Developmental	Biology	as	a	Science	of	Dependent	Co-origination Scott	F.	Gilbert Department	of	Biology Swarthmore	College Swarthmore,	PA	19081	USA Between fertilization and birth, the developing organism is known as an embryo, and forming an embryo is the hardest thing you will ever do. To become an embryo, you had to build yourself from a single cell. You had to respire before you had lungs, digest before you had a gut, build bones when you were pulpy, and form orderly arrays of neurons before you knew how to think. One of the critical differences between you and a machine is that a machine is never required to function until after it is built. Every multicellular organism has to function even as it builds itself. Developmental	biologists	are	those	privileged	to	study	the	origins	and development	of	the	embryo.	We	get	to	ask	some	of	the	most	important	questions about	life.	How	does	newness	come	into	the	world? How	does	one	cell--the fertilized	egg--divide	to	become	the	trillions	of	small	cells	that	comprise	my	body? How	does	this	one	fertilized	egg	cell	generate	all	the	different	types	of	cells-blood cells,	brain	cells,	liver	cells?	How	do	these	cells	become	organized	into	functional organs?	How	is	it	that	I	have	only	two	eyes,	and	they	are	both	in	my	head?	Why	do	I have	only	one	heart?	How	do	the	organs	know	their	correct	size?	How	do	organisms make	cells	that	can	reproduce?	Did	other	organisms	help	me	come	into	being?	Is	the form	of	the	adult	somehow	present	in	the	egg	or	does	form	arise	from	nothing? These	questions	have	been	explored	not	only	by	Tsongkhapa	and	many	other Buddhist	scholars	from	the	viewpoint	Buddhist	logic	but	also	by	myriads	of developmental	biologists	spanning	several	centuries	using	scientific	technologies and	the	empirical	method. As	a	developmental	biologist,	I	get	to	tell	animal	stories,	modern	jataka	tales	that not	only	illustrate	the	mystery	of	development	but	also	have	the	potential	to	help listeners	understand	the	processes	through	which	form	arises.	Here,	I	wish	to deliver	three	scientific	stories	about	animal	cells	and	about	the	origin	of	animal body	patterns.	The	first	will	be	a	story	of	early	development.	Indeed,	it	is	a	piece from	the	epic	tale	of	fertilization. The	second	will	be	from	the	middle	part	of development,	when	organs	are	forming.	It	will	be	the	story	of	the	coming-into-being of	the	eyes. And	the	third	story	will	be	from	a	later	stage	of	development,	soon	after we	are	born.	It	will	be	a	story	of	blood	vessel	formation. I	will	first	provide	the	stories.	Afterward,	I	will	provide	some	of	the	scientific data	behind	these	stories.	And	as	a	third	part,	I	will	suggest	that	these	stories	are relevant	to	thinking	of	the	world	in	terms	of	(1)	flux,	(2)	context,	and	(3)	the continuous	interdependent-coming-into-being. Part	1.	THREE	SMALL	STORIES A.	The	story	of	cellular	consummation The	human	body	is	composed	of	trillions	of	cells	that	are	constantly	being	born and	dying.	What	we	call	"life'	is	actually	as	much	about	death.	Throughout	life,	many trillions	of	cells	come	and	go,	yet	there	is	the	illusion	of	stasis. There	are	blood	cells, brain	cells,	stomach	cells,	and	many	others.	But	one	type	of	cell	is	very	special. These	are	the	germ	cells.	While	in	the	embryo,	the	germ	cells	will	migrate	into	the developing	testes,	if	the	embryo	is	male.	And	they	will	become	the	sperm	cells	of	the adult.	If	the	embryo	is	female,	the	germ	cells	migrate	into	the	developing	ovary,	and they	will	become	the	eggs	of	the	mature	adult. The	sperm	cells	and	egg	cells	are	remarkable	in	many	ways.	They	have	only	half the	genes	of	normal	cells.	So	when	sperm	and	egg	unite,	they	make	complete	the normal	number	of	genes,	and	these	genes	provide	most	of	the	instructions	for normal	development.	The	sperm	and	the	egg	are	two	cells	at	the	verge	of	death. Both	the	sperm	and	the	egg	will	soon	perish.	Yet,	by	their	interactions,	they	can make	an	organism	that	will	lives	several	decades.	Both	sperm	and	egg	are remarkable	partners.	Out	of	the	millions	of	sperm	ejaculated,	only	about	a	dozen make	the	full	journey	and	reach	the	vicinity	of	the	egg.	And	out	of	the	millions	of eggs	originally	in	the	ovary,	only	about	500	will	be	ovulated,	one	per	month;	and only	they	have	a	chance	of	meeting	a	sperm. For	the	sperm,	the	race	is	not	necessarily	to	the	quickest.	The	sperm	that fertilizes	the	egg	is	one	of	the	sperm	that	cooperates	best	with	the	woman. For	the woman's	reproductive	tract	is	not	a	passive	tube	through	which	sperm	race,	and	the sperm	that	are	ejaculated	are	not	mature	sperm.	In	fact,	they	cannot	fertilize	eggs. Rather,	the	sperm	that	get	ejaculated	are	immature	sperm.	They	have	to	complete their	formation.	And	this	is	accomplished	by	interacting	with	the	oviduct	cells	of	the woman's	reproductive	tract.	The	fastest	sperm,	those	getting	immediately	to	the egg,	cannot	fertilize	it.	That's	because	it	remained	immature.	The	women's	oviduct cells	change	and	mature	the	sperm,	giving	it	the	capacity	to	find	and	fertilize	the	egg. Molecules	in	these	oviduct	cells	bind	to	the	sperm,	slow	it	down,	and	change	the sperm	cell's	membrane.	After	the	membrane	has	changed,	the	sperm	can	then	bind sperm-activating	substances	produced	by	the	newly	released	egg,	and	this	binding makes	sperm	swim	faster,	and	gives	the	sperm	direction	to	propel	it	toward	the	egg. Only	after	interacting	with	the	oviduct	cells	can	the	sperm	find	the	egg	and	fuse	with it. And	when	the	sperm	meets	the	egg,	it	does	not	bore	into	it.	It	does	not	drill	into it;	it	does	not	punch	a	hole	in	it. Rather,	the	sperm	head	leans	against	the	egg,	and the	egg	sends	out	processes	to	envelop	it.	The	sperm	and	egg	membranes	fuse, causing	the	two	cells	to	become	one. And	now	the	sperm	reciprocates.	In	the	oviduct,	the	sperm	was	matured	and activated	by	the	egg.	Now,	the	sperm	activates	and	matures	the	egg.	For	the	human egg	is	also	immature.	It	has	not	completed	its	final	division.	This	completion	of	egg development	happens	when	the	sperm	enters.	Now,	the	activation	of	the	egg	allows development	to	begin. So	we	have	a	parable	of	two	immature	cells,	both	at	the	verge	of	death.	The	sperm gets	matured	and	activated	in	the	woman's	reproductive	tract,	allowing	it	to	mature and	activate	the	egg	to	begin	development.	This	is	how	our	life	begins.	Not	in combat,	not	in	violence,	but	in	reciprocal	interacting	and	partnership. B.	The	story	of	the	eye Imagine	the	head	of	an	early	human	embryo.	In	the	early	embryo,	there	are	no eyes,	ears,	nose,	tongue;	no	sound,	smell,	taste,	no	realm	of	seeing-a	starting	point that	is	fundamentally	similar	to	that	described	in	the	opening	portion	of "The	Heart Sutra." The	head	is	initially	covered	with	skin.	There	are	not	yet	holes	for	the	mouth or	nose.	There	are	no	eyes.	If	left	alone,	no	eye	lenses	will	form.	But	something	has to	tell	some	of	the	skin	cells	to	become	the	lenses	of	the	two	eyes.	What	does	this?	It is	the	brain.	In	a	specific	region	of	the	developing	brain,	a	pair	of	bulges	appears. They	travel	out	from	the	brain,	and	they	eventually	touch	the	skin.	When	these young	brain	cells	touch	the	embryonic	skin,	they	produce	chemicals	that	instruct these	skin	cells	to	turn	away	from	the	path	of	skin	development	and	to	enter	the path	of	lens	development.	The	brain	tells	these	skin	cells:	"You	are	to	become	the lens	of	the	eye."	And	as	the	lens	cells	form,	the	developing	lens	cells	tell	the	brain cells	that	formed	them:	"And	you	are	not	going	to	become	brain.	You	will	become the	retina	of	each	eye."	The	developing	lens	is	in	conversation	with	the	developing retina.	They	help	form	each	other.	Without	the	lens,	there	is	no	retina.	Without	the retina,	there	is	no	lens.	Eventually,	the	retina	will	secrete	a	fluid	that	fills	the chamber	of	the	eye,	separating	the	two.	Where	the	lens	and	retina	remain	in	contact, the	iris	muscles	form	from	the	retina,	thereby	allowing	the	lens	to	focus	light	onto the	retina.	The	stalk	connecting	the	retina	to	the	brain	becomes	the	optic	nerve. This	is	how	human	organs	form.	They	do	not	come	into	existence	independently. They	come	into	existence	through	the	effort	of	a	community	of	other	organs. The cells	that	become	the	heart	need	the	head	and	the	gut	in	order	to	form	properly.	The cells	that	become	the	bones	of	the	hand	need	signals	from	the	skin	in	order	to	grow. One	of	the	proteins	needed	for	eye	development	is	BMP4.	BMP4	is	a	chemical that	goes	from	one	cell	to	another	cell.	But	what	it	does	is	very	different	in	different parts	of	the	body.	In	the	head,	BMP4	is	one	of	the	proteins	made	by	the	brain	cells that	instruct	the	skin	cells	to	start	becoming	lens	cells. But	BMP4	in	the	connective tissue	of	the	body	says,	"build	bones."	BMP4	in	the	very	early	embryo	says,	"Become skin".	And	BMP4	between	the	bones	of	our	fingers	tells	the	cells	to	die,	thereby separating	our	digits. Context	is	everything.	There	is	no	essence	to	BMP4.	It	does different	things	in	different	situations. So	as	organs	form,	the	reciprocity	that	we	saw	in	the	sperm	and	egg	continues.	One sees	interdependent	co-origination.	The	retina	doesn't	form	without	the	lens forming.	The	lens	doesn't	form	without	the	retina	forming. One	also	sees	that	the context	in	which	a	molecule	functions	determines	the	function	of	that	molecule.	We also	see	the	eye	as	an	organ	in	flux.	It	was	made	by	immature	cells.	The	function	of the	adult	retina	is	to	receive	light.	The	function	of	the	embryonic	retina	is	to	induce the	formation	of	the	lens. C. The	story	of	the	intestinal	capillaries Our	gut	contains	trillions	of	bacterial	cells.	They	are	not	dangerous.	Quite	the opposite,	we	need	them,	and	they	need	us.	We	acquire	these	bacteria	at	birth-the moment	we	start	coming	through	the	birth	canal.	Our	mother	has	bacteria throughout	her	reproductive	tract	and	gut,	and	as	we	pass	through	the	birth	canal, these	bacteria	colonize	our	bodies.	The	first	thing	our	bodies	do,	before	even	the first	breath	is	taken,	is	to	acquire	these	bacteria. And	this	is	good.	One	can	experimentally	breed	mice	that	lack	such	bacteria. These	mice	are	not	normal.	First,	they	have	an	immune	deficiency	and	cannot	make the	normal	amount	of	antibodies.	Second,	they	lack	the	necessary	blood	vessels	to take	food	from	the	gut.	Third,	they	have	behavioral	problems.	Normal	mice	and normal	people	are	full	of	bacteria.	And	these	bacteria	help	construct	our	bodies. Bacteria	act	just	as	embryonic	cells	do.	Just	as	the	brain	cells	put	forth	chemicals that	change	gene	expression	in	the	skin	cells	to	turn	them	into	lenses-so	the bacteria	also	produce	the	chemicals	that	activate	certain	genes	in	the	surrounding tissues,	and	this	gene	expression	tells	the	cells	what	to	do.	Bacteria	activate	certain genes	in	our	gut	tissues,	and	they	suppress	the	expression	of	others	genes.	These changes	in	gene	expression	that	are	caused	by	the	bacteria	are	needed	to	make certain	organs.	We	are	told	how	to	develop	not	only	by	the	cells	we	acquire	from	the union	of	sperm	and	egg.	We	also	are	told	how	to	develop	from	over	100	species	of bacteria	that	inhabit	our	young	body.	We	expect	the	bacteria,	and	we	are	born	with poorly	formed	organs	if	these	bacteria	are	not	present. For	instance,	the	symbiotic	bacteria	in	the	gut,	especially	a	genus	called Bacteroides,	actually	tells	the	intestine	cells	to	turn	on	the	genes	that	make	a	protein called	angiogenin-4.	The	intestinal	cells	make	angiogenin-4	and	secrete	it	to	their neighboring	cells.	The	cells	around	the	intestine	bind	angiogenin-4,	and	angiogenin4	tells	these	nearby	cells	to	make	capillaries. But	angiogenin-4	does	more	than	help	produce	capillaries.	It	also	kills	Listeria,	a bacteria	that	is	a	competitor	for	Bacteroides.	Bacteroides	helps	us;	we	help Bacteroides. So	important	are	these	symbiotic	bacteria	that	we	have	integrated	them	into	our physiology.	During	the	last	months	of	pregnancy,	the	woman's	hormones	change	the types	of	bacteria	living	inside	her.	These	bacteria	actually	help	the	pregnant	woman maintain	the	fetus.	When	the	baby	is	born,	it	acquires	these	microbes	as	the	fetus passes	through	the	birth	canal.	Equally	amazing,	when	the	mother	feeds	the	baby, she	is	giving	the	baby	two	sets	of	nutrients.	One	type	of	food	feeds	the	baby.	The other	type	of	food	feeds	the	good	bacteria.	The	food	from	the	mother	contains sugars	that	that	humans	can't	digest.	However,	they	selectively	permit	the	growth	of certain	bacteria-the	ones	we	want	in	the	baby's	body. We	nourish	the	sin-boos, and	they	help	construct	us. Such	interactions	between	species	is	called	symbiosis,	and	we	find	that	symbiosis is	not	the	exception	to	the	rule.	Rather,	symbiosis	is	the	rule. One	sees	symbiosis inside	our	cells,	one	sees	symbiosis	in	making	organs.	One	sees	symbiosis	in	the production	of	oxygen	and	in	the	nitrogen	of	our	soil.	We	see	it	in	tidegrass communities	and	in	our	bodies. We	are	not	individual	bodies.	That	is	an	illusion.	We are	ecosystems	of	co-dependent	processes. So	we	do	not	develop	on	our	own.	The	fertilized	egg	does	not	have	within	it	all the	material	needed	for	the	completion	of	development.	We	literally	"become	with others."	This	is	one	of	the	great	biological	discoveries	of	the	21st	century,	and	one that	overturns	much	of	the	competitive	paradigms	of	the	19th	and	20th	century.	We need	the	other	species	to	survive.	That's	not	metaphor.	It	is	reality	as	science	knows it. Part	II.	Scientific	Explication In	this	section	I	would	like	to	provide	some	of	the	scientific	details	that	allow us	to	tell	such	stories1. A. FERTILIZATION.	The	essence	of	fertilization	is	the	mutual	activation of	the	sperm	and	egg	such	that	development	can	be	activated	in	the egg	and	that	the	inherited	material	can	be	transmitted	from	one generation	to	the	next. Fertilization	is	about	the	interaction	of	cells to	transform	each	other. Fertilization	is	the	story	of	interaction	between	two	cells,	the	sperm	from	the male,	the	egg	from	the	female. Both	the	sperm	and	egg	are	immature	cells	and	have to	be	activated.	And	this	is	done	by	activating	certain	proteins	within	the	sperm	and egg. 1. Activation	of	the	sperm:	I.	Capacitation.	The	activation	of	the	mammalian sperm	is	done	in	two	steps,	the	capacitation	reaction	and	the	acrosome reaction.	Both	steps	alter	the	membrane	of	sperm	cells	to	make	their	next steps	possible.	Capacitation	allows	the	sperm	to	find	the	egg.	The	acrosome reaction	allows	the	sperm	to	bind	to	and	enter	the	egg.	During	capacitation, the	cells	of	the	female's	oviducts	bind	to	the	sperm	and	stop	the	sperm	from moving.	This	cessation	of	movement	allows	cholesterol	to	be	removed	from the	sperm	cell	membrane.	This	removal	of	cholesterol	allows	calcium	ions from	the	woman's	reproductive	tract	to	flow	into	the	sperm,	and	these calcium	ions	activate	the	adenylate	cyclase	enzyme	on	the	sperm	cell membrane.	This	enzyme	is	a	protein	that	turns	a	small	molecule,	AMP,	into another	small	molecule	called	cyclic	AMP. Cyclic	AMP	activates	tyrosine kinase	proteins,	and	these	proteins	add	phosphate	groups	onto	other	proteins. These	changes	cause	the	sperm	membrane	proteins	to	reorient	on	the	sperm. 1	All	the	details	can	be	found	in	Gilbert	and	Barresi	(2016).	The	notion	that descriptions	of	development	might	benefit	from	Buddhist	philosophy	is	not necessarily	new	(Rose	1997,	p.	34; Barash	2013). As	a	result	of	capacitation,	the	Izumo	protein,	which	is	necessary	for	spermegg	binding,	migrates	into	the	membrane,	where	it	will	be	functional	in	biding to	the	egg.	The	proteins	that	are	needed	to	receive	the	directional	signals	from the	egg	are	also	activated.	Capacitated	sperm	can	now	recognize	these chemical	signals	and	swim	quickly	to	the	egg.	The	uncapacitated	sperm cannot. 2. Activation	of	the	sperm.	II.	The	acrosome	reaction.	Once	near	the	egg,	the membrane	formed	during	capacitation	is	exchanged	for	another	cell membrane,	coming	from	inside	the	sperm.	This	change	is	called	the	acrosome reaction.	As	the	sperm	approach	the	egg,	substances	from	the	egg	or	from	the cells	surrounding	the	egg	(the	"cumulus"	of	cells	that	had	been	connected	to	it in	the	ovary)	cause	the	tip	of	the	sperm	cell	membrane	to	disintegrate,	while another	membrane	is	put	in	its	place.	This	new	membrane	contains	the proteins	(such	as	Izumo)	that	will	bind	to	the	egg. This	new	membrane	also has	the	proteins	that	bind	to	outer	surface	of	the	egg. After	undergoing capacitation	and	acrosome	reactions,	the	sperm	is	competent	to	fertilize	the egg. 3. Sperm-egg	binding.	I.	Zona	pellucida.	The	binding	of	sperm	and	egg	also occurs	in	two	steps.	First,	the	sperm	binds	to	the	protective	layer	of	the	egg, the	zona	pellucida.	In	humans,	this	layer	is	made	of	4	proteins,	and	it	has	two functions.	First,	it	only	binds	active	sperm.	Second,	this	protein	shell	serves	a protective	function	for	the	embryo	developing	inside	it,	preventing	the embryo	from	adhering	to	the	oviduct	cells	as	it	travels	to	and	into	the	uterus. (Once	inside	the	uterus,	the	embryo	digests	the	zona	pellucida	and	is	able	to adhere	to	and	enter	into	the	uterus.)	The	proteins	on	the	sperm	bind	to proteins,	mainly	protein	ZP2,	on	this	protective	outer	layer	of	the	egg. Chemicals	released	by	the	sperm	can	then	digest	a	small	channel	in	the	zona pellucida,	allowing	the	sperm	to	reach	the	egg. 4. Sperm-egg	binding	.	II.	Membrane	fusion.	When	the	sperm	reach	the	egg, they	do	not	bore	into	it	or	drill	into	it.	Rather,	the	sperm	head	places	itself adjacent	to	the	huge	egg	surface,	and	the	egg	cell	membrane	extends	folds	that envelop	the	sperm.	The	Izumo	protein	on	the	sperm	membrane	recognizes	a receptor,	Juno,	on	the	egg	membrane. If	one	wants	to	use	metaphors,	the	egg embraces	the	sperm.	And	then,	the	sperm	cell	membrane	melts	into	the	egg cell	membrane,	and	sperm	and	egg	become	one. 5. Egg	activation.	I.	Re-initiating	cell	division	and	development.	The	sperm can	now	reciprocate	and	activate	the	egg.	A protein	from	the	sperm-PLCzeta-releases	calcium	ions	from	their	storage	vesicles	inside	the	egg.	This	is very	similar	to	the	use	of	calcium	ions	during	the	capacitation	and	acrosome reactions	in	the	sperm.	The	calcium	ions	activate	certain	egg	proteins	that activate	other	egg	proteins.	Again,	this	is	very	much	like	what	happens	in capacitation.	The	activated	egg	proteins	do	several	things.	First,	they	change the	egg	cell	membrane	such	that	it	cannot	bind	any	more	sperm.	Only	one sperm	is	permitted	to	enter	the	egg.	Second,	the	activated	proteins	re-start	the maturation	of	the	egg.	The	human	egg	is	stopped	in	the	middle	of	its	second meiotic	division. It	is	still	immature.	The	entry	of	the	sperm	allows	the	egg	to mature	and	complete	its	second	meiotic	division	to	give	it	half	the	number	of genes. And	third,	the	newly	activated	enzymes	re-start	the	production	of	new proteins,	the	proteins	that	will	allow	cell	division	to	take	place. 6. Egg	activation.	II.	The	union	of	genetic	materials.	Fertilization	has	two functions-the	initiation	of	development	and	the	creation	of	a	new	genome whose	genes	are	derived	half	from	the	mother	and	half	from	the	father.	After the	sperm	has	activated	the	last	cell	division	of	the	egg,	the	egg	now	has	a nucleus	with	half	the	number	of	genes,	and	the	sperm	nucleus	also	has	half	the number	of	genes.	How	do	these	two	nuclei	find	each	other?	This	feat	involves another	step	of	sperm-egg	cooperation.	The	sperm	brings	in	not	only	a nucleus,	but	also	the	centrosome,	a	set	of	proteins	that	make	fibers. The chemicals	that	make	these	fibers,	the	tubulin	proteins,	come	from	the	mother. The	sperm	centrosome	spins	its	net	of	egg	proteins,	catching	the	female nucleus.	Then,	the	male	and	female	nuclei	move	toward	each	other	in	this	net, and	finally	come	together	and	fuse.	The	chromosomal	genes	of	the	mother	join with	the	chromosomal	genes	of	the	father	and	cell	division	occurs.	The formation	of	the	new	person	has	begun. Thus,	there	are	enormous	amounts	of	cooperation	taking	place	during fertilization.	The	female	reproductive	tract	and	egg	are	not	always	passive.	They mature	and	activate	the	sperm.	Once	activated,	the	sperm	becomes	capable	of initiating	the	maturation	of	the	egg.	The	sperm	and	the	egg	are	both	active	and passive,	and the	sperm	and	the	egg	activate	each	other	by	similar	chemical	means. (Interestingly,	these	mechanisms	of	activation	use	many	of	the	same	proteins	that will	later	be	used	in	transmitting	neural	signals.) Moreover,	the	sperm	and	the	egg bring	different	elements	into	the	fertilized	egg.	First,	while	both	sperm	and	egg bring	the	same	number	and	type	of	genes,	some	genes	can	only	be	active	if	they come	from	the	egg,	while	other	genes	are	only	active	if	they	come	from	the	sperm. Like	the	Buddhist	notions	of	red	matter	making	some	organs	and	white	matter making	other	organs,	the	sperm	and	egg	have	some	complementary	functions	and are	both	needed	to	make	a	complete	body.	The	sperm	brings	in	the	centrosome, which	is	necessary	for	cell	division.	The	mother	brings	all	the	mitochondria,	which provide	the	energy	for	such	division. So	while	the	sperm	and	egg	are	two	cells	on the	verge	of	death,	if	they	cooperate	successfully,	the	human	embryo	begins	to	form. B. ORGAN	FORMATION.	The	essence	of	organ	formation	is	the expression	of	different	genes	in	the	cells	of	different	organs. Vertebrate	organ	formation	is	about	the	interaction	of	tissues	to mutually	transform	each	other. Fertilization	gives	each	of	us	our	genome-the	set	of	genetic	instructions	that	are critical	in	constructing	and	maintaining	our	bodies.	As	the	fertilized	egg	divides	to produce	all	different	the	cell	types	of	the	body,	the	genes	in	each	cell	replicate	as	the cell	divides,	so	that	every	cell	has	the	same	number	and	types	of	genes.	Cloning	has shown	that	the	genes	of	each	cell	are	the	same.	The	genes	are	the	instructions	that make	proteins,	and	the	proteins	do	the	work	of	the	cell.	But	each	gene	is	not	active in	every	cell.	Quite	the	contrary;	different	genes	are	active	in	different	types	of	cells, and	the	proteins	made	by	these	different	genes	are	what	give	the	organs	their different	functions.	In	the	red	blood	cells,	the	genes	for	hemoglobin are	active,	and this	red	compound	transports	oxygen	to	the	cells.	The	pancreatic	beta	cells	do	not make	hemoglobin.	Rather	they	activate	the	genes	that	make,	among	other	things, insulin,	the	protein	needed	for	sugar	metabolism.	The	lenses	of	our	eyes	are	told	to activate	the	genes	that	make	the	transparent	crystalline	proteins,	while	the	genes	in the	epidermis	of	our	skin	are	told	to	makes	special	keratin	proteins	that	that	are water-resistant	and	elastic. So	the	genome	has	to	be	told	which	genes	to	activate	in	which	cells. How	is	this done?	The	agents	of	differential	gene	expression	are	a	set	of	proteins	called transcription	factors.	These	proteins	bind	to	a	certain	region	of	the	gene	and	allow the	binding	of	an	enzyme,	RNA	polymerase	II,	which	starts	the	processes	by	which the	gene	becomes	active	and	makes	proteins. Different	transcription	factors	bind	to different	genes,	and	the	combination	of	certain	transcription	factors	allow	the	genes to	become	active. Which	transcription	factors	act	in	a	cell	depends	on	where	the	cell	is	and	what that	cell's	neighbors	are.	Context	is	critical.	We	are	thinking	with	cells	that	could have	been	used	for	eating,	had	they	been	in	a	different	part	of	the	embryo.	As	the fertilized	egg	divides	to	become	a	ball	of	cells,	different	transcription	factors	are activated	in	the	inside	cells	than	the	outer	cells.	This	is	the	first	distinction	in	the embryo.	The	outer	cells	will	become	the	placenta;	the	inner	cells	will	become	the body.	These	tissues,	now	different,	influence	each	other	to	become	more	tissues (Stephenson	et	al	2012;	Harrison	et	al	2017)	. One	of	the	best	examples	of	organ	formation	is	that	of	the	eye.	The	formation	of the	eye	begins	when	two	areas	of	the	developing	forebrain	brain,	each	expressing the	Rx	transcription	factor,	are	instructed	(by	the	proteins	activated	by	this transcription	factor)	to	grow	toward	the	skin. When	these	brain	cells	reach	the	skin, they	flatten	against	it	and	secrete	a	group	of	proteins	including	BMP4,	Fgf8,	and Notch.	Each	of	these	proteins	binds	to	a	specific	receptor	protein	on	the	surface	of the	embryonic	skin	cells.	When	they	are	bound	to	the	receptor	proteins	on	the membranes	of	the	neighboring	skin	cells,	the	receptors	activate	certain transcription	factors	that	tell	the	embryonic	skin	cells	to	elongate	and	to	become	the transparent	cells	of	the	lens.	These	cells	start	making	the	crystalline	proteins	that characterize	the	lens	cells.	One	of	the	transcription	factors	induced	in	the	developing lens	cells	activates	the	gene	for	another	protein	that	is	secreted	from	the	elongating lens	cell.	This	protein	binds	to	receptors	on	the	brain	cells	and	tells	the	brain	cells	to become	the	neural	retina	cells. As	the	brain	cells	are	telling	the	skin	cells	to	become lenses,	the	skin	cells	reciprocate	by	telling	those	particular	brain	cells	to	become	the retina. In	addition,	the	physical	adhesion	of	the	developing	lens	cells	and	the	developing retinal	cells	prevents	other	cells	from	migrating	into	this	area.	The	migrating	cells would	have	been	the	neural	crest	cells	that	form	the	dermis	of	the	head	skin.	The neural	crest	cells	also	have	the	ability	to	block	the	signals	made	by	the	developing lens	and	brain.	So	these	antagonistic	cells,	which	would	have	prevented	lens formation,	are	physically	blocked	from	entering	the	eye-forming	areas. The	FGF8,	BMP4,	and	Notch	signals	activate	transcription	factors	to	activate	or repress	particular	genes. Pax6,	Sox2,	and	L-MAF	are	transcription	factors	that	are needed	to	activate	many	of	the	crystalline	gene	of	the	lenses.	Pax6	is	in	the	entire head	ectoderm,	and	it	is	placed	there	by	earlier	inductions	involving	the	heart	and gut	cells.	Sox2	is	activated	in	the	lens	by	BMP4	from	the	brain	tissue,	and	L-Maf	is similarly	activated	by	Fgf8.	Pax6,	Sox2,	and	L-Maf	bind	close	to	each	other	on	the DNA	of	certain	genes,	such	as	the	crystalline	genes.	And	by	their	interactions,	RNA polymerase	is	allowed	to	bind	to	them,	and	the	crystalline	gene	is	activated.	Usually, it	is	a	combination	of	transcription	factors	that	activates	genes.	And	these transcription	factors	are	activated	by	signaling	chemicals	originating	in	the neighbors.	The	rule	of	organ	formation	is	that	neighbors	build	neighbors. Again	one	sees	this	co-dependence	of	embryonic	development.	The	genes	are both	active	and	acted	upon;	the	cells	are	both	acted	and	acted	upon.	Each	group	of cells	helps	determine	the	fate	of	the	other. C. The	essence	of	developmental	symbiosis	is	that	certain microorganisms	signal	normal	development	in	the	host	organism. This	type	of	development	involves	the	interactions	between	cells	of different	biological	species. We	were	never	individuals2	.	We	are	not	individuals	anatomically,	as	at	least	50%	of the	cells	in	our	body	are	microbes.	We	are	not	individuals	physiologically,	as	30%	of the	soluble	material	in	our	blood	is	derived	from	these	bacteria.	Our	metabolism	is intimately	linked	to	theirs.	We	are	not	individuals	by	developmental	criteria,	since 2	Details	of	these	studies	can	be	found	in	Gilbert	et	al	(2012),	McFall-Ngai	et	al 2013). bacteria	are	necessary	for	our	normal	development.	In	fact,	none	of	us	are	individual animals.	For	over	a	decade	now,	several	biologists	have	been	considering	animals	as holobionts-the	organism	plus	its	colonies	of	persistent	microbial	symbionts. When you	think	of	a	cow,	you	may	think	of	a	slow	moving	animal	that	eats	grass.	Only,	it can't	eat	grass.	The	genes	of	the	cow	encode	no	proteins	that	allow	her	to	digest cellulose	or	any	of	the	woody	parts	of	grass.	Those	proteins	are	made	by	the bacterial	symbionts	of	its	stomach.	The	cow	is	not	a	cow	without	these microorganisms.	Similarly,	termites	can't	eat	wood.	That	ability	is	given	to	them	by their	microbes. The	microbes	activate	normal	gene	expression	just	like	an	embryonic	tissue would.	The	vertebrate	gut	without	its	symbionts	has	a	different	pattern	of	gene expression	and	is	like	a	genetic	mutant. In	fish,	the	division	of	the	gut	stem	cells	is induced	by	the	gut	bacteria,	and	without	the	bacteria	certain	cells	don't	form.	I	wish to	give	two	fascinating	examples	of	the	need	for	microbial	involvement	in	normal development. First,	the	bobtail	squid	feeds	in	the	shallow	waters	off	the	Hawaiian	islands. However,	it	is	only	a	big	as	your	palm,	and	many	other	creatures	find	it	tasty.	When it	feeds	during	the	full	moon,	the	light	of	the	moon	can	cast	the	squid's	shadow	on the	sea	floor,	showing	it	to	its	predator.	To	avoid	this	happening,	the	squid	has evolved	an	amazing	structure-the	light	organ.	On	the	belly	of	the	squid,	there	is	a pouch	that	glows	softly	and	can	cancel	its	shadow.	This	is	called	the	light	organ	of the	squid. However,	it	is	not	there	at	birth.	It	is	made	by	a	single	species	of	bacteria, Vibrio	fischeri.	The	squid	collects	these	bacteria	in	such	a	high	quantity	that	they start	glowing,	something	they	do	not	do	on	their	own.	So	the	light	organ	is	a	piece	of anatomy	that	is	made	in	one	organism	by	another	organism	for	the	benefit	of	both. The	squid's	development	is	not	complete	without	the	microbe;	and	the	microbe's development	is	also	changed	by	its	being	inside	this	organ,	which	provides	it	a	safe home. But	let	me	now	talk	of	some	science	that	would	border	on	science-fiction were	not	the	proper	controls	done.	One	large	study	(Hsaio	et	al	2013)	used	viral stress	in	mothers	to	induce	an	autism-like	condition	in	their	offspring.	These "autistic"	mice	spend	a	lot	of	time	self-grooming,	lack	normal	exploratory	behaviors, and	prefer	solitary	cages. This	study	found	that	the	autistic-like	mice	act	more	like normal	mice	when	you	alter	their	bacteria.	If	one	adds	certain	species	of Bacteroides,	this	alters	the	community	of	the	bacterial	symbionts,	and	it	increases the	integrity	of	the	gut	epithelium.	This	simple	procedure	stops	the	leaking	of bacterial	products	into	the	gut	and	normalizes	several	of	the	autism-like	behavioral abnormalities. One	of	these	chemicals,	4EPS,	is	made	by	bacteria	and	causes anxiety-like	symptoms	in	mice. In	the	"autistic"	mice	this	product	is	seen	in relatively	high	amounts	in	the	circulation.	In	the	normal	(bacteria-containing)	mice without	these	symptoms-and	in	the	"autistic"	mice	that	were	treated	with	the bacteria-4EPS	can	hardly	be	detected.	This	study	opens	up	a	new	area	that investigates	cognitive	and	emotional	situations	as	products	of	bacterial	metabolism (Hsaio	et	al	2013;	Desbonnet	et	al.	2014).	Different	microbes	may	make	us	different people.	Different	microbes	provide	different	amounts	of	resistance	to	kwashiorkor in	humans	(Smith	et	al	2013)	and	malaria	in	mice.	(Villarino	et	al	2016). We	are	multilineage	organisms.	The	separation	of	us	from	our	environment	is	an artificial	one,	based	on	visual	cues	and	not	on	the	evidence	of	anatomy,	physiology, or	developmental	biology.	We	have	numerous	ecosystems	within	us,	and	we	are part	of	each	of	these	ecosystems	(Gilbert	2014). . III. CODA:	Becoming	with	others We	always	tell	stories	by	linking	perceptions	into	a	narrative,	a	plot	with	a beginning,	middle,	and	an	end.	However,	scientific	stories	differ	from	many	other stories	because	they	are	severely	constrained	by	data3	. They	are	also	severely limited	by	controls,	which	mean	not	only	that	a	certain	story	is	possible,	but	also that	other	stores	are	not	possible. For	the	past	century,	there	have	been	three	major	biological	stories	that	have failed	the	test	of	data. The	first	has	been	has	been	that	the	story	that	fertilization	is all	about	male	struggles	and	success.	The	egg	was	a	passive	recipient	of	the	sperm, and	the	female	reproductive	tract	a	passive	conduit.	That	story	is	wrong. Fertilization	is	a	story	about	interaction	and	cooperation.	If	there	is	competition,	it	is usually	in	the	form	of	which	sperm	cell	cooperates	best. Second,	we	were	often	told	a	story	that	the	creation	of	an	embryo	is	strictly controlled	by	our	genes.	The	genes	were	considered	to	be	our	essence;	they	are	who we	are.	The	notion	that	our	DNA	is	seen	as	the	basis	for	our	autonomous	self-hood has	been	documented	by	historians	and	sociologists	who	studied	the	rhetoric	of DNA	in	Western	society	(for	instance,	Nelkin	and	Lindee	1985). In	Western countries,	anti-abortion	websites	maintain	that	we	are	exactly	who	we	are	at fertilization;	even	automobile	ads	use	DNA	as	metaphor	for	essence	(Gilbert	and Howes-Mischel,	2004). This	story	has	fallen	apart.	We	now	know	that	the	environment	plays	critical	roles, and	that	the	environment	can	also	change	gene	expression. We	also	know	that development	(lus	kyi	chags	tshul;	how	the	body	is	made)	consists	of	the	making	of parts	that	become	different,	and	that	once	different,	these	parts	interact	with	one 3	Garrett	(2008)	has	claimed	that	the	stories	told	about	embryology	in	the	Tibetan Buddhist	tradition	are	not	scientific	stories,	as	they	are	stories	not	about	the	embryo but	about	the	adept	(P.	57,	157).	Exoteric	Buddhist	stories	are	about	gestation	being a	realm	of	suffering;	exoteric	Buddhist	stories	concern	the	adept's	being	reborn	into an	enlightened	body. Garrett	(p.	130)	claims	that	the	12	steps	of	dependent	selforigination	creates	a	middle	ground	between	the	extremes	of	eternalism	(that	there is	an	eternal	essence	of	each	person)	and	nihilism	(that	the	person	is	destroyed	at death). another	to	form	organs4.	Embryonic	development	is	based	on	specific	induction, such	as	the	formation	of	the	lens	by	brain	tissue	touching	the	skin.	No	other	tissue but	the	brain	will	turn	skin	into	lens.	No	other	tissue	but	the	developing	lens	will turn	brain	into	retina.	Developmental	biology	is	a	science	based	on	the	notion	of "specific	conditionality,	idaṃpratyayatā,"	namely,	that	one	part	comes	into	being	by interacting	with	another	part.	"This	is	because	that	is.	This	is	not	because	that	is not." However,	the	third	postulate	of	specific	conditionality	--as	this	ceases	to	be,	so does	that-is	often	circumvented	by	the	embryo.	When	cell	A	tells	cell	B	to	become B',	the	product	of	the	genes	that	are	activated	in	B	to	effect	this	conversion	often activate	themselves.	The	cell	becomes	B'	even	after	cell	A	dies	or	moves	to	a	new location.	If	the	teacher	dies	or	moves,	the	teaching	is	still	continued. We	are	not	merely	self-manifestations	,	the	"readouts,"	of	our	genes.	"Selfmanifestation,"	as	the	third	Karmapa,	His	Holiness	Rangjung	Dorje(1284-1339), explained	in	his	Wishing	Prayer	for	the	Attainment	of	the	Ultimate	Mahamundra,	"has never	existed	as	such,	and	is	erroneously	seen	as	an	object."	Indeed,	according	to	the Buddhist	tradition	(as	in	the	Mahamudra),	attachment	to	this	non-existent	selfmanifestation	is	a	root	of	the	pernicious	duality	of	"I	and	other."	However,	rather than	our	body	having	a	genome-defined	"essence,"	we	are	constructed	by	parts	that receive	their	identity	as	they	are	being	constructed.	This	relates	directly	to	the principle	of	Pratityasamutpada,	which	emphasizes	that	what	appears	to	be	an individual	entity	comes	into	existence	though	interdependent	relationships	that create	one	another,	in	a	process	of	continual	arising	and	ceasing. 4	Development	finds	itself	as	the	integrator	between	structural	biology	(anatomy and	physiology)	and	evolution.	One	achieves	evolutionary	changes	by	altering	the patterns	of	development.	This	is	the	science	of	evolutionary	developmental	biology. One	of	the	fundamental	principles	of	evolutionary	developmental	biology	is	that	of the	"small	toolbox."	From	using	the	same tools	in	different	contexts,	one	can generate	the	diversity	of	organisms.	In	Buddhist	philosophy,	this	is	the	problem	of homologous	cause	and	effect	(rgu	'bras	bu	dang	rjes	su	mthun	pa).	According	to Garrett	(2008),	both	Kyempa	Tsewang	and	Lodrö	Gyelpo	asked	how	an	infinite variety	of	forms	can	be	generated	from	a	small	set	of	causes.	This	is	a	central question	of	evolutionary	developmental	biology. Indeed,	not	only	is	interaction	is	critical,	but	so	is	impermanence.	Impermanence is	seen	in	the	transient	organs	of	the	embryo,	which	exist	to	make	other	organs	but then	perish	themselves.	The	primitive	streak	and	notochord	are	critical	in	forming the	embryo;	but	they	are	not	organs	of	the	newborn.	Impermanence	is	also	seen	in the	fundamental	metabolism	of	the	cells.	We	retain	our	identity	solely	by	changing our	component	parts,	as	we	eat,	drink,	and	excrete.	The	world	passes	through	us	as we	pass	through	the	world	(Jonas	1966;	Gilbert	1982). And	in	developmental	biology,	context	is	also	critical.	BMP4	is	important	in making	the	lens	of	the	eye.	But	in	another	context,	the	hand,	BMP4	tells	the	cells between	our	fingers	to	die.	In	another	context,	the	early	embryo,	it	tells	cells	to become	the	skin	and	not	the	nervous	system.	In	another	context,	it	instructs	cells	to become	bone,	and	in	a	different	context,	it	instructs	cells	to	become	heart. So	what this	molecule	does	depends	on	where	and	when	it	is	expressed. Specifically,	the function	of	the	molecule	depends	upon	the	history	of	the	cell	receiving	it.	The	same pathways	used	for	activating	an	egg	will	be	used	for	neural	transmission. And	the	third	story	of	the	20th	century	that	doesn't	stand	the	scientific	scrutiny	of the	21st	century	is	that	we	are	unilineage	organisms	whose	genomes	are	in competition.	In	that	perspective,	life	is	seen	as	a	continuous	struggle	of	each	against all.	However,	a	new	story	is	emerging-that	each	organism	is	a	collection	of	species, a	holobiont,	and	that	most	evolution	occurs	though	interspecies	cooperation	rather than	intraspecies	competition. As	Margulis	and	Sagan	wrote	(1986), "In	short,	I believe	that	most	evolutionary	novelty	arose	and	still	arises	directly	from	symbiosis. Life	did	not	take	over	the	world	by	combat,	but	by	networking."	This	is	still	a controversial	story;	but	I	think	it	will	be	one	of	the	most	fundamental	changes	in	the way	Western	science	views	nature.	One	reviewer	(Bolker	2016)	recently	reported- "The	claim	that	'all	development	is	co-development'	...sounds	a	little	new	age	in	the context	of	current	individual-based	paradigms	for	thinking	about	development,	but	I suspect	that	within	the	next	decade,	we	will	take	our	status	as	holobionts	for granted." We	are	seeing	life	as	"becoming	with	the	other."	This	is	a	new	scientific	story	that may	make	the	competition	story	either	untenable	as	a	mechanism	for	change	or	a fine-tuning	mechanism	that	may	work	within	a	species. As	Lama	Tsong	Khapa noted,	one's	view	of	nature	changes	when	one	realizes	the	co-dependent	origins	of all	parts. "Just	seeing	that	interdependence	never	fails	brings	realization	that destroys	how	you	hold	to	objects,	and	then	your	analysis	with	view	is	complete." One	finds	context,	interdependence,	and	impermanence	as	normal	in	animal development.	One	can	meditate	on	an	embryo	as	one	can	on	a	mandala.	Indeed,	in his	book	on	the	emergence	of	order	in	development,	Johannes	Holtfreter	(1968,	p. xi),	one	of	the	most	important	biologists	of	the	Twentieth	Century,	wrote We	managed	more	or	less	successfully	to	keep	our	work	undisturbed by	humanity's	strife	and	struggle	around	us	and	proceeded	to	study the	plants	and	animals,	and	particularly,	the	secrets	of	amphibian development.	Here,	at	least,	in	the	realm	of	undespoiled	Nature, everything	seemed	peaceful	and	in	perfect	order.	It	was	from	our growing	intimacy	with	the	inner	harmony,	the	meaningfulness, the	integration,	and	the	interdependence	of	the	structures	and functions	as	we	observed	them	in	dumb	creatures	that	we	derived our	own	philosophy	of	life.	It	has	served	us	well	in	this	continuously troublesome	world. This	meditation	on	the	embryo	reflects	that	of	Lama	Tsongkhapa.	For	Holtfreter	the experience	of	the	embryo	instilled	faith,	banished	negativity,	and	stabilized	his otherwise	chaotic	mind. The	interdependence	of	structures	is	not	being	imposed from	without.	It	is	being	discovered	and	appreciated	by	the	scientists.	Similarly,	one of	the	world's	best	fertilization	researchers,	Edward	E.	Just	(1939,	p.	368),	wrote explicitly, Whether	we	study	atoms	or	stars	or	that	form	of	matter,	known as	living,	always	must	we	reckon	with	inter-relations. And in my science textbook on Ecological Developmental Biology, I cite Nagarjuna as someone who saw interdependent creation as the basis of the world. Developmental biologists do, as Lama Tsongkhapa (cited in Hixon, 1993) suggested, "listen to the harmonious symphony of interdependence." Embryology	is	always	replete	with	moral	and	political	categories	(BGSG	1988; Martin	1991;	Garrett	2008,	p.	17).	The	story	of	our	development	is	an	origin	story, and	such	stories	are	instructive	as	well	as	descriptive.	So	we	must	be	careful	and judge	such	stories	against	a	cultural	framework.	Are	these	scientific	stories	or	are these	stories	that	merely	repeat	on	a	microscopic	level	the	values	that	society	is expected	to	give	men	and	women?	Is	the	scientific	narrative	being	used	to	reinforce capitalist	values,	democratic	values,	authoritarian	values,	compassionate	values? And	if	so,	is	there	any	justification	to	it? There	is	a	story,	not	confirmable	by	science,	that	before	his	birth,	The	Buddha gave	sermons	from	his	mother's	womb	(Garrett	2008,	p.	102).	Perhaps	by	looking	at the	embryo,	though,	we	are	indeed	taught	that	all	things	are	impermanent,	that context	is	critical,	and	that	our	coming	into	existence	is	based	interdependent becomings	with	others.	This	co-dependent	origination,	Pratityasamutpada,	appears to	be	the	rule	of	nature,	whether	it	is	on	the	cellular	or	ecological	level.	It	is	probably most	easily	seen	in	development,	which	is	about	the	formation	of	bodies. Developmental	biology	is	a	science	of	becoming,	context,	and	transience. Of	the Twelve	Linked	Stages	of	Interdependent	Causation,	eleven	occur	before	or	during birth	(Samyutta	Nikaya;	Hopkins	1983;	Garrett	2008). Biologically	speaking,	we	are	not	and	have	never	been	individuals.	As expressed	by	anatman,	we	are	not	apart	from	nature.	We	must	become	used	to seeing	life	as	a	web	where	changes	in	one	process	can	cause	changes	in	all.	As	Rev. Martin	Luther	King,	Jr,	(1963)	noted	about	human	relations,	"We	are	caught	in	an inescapable	network	of	mutuality,	tied	in	a	single	garment	of	destiny.	Whatever affects	one	directly,	affects	all	indirectly." Or	as	Lama	Tsongkhapa	has	written	(quoted	in	Thurman	2014)	p.	178: Whatever	depends	on	conditions Is	empty	of	intrinsic	reality What	excellent	instruction	could	there	be More	amazing	than	this	discovery? So	I	will	finish	by	showing	something	amazing--a	photograph	taken	by developmental	biologist	and	Buddhist	monk	Willliam	Bates,	who	was	an	instructor in	the	Science	for	Monks	program	in	2006	and	2007. To	a	biologist,	it's	obvious	what	these	are.	They	are	frog	eggs	in	a	pond.	But	when you	see	the	context	of	the	photograph,	one	realizes	that	this	is	not	a	pond.	It	is	an elephant's	footprint.	Who	would	have	thought	that	these	frogs	have	an	existence that	depends	on	elephants,	and	that	the	elephant	has	become	part	of	the	life	cycle	of the	toad?	Maybe	these	are	not	merely	frog	eggs;	maybe	they	are	Indra's	pearls. Acknowledgements: First,	I	acknowledge	and	thank	my	teachers:	Randall	Huntsberry	for	introducing	to me	to	the	Prajnaparamita	texts	and	discussing	with	me	the	ideas	of	Nagarjuna;	and Robert	Auerbach	and	Donna	Haraway	for	their	discussions	on	embryos	and	coorigination. The	author	also	wishes	to	thank	Anna	Edlund	for	her	important contributions	to	making	my	ideas	accessible,	and	to	William	Bates	and	Steve	Borish for	their	discussions	concerning	the	meaning	of	Buddhist	embryological	texts.	The author	also	wishes	to	acknowledge	and	thank	ETSI	and	H.	H.	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