	Sydney,	NSW	2006,	Australia. The	lack	of	a	rigorous	account	of	biological	information	as	a	proximal	causal	factor in	biological	systems	is	a	striking	gap	in	the	scientific	worldview.	In	this	chapter	we outline	a	proposal	to	fill	that	gap	by	grounding	the	idea	of	biological	information	in	a contemporary	philosophical	account	of	causation.	Biological	information	is	a	certain kind	of	causal	relationship	between	components	of	living	systems.	Many	accounts	of information	in	the	philosophy	of	biology	have	set	out	to	vindicate	the	common assumption	that	nucleic	acids	are	distinctively	informational	molecules.	Here	we take	a	more	unprejudiced	approach,	developing	an	account	of	biological	information and	then	seeing	how	widely	it	applies. In	Section	2	we	begin	with	the	most	prominent	informational	idea	in	modern biology	–	the	coding	relation	between	nucleic	acid	and	protein.	A	deeper	look	at	the background	to	Francis	Crick's	Central	Dogma,	and	a	comparison	with	the	distinction in	developmental	biology	between	permissive	and	instructive	interactions,	reveals that	'information'	is	a	way	to	talk	about	specificity.	The	idea	of	specificity	has	a	long history	in	biology,	and	a	closely	related	idea	is	a	key	part	of	a	widely	supported contemporary	account	of	causation	in	philosophy	that	grounds	causal	relationships in	ideas	about	manipulability	and	control.	In	Section	3	we	describe	the	idea	of 'causal	specificity'	and	an	information-theoretic	measure	of	the	degree	of	specificity of	a	cause	for	its	effect.	Biological	specificity,	we	suggest,	is	simply	causal	specificity in	biological	systems.	Since	we	have	already	argued	that	'information'	is	a	way	to talk	about	biological	specificity,	we	conclude	that	causal	relationships	are 'informational'	simply	when	they	are	highly	specific.	Section	4	defends	this identification	against	the	claim	that	only	causal	relationships	in	which	the	relation between	cause	and	effect	is	'arbitrary'	should	count	as	informational.	Arbitrariness has	an	important	role,	however,	in	understanding	the	regulation	of	gene	expression via	gene	regulatory	networks.	Having	defended	our	identification	of	information with	specificity,	we	go	in	in	section	5	to	show	that	information	is	more	widely distributed	in	biological	systems	than	is	often	supposed.	Coding	sequences	of	DNA are	only	one	source	of	biological	specificity,	and	hence	only	one	locus	of	biological information. 2.	Information	in	biology One	of	the	best-known	uses	of	'information'	in	biology	occurs	in	Crick's	1958 statement	of	the	'central	dogma	of	molecular	biology': The	Sequence	Hypothesis ...	In	its	simplest	form	it	assumes	that	the	specificity	of	a	piece	of	nucleic	acid	is expressed	solely	by	the	sequence	of	its	bases,	and	that	this	sequence	is	a (simple)	code	for	the	amino	acid	sequence	of	a	particular	protein.	... The	Central	Dogma This	states	that	once	'information'	has	passed	into	protein	it	cannot	get	out again.	In	more	detail,	the	transfer	of	information	from	nucleic	acid	to	protein may	be	possible,	but	transfer	from	protein	to	protein,	or	from	protein	to nucleic	acid	is	impossible.	Information	means	here	the	precise	determination of	sequence,	either	of	bases	in	the	nucleic	acid	or	of	amino-acid	residues	in	the protein.	(Crick,	1958,	152-153,	italics	in	original) Here	Crick	simply	identifies	the	specificity	of	a	gene	for	its	product	with	the information	coded	in	the	sequence	of	the	gene.	By	doing	so,	he	linked	the	idea	of information	very	closely	to	one	of	the	fundamental	organizing	concepts	of	biology. Biological	specificity	is	nothing	less	than	the	"orderly	patterns	of	metabolic	and developmental	reactions	giving	rise	to	the	unique	characteristics	of	the	individual and	of	its	species"	(Kleinsmith,	2014)3.	From	the	second	half	of	the	19th	to	the	first half	of	the	20th	century	specificity	was	"the	thematic	thread	running	through	all	the life	sciences"	(Kay,	2000,	41),	starting	with	botany,	bacteriology,	immunology	and serology.	By	mid-century	quantum	mechanics	had	provided	the	necessary	insight	to explain	the	observed	structural	complementarity	between	molecules	in	terms	of	the 3	http://www.accessscience.com/content/biological-specificity/082900.	Accessed	29	January	2015. quantum-physical	forces	that	underlie	ability	of	enzyme	and	substrate	to	form	a certain	number	of	weak	hydrogen	bonds.	This	development	of	quantum	chemistry, majorly	driven	by	Linus	Pauling	and	Max	Delbrück	in	the	1940s,	transformed	the stereochemical	concept	of	specificity	based	on	the	abstract	and	intuitive	side-chain receptor	theory	(developed	by	Paul	Ehrlich),	and	their	lock-and-key	interaction	with a	ligand	(an	image	suggested	by	Emil	Fischer,	both	at	the	turn	of	the	century),	into stereochemical	specificity	based	on	weak	intermolecular	forces	(Pauling	&	Delbrück, 1940). Crick	introduces	a	new,	more	abstract	conception	of	high	selectivity	or	absolute specificity	in	terms	of	how	one	molecule	can	precisely	specify	the	linear	structure	of another.	For	him	it	is	the	colinearity	between	DNA,	RNA	and	amino	acid	chains	that embodies	its	specificity.	The	information	that	specifies	the	product	is	no	longer carried	by	a	three-dimensional	structure	but	instead	by	the	linear,	one-dimensional order	of	elements	in	each	sequence.	Amongst	other	consequences,	this	means	that specificity	becomes	independent	of	the	medium	in	which	this	order	is	expressed	(i.e. DNA,	RNA	or	amino	acid	chain)	and	of	the	kind	of	reaction	by	which	the	specificity	is transmitted	(i.e.	transcription	or	translation).	The	same	information/specificity flows	continuously	through	these	three	media	and	two	processes. According	to	Crick	the	process	of	protein	synthesis	contains	"the	flow	of	energy,	the flow	of	matter,	and	the	flow	of	information."	While	he	notes	the	importance	of	the "exact	chemical	steps",	he	clearly	separated	this	transfer	of	material	substances from	what	he	regarded	as	"the	essence	of	the	problem",	namely	the	problem	of	how to	join	the	amino	acids	in	the	right	order.	The	flow	of	"hereditary	information", defined	as	"the	specification	of	the	amino	acid	sequence	of	the	protein",	solved	for him	this	critical	problem	of	"sequentialization"	(Crick	1958,	143-144). In	his	later	paper	"Central	Dogma	of	Molecular	Biology"	Crick	clarified	these	earlier arguments: The	two	central	concepts	which	had	been	produced	...	were	those	of	sequential information	and	of	defined	alphabets.	Neither	of	these	steps	was	trivial.	...	This temporarily	reduced	the	central	problem	from	a	three	dimensional	one	to	a one	dimensional	one.	...	The	principal	problem	could	then	be	stated	as	the formulation	of	the	general	rules	for	information	transfer	from	one	polymer with	a	defined	alphabet	to	another.	(Crick,	1970,	561) The	philosopher	Gregory	Morgan4	corresponded	with	Crick	late	in	his	career	about his	original	inspiration	to	use	the	term	'information'.	Crick's	replies	of	March	20	and April	3	1998	show	the	consistency	of	his	view	over	forty	years.	He	states	that	his	use of	'information'	was	influenced	by	the	idea	of	Morse	code,	rather	than	Shannon's information	theory,	which	he	sees	as	more	concerned	with	the	reduction	of	noise during	transmission.	Like	Shannon,	however,	he	was	not	using	the	idea	of information	to	express	the	'meaning'	or	'aboutness'	of	genes.	Rather,	information was	"merely	a	convenient	shorthand	for	the	underlying	causal	effect",	namely	the "precise	determination	of	sequence".	Information	for	him	solely	meant	"detailed residue-by-residue	determination". The	concept	of	information	in	terms	of	the	precise	determination	of	sequence primarily	offered	Crick	a	way	to	reduce	the	transfer	of	specificity	from	a	threedimensional	to	a	one-dimensional	problem	by	abstracting	away	from	the biochemical	and	material	connotations	of	specificity.	The	conception	of	biological information	defended	in	this	paper	takes	this	abstraction	of	the	idea	of	specificity	a stage	further,	but	is	very	much	in	the	spirit	of	Crick's	original	proposal. Another	biological	field	in	which	the	concepts	of	information	and	specificity	have been	entwined	is	developmental	biology,	although	here	the	idea	of	information	is less	tightly	associated	with	DNA. We	refer	here	particularly	to	the	problem	of	tissue differentiation.	Interaction	between	neighboring	cells	or	tissues	in	development	can 4	Personal	communication.	We	are	extremely	grateful	to	Morgan	for	making	this	correspondence available	to	us. lead	to	further	differentiation	in	one,	the	responder,	as	a	result	of	its	interaction with	the	other,	the	inducer.	Developmental	biologists	commonly	distinguish between	'instructive'	(or	active,	explicit,	directive)	induction	on	the	one	hand	and 'permissive'	(or	passive,	implicit)	on	the	other. The	notion	of	the	specificity	of	interaction	is	closely	associated	with	the	terms 'instructive'	and	'permissive'	interaction.	When	the	action	system	is	largely responsible	for	the	specificity	of	the	interaction	through	the	transfer	of	a specific	message,	to	which	the	reaction	system	responds	by	entering	into	a particular	pathway	of	differentiation,	we	speak	of	an	instructive	action.	When, on	the	other	hand,	the	specificity	of	a	reaction	is	largely	due	to	the	state	of	the competence	of	the	reaction	system,	so	that	even	rather	unspecific	messages can	serve	as	signals	to	open	up	new	developmental	pathways,	we	speak	of	a permissive	action.	(Nieuwkoop,	Johnen,	&	Albers,	1985,	9) Papers	on	this	subject	cite	as	the	two	original	sources	of	the	distinction	between instructive	and	permissive	interactions	either	Holtzer	(1968)	or	(Saxen,	1977).	All seem	to	agree	that	instructive	interactions	provide	instructions	or	messages	simply because	these	interactions	have	a	high	degree	of	specificity.	But	the	informational language	also	enters	this	context	regularly: Embryonic	induction	is	generally	described	as	an	instructive	event.	The problem	itself	is	often	posed	in	terms	implying	the	transmission	of informational	molecules	[either	proteins	or	nucleic	acids]	from	one	cell	to another	cell	...	.	(Holtzer,	1968,	152,	italics	added) Gilbert's	treatment	of	the	vital	question	regarding	the	source	of	specificity	illustrates nicely	how	the	instructive/permissive	distinction	is	explained	both	in	terms	of specificity	and	information:	"Instructive	partners	provide	specificity	to	the	reaction, whereas	permissive	partners	...	do	not	provide	specificity.	...	[They	are	therefore not]	on	the	same	informational	level"	(Gilbert,	2003,	349). We	conclude	from	these	examples	that	there	are	at	least	some	contexts	in	which	the language	of	information	is	a	way	to	talk	about	the	relatively	high	degree	of specificity	seen	in	some	causal	processes	in	biology.	This	matters	to	us,	since	in	the next	section	we	will	present	an	information-theoretic	analysis	of	specificity.	If	the argument	of	this	last	section	is	correct,	then	what	follows	is	also	an	informationtheoretic	analysis	of	biological	information. 3.	Causal	Specificity:	an	information-theoretic	approach James	Woodward	(2010),	and	ourselves	(Griffiths	&	Stotz,	2013;	Stotz,	2006)	have argued	that	the	idea	of	causal	specificity	is	closely	related	to	the	idea	of	biological specificity.	Causal	specificity	is	an	idea	from	the	contemporary	philosophy	of causation. The	philosophy	of	causation	has	many	concerns,	some	of	them	entirely	in the	domain	of	metaphysics.	The	interventionist	(or	sometimes	'manipulatibility') account	of	causation,	however,	is	primarily	aimed	at	explaining	why	science	cares about	causation,	and	using	that	explanation	to	think	more	clearly	about	causation	in scientific	practice.	Because	of	its	applicability	to	actual	cases	of	scientific	reasoning it	has	been	widely	applied	to	problems	in	the	contemporary	philosophy	of	the	life and	social	sciences.	This	account	of	causation	focuses	on	the	idea	that	"causal relationships	are	relationships	that	are	potentially	exploitable	for	purposes	of manipulation	and	control"	(Woodward	2010,	314).	Causation	is	conceived	as	a relation	between	variables	in	an	organized	system	that	can	by	represented	by	a directed	graph.	A	variable	X	is	a	cause	of	variable	Y	when	a	suitably	isolated manipulation	of	X	would	change	Y.	This	theory	of	causation,	in	it	simplest	form,	can be	used	to	pick	out	which	variables	are	causes	rather	than	merely	correlates. However,	a	great	many	things	get	identified	as	causes.	So,	for	example,	a	gene	might be	a	cause	for	a	phenotype,	because	a	mutation	(a	'manipulation')	would	change	the phenotype.	But	equally,	a	change	in	the	environment	(another	'manipulation')	will be	picked	out	as	a	cause	if	it	changes	that	phenotype. A	comprehensive	theory	of	causation	doesn't	just	distinguish	cause	from	non-cause, but	can	also	differentiate	between	causes	in	various	ways-to	identify	ones	that "are	likely	to	be	more	useful	for	many	purposes	associated	with	manipulation	and control	than	less	stable	relationships"	(Woodward	2010,	315).	A	number	of different	ways	to	distinguish	types	of	causes	have	been	suggested,	and	two	of these-Stability	and	Specificity-are	particularly	relevant	to	understanding biological	information.	Stability	refers	to	whether	an	intervention	continues	to	hold across	a	range	of	background	conditions,	and	we	will	not	pursue	it	here.	Specificity refers	to	the	fine-grained	control	that	an	intervention	might	have,	controlling	a gradient	of	change,	rather	than	a	simple	on-off	switch,	for	example	(Griffiths	&	Stotz, 2013;	Stotz,	2006;	Waters,	2007;	Woodward,	2010). The	intuitive	idea	is	that	interventions	on	a	highly	specific	causal	variable	C	can	be used	to	produce	any	one	of	a	large	number	of	values	of	an	effect	variable	E, providing	what	Woodward	terms	'fine-grained	influence'	over	the	effect	variable (Woodward	2010,	302).	The	ideal	limit	of	fine-grained	influence,	Woodward explains,	would	be	a	bijective	mapping	between	the	values	of	the	cause	and	effect variables:	every	value	of	E	is	produced	by	one	and	only	one	value	of	C	and	vice	versa. The	idea	of	a	bijective	mapping	does	not	admit	of	degrees,	but	in	earlier	work	with collaborators	we	have	developed	an	information-theoretic	framework	with	which	to measure	the	specificity	of	causal	relationships	within	the	interventionist	account (Griffiths	et	al.,	In	press;	Pocheville,	Under	review).	Our	work	formalizes	the	simple idea	that	the	more	specific	the	relationship	between	a	cause	variable	and	an	effect variable,	the	more	information	we	will	have	about	the	effect	after	we	perform	an intervention	on	the	cause.	This	led	us	to	propose	a	simple	measure	of	specificity: Spec:	the	specificity	of	a	causal	variable	is	obtained	by	measuring	how	much	mutual information	interventions	on	that	variable	carry	about	the	effect	variable The	mutual	information	of	two	variables	is	simply	the	redundant	information present	in	both	variables.	Where	H(X)	is	the	Shannon	entropy	of	X,	and	H(X ∣ Y)	the conditional	entropy	of	X	on	Y,	the	mutual	information	of	X	with	another	variable	Y, or	I (X;Y),	is	given	by: I(X;Y) = H(X)− H(X ∣ Y) Mutual	information	is	symmetrical:	I(X;Y) = I(Y;X).	So	variables	can	have	mutual information	without	being	related	in	the	manner	required	by the interventionist criterion	of	causation.	However,	our	measure	of	specificity	measures	the	mutual information	between	interventions	on	C	and	the	variable	E.	This	is	not	a	symmetrical measure	because	the	fact	that	interventions	on	C	change	E	does	not	imply	that interventions	on	E	will	change	C:	I(C;E) ≠ I(E;C),	where	C	is	read	'do	C'	and means	that	the	value	of	C	results	from	an	intervention	on	C	(Pearl,	2009). This	measure	adds	precision	to	several	aspects	of	the	interventionist	account	of causation.	Any	two	variables	that	satisfy	the	interventionist	criterion	of	causation will	show	some	degree	of	mutual	information	between	interventions	and	effects. This	criterion	is	sometimes	called	'minimal	invariance'	–	there	are	at	least	two values	of	C	such	that	a	manipulation	of	C	from	one	value	to	the	other	changes	the value	of	E.	If	the	relationship	C → E	is	minimally	invariant,	that	is,	invariant	under	at least	one	intervention	on	C,	then	C	has	some	specificity	for	E,	that	is,	I(C;E) > 0. Moreover,	our	measure	of	specificity	is	a	measure	of	what	Woodward	calls	the 'range	of	invariance'	of	a	causal	relationship	–	the	range	of	values	of	C	and	E	across which	the	one	can	be	used	to	intervene	on	the	other.	Relationships	with	a	large range	of	invariance	have	high	specificity	according	to	our	measure	(Griffiths	et.	al., In	press;	Pocheville,	Under	review).5 5 Here we give a simple, absolute measure of specificity. Normalised relatives of our measure are available, as we discuss in these papers. In	light	of	the	examples	in	Sections	2,	we	propose	that	causal	relationships	in biological	systems	can	be	regarded	as	informational	when	they	are	highly	causally specific.	Biological	specificity,	whether	stereochemical	or	informational,	seems	to	us to	be	simply	the	application	of	the	idea	of	causal	specificity	to	biological	systems. The	remarkable	specificity	of	reactions	in	living	systems	that	biology	has	sought	to explain	since	the	late	C19th	can	equally	be	described	as	the	fact	that	living	systems exercise	'fine	grained	control'	over	many	variables	within	those	systems.	Organisms exercise	fine-grained	control	over	which	substances	provoke	an	immune	response through	varying	the	stereochemistry	of	recognition	sites	on	antibodies	for	antigens. They	catalyze	very	specific	reactions	through	varying	the	stereochemistry	of enzymes	for	their	substrates,	or	of	receptors	and	their	ligands.	Organisms	reproduce with	a	high	degree	of	fidelity	through	the	informational	specificity	of	nucleic	acids for	proteins	and	functional	RNAs.	Genes	are	regulated	in	a	highly	specific	manner across	time	and	tissue	through	the	regulated	recruitment	of	trans-acting	factors	and the	combinatorial	control	of	gene	expression	and	post-transcriptional	processing	by these	factors	and	the	cis-acting	sites	to	which	they	bind.	These	are	all	important aspects	of	why	living	systems	appear	to	be	'informed'	systems,	and	what	is distinctive	about	all	these	processes	is	that	they	are	highly	causally	specific. 4.	Arbitrariness,	information	and	regulation In	this	section	we	consider	another	property	that	has	been	said	to	essentially characterize	informational	relationships	in	biology.	This	is	'arbitrariness',	the	idea that	the	relationship	between	symbols	and	the	things	they	symbolize	represent	only one	permutations	of	many	possible	relationships	between	them.	This	is	a	familiar property	of	human	languages	–	'cat'	could	equally	well	be	used	to	mean	'cow'	and vice-versa.	Like	Crick,	we	have	so	far	eschewed	ideas	of	meaning	and	representation, so	with	respect	to	our	proposal	arbitrariness	would	mean	that	the	systematic mapping	between	values	of	C	and	E	is	only	one	of	may	possible	systematic	mappings. Sahotra	Sarkar	imposes	just	such	a	condition	on	the	informational	relationships	in biology.	Sarkar,	known	for	his	critical	stance	towards	the	use	of	informational language	in	biology,	argued	that	"[e]ither	informational	talk	should	be	abandoned altogether	or	an	attempt	must	be	made	to	provide	a	formal	explication	of 'information'	that	shows	that	it	can	be	used	consistently	in	this	context	and, moreover,	is	useful"	(Sarkar,	2004,	261).	He	makes	a	serious	attempt	to	provide	the required	formal	explication,	a	definition	of	information	that	both	performs	a significant	explanatory	or	predictive	role	and	applies	to	information	as	it	is customarily	used.	He	proposes	two	adequacy	conditions	for	a	biological	or	genetic account	of	information: Whatever	the	appropriate	explication	of	information	for	genetics	is,	it	has	to come	to	terms	with	specificity	and	the	existence	of	this	coding	relationship.	... Along	with	specificity,	this	arbitrariness	is	what	makes	an	informational account	of	genetics	useful.	(Sarkar	2004,	261	and	266) Sarkar's	analysis	of	specificity	is	similar	to	Woodward's	and	we	would	urge	that	he adopt	our	information-theoretic	extension	of	that	analysis.	His	second	condition, arbitrariness,	relies	on	his	interpretation	of	the	Central	Dogma,	according	to	which it	introduces	two	different	types	of	specificity,	namely	"that	of	each	DNA	sequence for	its	complementary	strand,	as	modulated	through	base	pairing;	and	that	of	the relationship	between	DNA	and	protein.	The	latter	was	modulated	by	genetic information"	(Sarkar,	1996b,	858).	Sarkar	needs	to	distinguish	these	two	because the	relationship	between	DNA	and	RNA	is	not	arbitrary	–	it	is	dictated	by	the	laws	of chemistry.	Only	the	relationship	between	RNA	and	protein	is	arbitrary,	because	it depends	on	the	available	t-RNAs.	Many	different	t-RNAs	are	available,	and substituting	these	would	lead	to	different	genetic	codes. In	our	view,	however,	Crick	clearly	states	that	'genetic	information'	applies	to	the specification	"either	of	bases	in	the	nucleic	acid	or	in	amino	acid	residues	in	the protein"	(Crick	1958,	153).	DNA	provides	informational	specificity	for	RNA	as	much as	RNA	provides	specificity	for	amino	acid	chains.	Ulrich	Stegmann	agrees	that	the difference	between	the	two	is	"irrelevant	to	the	question	of	whether	they	carry information:	they	all	do"	(Stegmann,	2014,	460).	There	is	just	one	type	of informational	specificity,	and	what	distinguishes	it	from	conformational	specificity is	its	independence	from	the	medium	in	which	it	is	expressed	or	the	mechanism	by which	it	is	transferred.	Hence	if	arbitrariness	should	be	regarded	as	an	important condition	for	informational	language	in	biology,	it	should	be	for	the	reason	of	this medium-independence	in	general,	rather	than	the	coding	relationship	between	RNA and	amino	acids	in	particular.	The	coding	relationship	between	RNA	and	amino	acid is	not	the	reason	that	led	to	Crick's	use	of	the	idea	of	information	in	formulating	the central	dogma. Like	ourselves,	Sarkar	aims	to	explicate	the	notion	of	information	in	such	a	way	as	to make	it	a	useful	tool	for	biology.	But	adding	the	second	condition	of	arbitrariness,	at least	when	applied	just	to	the	coding	relationship,	to	his	definition	of	information seems	to	us	to	come	with	some	substantial	costs.	It	may	exclude	the	concept	of information	from	what	seems	to	us	one	of	its	most	useful	roles,	namely	as	a	way	to compare	different	sources	of	biological	specificity,	as	we	do	in	Section	5.	This	is because	many	of	these	alternative	sources	of	specificity,	like	the	DNA-RNA relationship,	are	not	arbitrary. This	is	not	to	say	that	arbitrary	relationships	play	no	vital	role	in	biology.	It	is interesting	that	the	notion	of	arbitrariness	has	been	introduced	in	another	area	of biology	that	regularly	deploys	informational	language,	namely	the	regulation	of gene	expression	through	gene	regulatory	networks. The	pioneers	of	research	into	gene	regulation,	Francois	Jacob	and	Jacques	Monod, derived	a	notion	of	arbitrariness	from	their	operon	model	(Jacob	&	Monod,	1961). The	biosynthesis	of	the	enzyme	ß-galactosidase	is	indirectly	controlled	by	its substrate,	ß-galactosides.	This	indirect	control	is	made	possible	by	the	intervening repressor	of	the	gene,	an	allosteric	protein,	which	is	rendered	inactive	by	its	effector, the	substrate	of	the	enzyme	expressed	by	the	gene.	The	repressor	thereby	indirectly transduces	the	controlling	signal. There	is	no	chemically	necessary	relationship	between	the	fact	that ß-galactosidase	hydrolyses	ß-galactosides,	and	the	fact	that	its	biosynthesis	is induced	by	the	same	compounds.	Physiologically	useful	or	"rational",	this relationship	is	chemically	arbitrary	–	"gratuitous",	one	may	say.	This fundamental	concept	of	gratuity	–	i.e.,	the	independence,	chemically	speaking, between	the	function	itself	and	the	nature	of	the	chemical	signal	controlling	it –	applies	to	allosteric	proteins.	(Monod,	1971,	78) Most	controlling	environmental	stimuli	have	only	an	indirect	controlling	effect	on gene	expression,	which	is	mediated	or	transduced	by	the	processes	of	transcription, splicing	or	editing	factors.	The	latter	relay	the	environmental	information	to	the genome.	So	the	role	of	allosteric	proteins	in	signal	transduction	due	to	their chemical	arbitrariness	that	Monod	has	identified,	could	be	assigned	to	many signaling	molecules	in	biological	signal	transduction	systems,	just	as	is	the	case	for many	human-designed	signaling	systems.	It	is	this	arbitrariness	that	renders	the system	flexible	and	evolutionarily	evolvable. "The	result	–	and	this	is	the	essential	point	–	is	that	...	everything	is	possible. An	allosteric	protein	should	be	seen	as	a	specialized	product	of	molecular "engineering"	enabling	an	interaction,	positive	or	negative,	to	take	place between	compounds	without	chemical	affinity,	and	thereby	eventually subordinating	any	reaction	to	the	intervention	of	compounds	that	are chemically	foreign	and	indifferent	to	this	reaction.	The	way	hence	in	which allosteric	interactions	work	permits	a	complete	freedom	in	the	choice	of control.	And	these	controls,	subject	to	no	chemical	requirements,	will	be	the more	responsive	to	physiological	requirements,	by	virtue	of	which	they	will	be selected	according	to	the	increased	coherence	and	efficiency	they	confer	on the	cell	or	organism.	In	short,	the	very	gratuitousness	of	the	systems,	giving molecular	evolution	a	practically	limitless	field	for	exploration	and	experiment, enabled	I	to	elaborate	the	huge	network	of	cybernetic	interconnections	which makes	each	organism	an	autonomous	functional	unit,	whose	performances appear	to	transcend,	if	not	to	escape,	the	laws	of	chemistry."	(Monod	1971,	789) The	mutual	information	between	the	specificity	of	the	environmental	signal	for	the regulatory	factor	on	the	one	hand,	and	the	specificity	of	the	regulatory	factors	for	a certain	gene	via	its	regulatory	sequence,	are	chemically	arbitrary	and	subject	to	the convention	of	an	intervening	allosteric	biomolecule. The	central	feature	of	such	a	relationship	between	any	two	pathways	is	that	it	is subject	to	heritable	variation.	This	means	that	an	environmental	stimulus	may	lead in	future	to	a	quite	different,	adaptive	response	by	the	system,	if	mediated	by	a novel	signaling	protein	that	has	evolved	independent	specificities	to	both	the environmental	stimulus	(its	effector)	and	the	appropriate	regulatory	sequence	(its substrate). We	can	understand	the	regulation	of	gene	expression	as	an	internal signaling	game	where	sender	and	receiver	are	not	two	organisms	but	parts	within one	plastic	organism	(Calcott,	2014).	The	organism	encounters	two	environments, and	a	different	behaviour	is	optimal	in	each	environment.	The	sender	is	a	sense organ,	or	transducer,	reacting	to	the	environment	by	sending	a	signal	inside	the organism.	The	receiver	is	an	effector	converting	the	signal	into	some	behaviour	that changes	how	the	organism	as	a	whole	interacts	with	that	environment.	Signaling occurs	inside	the	organism,	and	the	evolution	of	a	signaling	system	allows	it	to optimally	map	the	different	environments	to	the	appropriate	behaviour.	Signaling arose	because	the	modular	structure	–	the	separation	of	transducer	and	effector	– created	a	coordination	problem.	For	the	organism	to	respond	adaptively,	it	needed to	coordinate	these	parts,	and	a	signaling	system	provided	the	solution.	Signaling, from	this	internal	perspective,	is	a	way	of	building	adaptive,	plastic	organisms. What	such	a	signaling	system	allows	is	the	decoupling	of	informational	dynamics from	the	dictates	of	local	chemistry.	According	to	Walker	and	Davies	one	of	the hallmark	of	biological	versus	non-biological	systems	is	the	separation	between	their informational	and	mechanical	aspects	(Walker	and	Davies	2012,	4).	This	reminds	us of	Crick's	insistence	on	the	importance	of	the	medium	independence	of informational	specificity.	But	more	importantly,	it	stresses	the	relationship	between arbitrariness	and	informational	control. So	arbitrariness	is,	indeed,	an	important	feature	of	information	processing	in	living systems.	It	is	at	last	one	of	the	fundamental	keys	to	evolvability.	But	this,	we	would argue,	is	not	a	good	reason	to	add	arbitrariness	to	the	definition	of	biological information.	Arbitrary	relationships	are	prevalent	in	biological	signaling	networks because	of	their	biological	utility,	not	because	of	the	definition	of	information! 5.	Distributed	specificity Griffiths	and	Stotz	(Griffiths	&	Stotz,	2013)	have	termed	the	encoding	of	specificity 'Crick	information'.	If	a	cause	makes	a	specific	difference	to	the	linear	sequence	of	a biomolecule,	it	contains	Crick	information	for	that	molecule.	This	definition embodies	the	essential	idea	of	Crick's	sequence	hypothesis,	without	in	principle limiting	the	location	of	information	to	nucleic	acid	sequences	as	Crick	does.	Our definition	of	Crick	information	can	clearly	be	applied	to	other	causal	factors	that affect	gene	expression.	However,	it	is	a	specifically	biological	conception	of information,	rather	than	a	general	one	such	as	Shannon's	mutual	information,	or	our measure	of	causal	specificity,	because	by	definition	it	only	applies	to	causes	that specify	the	order	of	elements	in	a	biomolecule. Crick's	Central	Dogma	was	based	on	a	very	simple	picture	of	how	the	specificity	of biomolecules	is	encoded	in	living	cells.	We	now	know	that	in	eukaryotes	coding regions	are	surrounded	by	a	large	number	of	non-coding	sequences	that	regulate gene	expression.	The	discrepancy	between	the	number	of	coding	sequences	and	the number	of	gene	products	lead	to	the	insight	that	the	informational	specificity	in coding	regions	of	DNA	must	be	amplified	by	other	biomolecules	in	order	to	specify the	whole	range	of	products.	'Precise	determination'	implies	a	one-to-one relationship,	and	if	we	focus	on	coding	sequences	alone,	we	find	a	one-to-many relationship	between	sequence	and	product.	Different	mechanisms	of	gene regulation	co-specify	the	final	linear	product	of	the	gene	in	question,	first	by activating	the	gene	so	it	can	get	transcribed,	second	by	selecting	a	chosen	subset	of the	entire	coding	sequence	(e.g.	alternative	splicing),	and	thirdly	by	creating	new sequence	information	through	the	insertion,	deletion	or	exchange	of	single nucleotide	letters	of	the	RNA	(e.g.	RNA	editing).	Thus	specificity,	and	hence	Crick information,	is	distributed	between	a	range	of	factors	other	than	the	original	coding sequence:	DNA	sequences	with	regulatory	functions,	diverse	gene	products	such	as transcription,	splicing	and	editing	factors	(usually	proteins),	and	non-coding	RNAs (Stotz,	2006). Absolute	specificity	turns	out	to	be	not	inherent	in	any	single	biomolecule	in	these molecular	networks	but	induced	by	regulated	recruitment	and	combinatorial control.	And	it	is	here	that	we	will	find	that	the	networks	cannot	be	reduced	to	DNA sequences	plus	gene	products,	because	many	of	the	latter	need	to	be	recruited, activated	or	transported	to	render	them	functional.	The	recruitment,	activation	or transportation	of	transcription,	splicing	and	editing	factors	allow	the	environment to	have	specific	effects	on	gene	expression	(being	'instructive'	rather	than	merely 'permissive'	in	the	terms	introduced	in	section	2).	Some	gene	products	serve	to relay	environmental	(Crick)	information	to	the	genome.	While	in	embryology	and morphogenesis	it	is	often	acknowledged	that	environmental	signals	play	a	role	in the	organisation	of	global	activities,	they	are	rarely	seen	to	carry	information	for	the precise	determination	of	the	nucleic	acid	or	amino	acid	chains	in	gene	products.	But this	is	precisely	what	occurs.	Not	just	morphogenesis	at	higher	levels	of	organisation, but	even	the	determination	of	the	primary	sequence	of	gene	products	is	a	creative process	of	(molecular)	epigenesis	that	cannot	be	reduced	to	the	information encoded	in	the	genome	alone	(Stotz	2006;	Griffiths	and	Stotz	2013). Interestingly,	concurrent	with	Crick's	Central	Dogma,	the	ciliate	biologist	David	L. Nanney	acknowledged	that	the	'library	of	specificities'	found	in	coding	sequences needed	to	be	under	the	control	of	an	epigenetic	control	system.	In	other	words,	in addition	to	requiring	both	an	analogue	and	a	digital	conception	of	specificity,	the study	of	biological	development	requires	two	sources	of	information.	In	an immediate	response	to	Crick's	new	picture	of	sequential	information	coded	in	DNA, Nanney	pointed	out: This	view	of	the	nature	of	the	genetic	material	...	permits,	moreover,	a	clearer conceptual	distinction	than	has	previously	been	possible	between	two	types	of cellular	control	systems.	On	the	one	hand,	the	maintenance	of	a	"library	of specificities,"	both	expressed	and	unexpressed,	is	accomplished	by	a	template replicating	mechanism.	On	the	other	hand,	auxiliary	mechanisms	with different	principles	of	operation	are	involved	in	determining	which specificities	are	to	be	expressed	in	any	particular	cell.	...To	simplify	the discussion	of	these	two	types	of	systems,	they	will	be	referred	to	as	"genetic systems"	and	"epigenetic	systems".	(Nanney	1958,	712) In	a	similar	vein,	Crick's	biographer	Robert	Olby	remarks	of	the	Central	Dogma	that Clearly,	in	concentrating	on	this	aspect	of	informational	transfer	he	was	setting aside	two	questions	about	the	control	of	gene	expression	–	when	in	the	life	of	a cell	the	gene	is	expressed	and	where	in	the	organism.	But	these	are	also questions	of	an	informational	nature,	although	not	falling	within	Crick's definition.	(Olby,	2009,	251,	italics	added) As	it	has	turned	out,	many	epigenetic	mechanisms	are	strongly	associated	with	DNA. Developmental	biologist	Scott	Gilbert	argues	that	the	specificity	of	a	reaction	"has	to come	from	somewhere,	and	that	is	often	a	property	of	the	genome"	(2003,	349).	But since	all	cells	start	with	exactly	the	same	genetic	"library	of	specificities"	that	can't be	the	whole	story	of	differentiation.	Nanney	describes	this	as	a	developmental paradox:	"How	do	cells	with	identical	genetic	composition	acquire	adaptive differences	capable	of	being	maintained	in	clonal	heredity"	(Nanney,	1989)?	Gilbert indeed	acknowledges	that	the	action	of	a	gene	itself	"depends	upon	its	context. There	are	times	where	the	environment	gets	to	provide	the	specificity	of developmental	interaction"	(2003,	350).	So	we	conclude	that	while	genes	are	seen as	a	key	source	of	specificity,	in	biology	causes	are	not	regarded	as	informative merely	because	they	are	genetic,	but	whenever	they	are	highly	specific. Many	years	later	Nanney	looked	back	on	this	period	in	the	late	1950s	as	one	in which	the	powerful	image	of	the	double	helix	caused	a	"near	disruption	of	an incipient	merging	of	cybernetics	with	regulatory	biology".	It	"may	have	hindered	the exploration	of	the	systemic	components	of	living	systems,	which	are	not	just creatures	reified	from	the	'blueprints',	but	essential	complementary	components	of life	that	reciprocally	regulate	the	nucleic	system"	(Nanney	1989).	In	recent	years, however,	our	image	of	how	biological	systems	exercise	fine-grained	control	over their	internal	processes	has	developed	to	the	point	where	his	description	of	the	two complementary	control	systems	seem	quite	conservative. It	is	now	clear	that	the	epigenetic	control	system,	if	we	still	want	to	call	it	that,	not only	regulates	when	and	where	the	specificities	encoded	in	the	DNA	library	are	to	be expressed6.	It	also	substantially	augments	the	information	of	the	literal	coding sequence.	A	strange	aspect	of	the	management	of	genetic	information	is	that	the epigenetic	control	system	–	which	Paul	Davies	likens	to	"an	emergent	selforganizing	phenomenon"	(Davies,	2012,	42)	–	does	not	just	provide	a	supervising 6	Woodward	suggests	that	specificity	includes	both	the	"systematic	dependencies	between	a	range	of different	possible	states	of	the	cause	and	different	possible	states	of	the	effect,	as	well	as dependencies	of	the	time	and	place	of	occurrence	of	E	on	the	time	and	place	of	C"	(Woodward	2010, 304-305,	italics	added).	So	even	in	Nanney's	original	vision,	the	epigenetic	systems	is	an	additional source	of	specificity. function	on	the	expression	of	the	specificities	encoded	in	the	DNA,	in	the	sense	of when,	where,	and	how	much	will	be	expressed.	Since	the	information	encoded	in	the DNA	does	not	entail	a	complete	set	of	instruction	for	which	biomolecules	shall	be synthesized,	the	epigenetic	control	system	amplifies	the	information	of	the	literal code	(Davidson,	2002).	Genes	are	not	only	switched	on	and	off,	even	though	this already	"leads	to	exponentially	more	information	being	stored	in	the	system	(since	a set	of	N	genes	can	have	2N	distinct	states)"	(Davies,	2012,	43).	Eukaryotes	have epigenetic	mechanisms	that	allow	them	to	produce	many	products	from	a	single coding	region,	ranging	from	just	two	up	to	thousands	of	isoforms	of	the	resulting protein. Most	epigenetic	mechanisms	are	now	fairly	well	understood	at	the	molecular	level, most	of	them	include	chemical	modifications	of	the	DNA	or	the	tails	of	the	histone protein	around	which	the	DNA	is	wrapped.	The	posttranscriptional	processing mechanisms,	mainly	alternative	slicing	and	RNA	editing	that	create	this	large	range of	gene	product,	are	also	fairly	well	understood.	But	if	epigenetic	mechanisms	are simply	a	set	of	physical	modifications	of	DNA,	isn't	the	organism	still	an	expression of	its	genome,	even	if	the	genome	is	a	little	more	complex	than	initially	supposed? This	will	not	do	because	the	molecular	mechanisms	and	epigenetic	marks	are	just the	final	stages	of	regulatory	processes	that	start	far	from	the	genome.	For	instance the	upor	down-regulation	of	the	glucocorticoid	receptor	gene	in	the	hypothalamus of	a	rat	pup	is	proximally	caused	by	the	increased	or	decreased	methylation	state	of the	receptor's	promoter	region.	This	in	turn	is	influenced	by	the	increased	or decreased	expression	and	activation	of	the	transcription	factor	NGF1-A.	Increased expression	of	NGF1-A	is	due	to	an	increased	serotonin	tone	in	the	hippocampus.	But this	in	turn	is	being	caused	by	the	mother	rat's	licking	and	grooming	of	her	pup, which	in	turn	reflects	the	more	or	less	stressed	state	of	the	mother	due	to	the environment	in	which	she	finds	herself.	The	mother's	maternal	care	behavior comprised	part	of	the	environmental	context	of	the	rat	pup.	The	increased	serotonin tone	represents	a	change	of	the	overall	state	of	the	whole	system,	with	a	range	of downstream	effects,	one	of	which	is	a	change	in	the	expression	of	the	glucocorticoid receptor.	This	in	turn	produces	a	range	of	bottom-up	effects	on	the	system	in	terms of	a	changed	behavioral	repertoire.	This	is	just	one	example	of	how	the	environment or	the	system	as	the	whole	is	ultimately	affecting	the	expression	of	genes	(Meaney, 2001;	Weaver	et	al.,	2007).	Therefore	we	can	say	that	a	substantial	amount	of information	needed	to	construct	an	organism	is	derived	from	elsewhere,	such	as	the organism's	environment.	This	information	augments	or	amplifies	the	information inherited	via	the	genome. 6.	Information	and	'downwards	causation' We	have	argued	that	additional	specificity,	or	information,	is	derived	from	the environmental	context,	but	it	may	also	be	generated	de	novo	by	physical	processes of	self-organisation.	Self-organisation	is	the	spontaneous	formation	of	wellorganized	structures,	patterns,	or	behaviors.	In	biology	it	means	the	selfmaintaining	organisation	of	constraints	that	harness	flows	of	matter	an	energy	and allow	the	"constrained	release	of	energy	into	relatively	few	degrees	of	freedom" (Kauffman,	2003,	1094).	Biological	systems,	in	Kauffman's	term,	'acting	on	their	own behalf'	when	they	constrain	exergonic	processes	in	a	specific	way	to	produce	work, which	can	be	used	to	generate	endergonic	processes,	which	in	turn	generate	those constraints	canalizing	exergonic	processes.7 It	has	often	been	suggested	that	such processes	are	an	additional	source	of	order	in	biological	systems. Walker	and	Davies	have	recently	characterized	life	by	"context-dependent	causal influences,	and	in	particular,	that	top-down	(or	downward)	causation	–	where higher-levels	influence	and	constrain	the	dynamics	of	lower-levels	in	organizational hierarchies	–	may	be	a	major	contributor	to	the	hierarchal	structure	of	living systems"	(Walker	&	Davies,	2013,	1). 7	An	endergenic	reaction	absorbs	and	stores	energy	from	the	surrounding.	During exergenic	reactions	stored	energy	is	released	to	drive	various	functions. Downward	causation	shouldn't	be	understood	as	the	direct	dynamic	interaction	of the	whole	with	some	of	their	parts.	It	has	long	been	acknowledged	in	the	physical science	that	in	dynamic	efficient	causation,	only	the	interaction	between	parts	at the	same	ontological	level	has	causal	effectiveness.	The	way	that	the	overall biological	system	is	still	able	to	exert	real	causal	effects	is	by	way	of	informational control	via	feedback	mechanisms	that	influences	the	dynamic	interaction	between the	parts	(Auletta,	Ellis,	&	Jaeger,	2008).	Philosophers	Carl	Craver	and	William Bechtel	have	advocated	this	view	more	generally,	in	an	attempt	to	rid	the	idea	of downwards	causation	of	any	mysterious	overtones	(2006).	They	suggest	that interlevel	relationships,	such	as	the	interactions	between	parts	and	whole,	should not	be	understood	as	causal	relationships	at	all,	even	though	these	relationships exert	real	influences	on	the	system	at	different	levels.	Both	top-down	and	bottom-up causation, ...	describe	mechanistically	mediated	effects.	Mechanistically	mediated	effects are	hybrids	of	constitutive	and	causal	relations	in	a	mechanism,	where	the constitutive	relations	are	interlevel,	and	the	causal	relations	are	exclusively intralevel.	(Craver	&	Bechtel,	2006,	547) A	system	as	a	whole	–	a	higher	level	entity	–	is	engaged	in	a	process	that	would not	happen	without	some	aspects	of	the	organization	of	that	system,	and	which therefore	needs	to	be	understood	at	the	higher	level.	But	this	system	is	composed of	parts,	and	as	the	system	as	a	whole	changes,	so	do	the	parts,	obviously.	The relation	between	the	process	going	on	at	the	systems	level	and	a	change	in	one part	is	not	because	of	an	additional	causal	relation	between	system	as	a	whole and	that	part	(over	and	above	the	interaction	of	the	part	with	other	parts)	but	the relation	of	constitution	between	the	system	and	its	parts. It	is	in	this	sense	that	we	understand	and	endorse	Walker	and	Davies'	claim	that, "algorithmic	information	gains	direct,	context-dependent,	causal	efficacy	over matter"	(2013,	2).	That	does	not	just	mean	that	the	digital	information	within	the genetic	code	just	by	itself	gains	such	control	over	matter.	After	all,	as	Nanney	has already	realized	some	65	years	ago,	the	expression	of	the	repository	of	information within	DNA	is	in	need	of	epigenetic	control.	"The	algorithm	itself	is	therefore	highly delocalized,	distributed	inextricably	throughout	the	very	physical	system	whose dynamics	it	encodes"	(Walker	&	Davies	2013,	5).	The	causal	efficacy	is	achieved through	some	"unique	informational	management	properties. ...	Focusing	strictly on	digital	storage	therefore	neglects	this	critical	aspect	of	how	biological information	is	processed"	(Walker	&	Davies	2012,	2-3). 7.	Conclusion Sarkar	has	argued	that	the	conventional	account	of	biological	information	as	coded instructions	in	the	sequence	of	DNA	nucleotides	lacks	explanatory	power.	He	calls for,	first,	the	development	of	a	"systematic	account	of	specificity",	and	second,	an "elaboration	of	a	new	informational	account"	with	wider	applicability	than	nucleic acid	alone	(Sarkar,	1996a,	222).	If	the	latter	course	was	to	be	adopted,	he	suggested, it	would	be	"highly	unintuitive	not	to	regard	[epigenetic	specifications]	as	'transfers of	information'	if	'information'	is	to	have	any	plausible	biological	significance" (Sarkar	1996a,	220).	Our	proposal	in	this	paper	represents	a	synthesis	between Sarkar's	two	ways	forward,	namely	a	systematic	account	of	specificity	and	a	new approach	to	biological	information	(see	Griffiths	et	al.,	Forthcoming;	Pocheville, Under	review). Biological	specificity	is	simply	causal	specificity	in	biological	systems.	Causal specificity	is	a	degree	property	of	causal	relationships	–	the	more	specific	a relationship	the	more	apt	it	is	for	the	exercise	of	fine-grained	control	over	the	effect. In	section	3	we	gave	a	brief	summary	of	how	this	property	can	be	measured	using tools	from	information	theory.	Informational	language	in	biology	represents	a	way to	talk	about	specificity.	No	doubt	informational	language	is	used	for	many	other purposes	in	biology	as	well,	but	the	cases	we	have	presented	in	which	it	relates	to specificity	are	central	to	molecular	and	developmental	biology.	As	a	result	we	feel justified	in	calling	our	information-theoretic	analysis	of	specificity	an	analysis	of biological	information. What	is	distinctive	about	living	systems,	we	would	argue,	is	that	they	are	structured so	that	many	of	their	internal	processes	have	an	outstanding	degree	of	causal specificity	when	compared	to	most	non-living	systems.	This	underlies	the phenomenon	that	first	attracted	the	label	of	'specificity'	in	biology	–	the	ability	of organisms	to	develop	in	a	very	precise	way,	and	to	respond	in	a	very	selective	and precise	way	to	their	circumstances.	The	idea	that	living	systems	differ	from	nonliving	systems	by	being	'informed'	–	under	the	control	of	information	–	makes	a great	deal	of	sense	in	terms	of	our	analysis	of	biological	information	as	causal specificity.	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