Neonatology and the DevelopmentalEvolutionary Parallel
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Endodermal and Ectodermal
Tissues follow a common
developmental sequence throughout
all vertebrates
Disruption of this developemental
sequence results in predictable
consequences
In the surviving neonate, the
consequences of developmental
disruption equal congenital
anomalies (e.g. holoprosencephaly,
pulmonary hypoplasia) or
morbidities of prematurity (e.g.
RDS, apnea of prematurity).
We can flip this logic around by
asking ourselves, “how can the
developmental – evolutionary
parallel be used to better
understand these diseases?”
What is the DevelopmentalEvolutionary Parallel?
The mesoderm is unfaithful in terms of the
developmental – evolutionary parallel. By 21
days, the mesoderm of the human fetus has
created the basic form of a salamander, but it
takes another 21 weeks before the endoderm
and ectoderm mature sufficiently for viability
(at the saccular stage of lung development).
But endoderm and ectoderm are faithful
because of growth factor ontogeny (more later).
Today
500,000,000 years ago
Development:
10 weeks
20 weeks
30 weeks
40 weeks
Perturbations result Perturbations are The limits of
Perturbations are
in spontaneous
associated with
associated with diseases
viability
abortions
congenital anomalies
of prematurity and birth
500,000,000 years ago
Notochordata (lampreys, lancets, hagfish)
Today
Larvea
Pineal gland (the 3rd eye)
Polymicrogyria
2 = the notochord
Ram Jet Ventilation
-/- PAX 6
Does he have 3 eyes too?
GI tract = stoma +
gut tube
(no pineal gland and…)
The lamprey gives us our
hypothalamus, pituitary / pineal
tracts and basal brain stem nuclei.
Elasmobranchs part 1
500,000,000 years ago
Development:
10 weeks
20 weeks
Today
30 weeks
40 weeks
proximal to distal
gut development
Elasmobranchs have 13
cranial nerves #13 = the
nervous terminalis (an
accessory olfactory nerve)
“The brain follows the nose”
holoprosencephaly
BMP
Elasmobranchs have
keen smell and well
developed olfactory
cortex
IGF-I + IGF-II
FGF10
Elasmobranchs part 2
500,000,000 years ago
Development:
10 weeks
20 weeks
Some Elasmobranchs develop the first gill
chambers (operculums) and along with it they
develop primary respiratory drive (a brain
stem function). In parallel with evolution, fetal
breathing starts in the first trimester.
Today
30 weeks
40 weeks
If a fetus can’t breath in fluid (due
to a swallowing defect, neuro or
muscular defects, or insufficient
amniotic fluid) the result is
pulmonary hypoplasia
Elasmobranchs gave us our brainstem, cranial
nerves and first highly developed lobe of cortex
Boney Fish
500,000,000 years ago
Development:
10 weeks
20 weeks
Today
30 weeks
metanephric kidney
BMPs &
FGFs
Fish bring two crucial things to the developmentalevolutionary parallel:
1st – they evolve the first high resolution, complex
eye into being (which comes with the optic cortex).
2nd – elasmobranchs convert ammonia to urea and
permeate their tissues with it for buoyancy. Fish
evolve the swim bladder for buoyancy as well as
metanephric kidneys. They excrete all their
ammonia. This become the basis for the terrestrial
kidney.
Pop Quiz: what is
this syndrome?
40 weeks
IGFs &
TGFa
Amphibians part 1
500,000,000 years ago
Development:
10 weeks
20 weeks
Today
30 weeks
40 weeks
TH
The limit of gestational viability is the late cannicular
phase of lung development. Artificial surfactant has little
effect on the surface tension of lungs that have no air
sacks but can almost completely normalize saccular lung.
Amphibians
stop here
BMP, EGF, FGF, TGFb, VEGF, SPARC
Surfactant deficiency = respiratory distress syndrome
Mature type II
pneumocytes are required
to recycle surfactant and
may explain why older
infants (>30 weeks) require
fewer repeat doses.
Amphibians part 2
500,000,000 years ago
Development:
10 weeks
* Optic cortex and retinal
density reach the optimum now
that amphibians have to track
flying prey (Bufo Marinus).
20 weeks
Proximal – Distal effect
*The skin becomes keratinized
and semi- permeable to water as
amphibians forage onto land.
KGF
SIP occurs because the
distal small intestine
(ileum) is “under grown”
in comparison to the
proximal bowel, which
distends it and perforates
it with bowel gas
Today
30 weeks
40 weeks
Cloaca evolves as amphibians
must hide their feces from
predators & carry their eggs to
water (precurser to colon and
1st durable gut modification
since elasmobranchs).
BMP + ?
ELBW infants have extreme insensible water loss. If poorly
managed it leads to hypernatremia and is associated with IVH
Reptiles
500,000,000 years ago
Development:
10 weeks
20 weeks
Today
30 weeks
40 weeks
“Reptilian lung”
Keritinization is more complete after 28 weeks of
gestation and water loss is less profound.
Keritinization can be accelerated by stress.
Apnea of Prematurity resolves around 3032 weeks of gestation when the nuclei of
the respiratory drive centers mature fully.
Reptiles are the 1st vertebrates fully
SNO
dependent upon active respiration
Reptiles have
aveolar lungs and
aveolar histology
emerges after 34
weeks of
development,
coincident with
final maturation
of type II
pneumocytes
Mammals part 1
500,000,000 years ago
Development:
10 weeks
20 weeks
Transient Tachypnea is a disease of
term infants that results from failure
of clara cells and type II cells to insert
ENaC in the cell surface (associated
with c-sections / rapid progression)
due to insufficient cortisol exposure.
Today
30 weeks
40 weeks
More Proximal – Distal effect
Long gestations
require large
meconium
resevoirs
Development: 20 weeks
Preterm NEC
s[cortisol]
during
pregnancy
Pre- ileocecal valve
bacterial overgrowth
formula feeds
functional ileus
30 weeks
40 weeks
Term NEC
Post ileocecal valve
isechemic preconditions
formula feeds
rapid feeding advances
Mammals part 2
500,000,000 years ago
Development:
10 weeks
20 weeks
Today
30 weeks
40 weeks
The phenomenon of postnatal brain
development in higher mammals (primates)
has created additional opportunity for
developmental perturbation. There are two
primary mechanisms of insult:
1) hypoxia-ischemia, which can occur either
secondary to anoxic birth injury or in concert
with prematurity and the combination of low
O2 tensions + low flow states
2) Inflammatory cytokines
associated with sepsis make
premature infants even more
vulnerable to PVL
PVL is associated with
cerebral palsy
So What?
500,000,000 years ago
Development:
10 weeks
20 weeks
Today
30 weeks
The Take Home Message:
Perturbation
40 weeks
prematurity
infection
teratogens
gene defects
Evolution
Neonatal
Well Being
versus
Fetal
Development
Neonatology
Neonatal
Disease