The Medicine

It doesn’t take a neonatologist to know how intimidating the multitude of potential issues are that come along with premature birth. Hypoglycemia, anemia, sepsis an intracranial hemorrhaging are a few of the complications pediatricians have to manage in the fight for life in the NICU. Thanks to a study published recently in the Journal of Physiology, however, researchers have made headway into reducing this number. Work by Dr. Daniela Riccardi and Dr. Paul Kemp (Cardiff University, UK), and colleagues, on mouse embryos has identified a new avenue for altering the lung development of the human fetus in anticipation of such complications as Respiratory Distress Syndrome and Chronic Lung Disease.

The broad issue here is one of developmental timing: because the final stages of lung development happen during the latest stages of pregnancy in humans (As can been seen in the image above), premature birth leaves many infants with severe respiratory problems. Lung development in mammals in general is not complete at birth, and taking this immaturity a step further rarely ends well… With their discovery of the role of CaR (Calcium receptor) in lung morphogenesis, however, particularly its role in peripheral tubule formation and airway expansion, the authors hope that premature lung development can be dealt with in the very near future. According to the study, fetal Ca²⁺ levels exert a “brake” on branching morphogenesis while stimulating lung fluid secretion, which in turn actually disrupts branching. These processes, the authors have discovered, are regulated by CaR, and given the current ability of drugs to manipulate calcium levels the potential for pharmacological manipulation of lung development is vast. In the future we may very well see the elimination of the majority of lung immaturity issues in premature infants due to this understanding of the role of CaR in lung development.

The Natural History

So, how can I put this in perspective? Both you and I know that soft tissue does not preserve well in the fossil record (Ignore this); so, instead of approaching this from the available human paleontologic evidence I am going to take a few steps back. I direct your attention to an article on early view in The Anatomical Record. In this research, scientists from the Museum of Natural History in Germany and The University of Melbourne in Australia have taken it upon themselves to reconstruct what they believe to be the ancestral mammalian lung morphotype. Using histological investigation of the lung structure of a few monotremes (Ornithorhynchus anatinus and Tachyglossus aculeatus), a marsupial (Monodelphis domestica), and a eutherian (Suncus murinus), chosen due to the suitable representation of the opposums and shrews as basal marsupials and eutherians, respectively, the authors set off on a journey to uncover the differences in developmental timing of the respiratory system of some of our closest (relatively) extant ancestors.

Before explaining what they found, let me first give you a brief overview of the steps of posnatal lung development in mammals:

1. The volume of the developing lung increases simply as a result of the expanding airspace
2. Subsequent to this expansion, the lung tissue mass increases at a rapid rate, coupled with a large increase in internal surface area
3. Finally, microvascular maturation concludes the process with remodeling of the interalveolar walls and the transformation of the septal capillary system from a “double- to a largely single-network structure”

So, what is it that the authors found?

First, it takes a significantly longer amount of time for marsupials to reach the same stage of development found in eutherians (The infraclass of which humans are members). For instance, it takes Monodelphis domestica 21 days to reach the stage of development that Suncus murinus possesses at birth.

Secondly, a peculiarity was found in the development of the monotreme lung that suggests the third step listed above may not proceed to completion in all mammals. Instead of having a majorly single capillary septa, a double capillary “net” exists over large portions of the alveolar surface in monotremes, according to previous research (Perry et al., 2000), and when viewed in the light of the developing mammalian morphotype does not quite fit. A similar anatomical anomaly is seen in some diving eutherian mammals, and an entire group of fossorial rodents. It is considered, thus, that the double capillary net is ancestral in monotremes and derived in diving mammals. This peculiarity suggests a derived character state due to the demands of breath-holding due to diving or burrowing.

The resulting morphotype is one that is derived from the understanding that pulmonary structure depends almost entirely on the extent of intrauterine development. So, the contrast of eutherians to monotremes and marsupials is due to the relatively greater degree of immaturity at birth of the latter two. The authors argue that the state of the lung at birth in monotremes and marsupials is likely the degree of development that would be seen in the mammalian morphotype at birth, whereas eutherians span from a more altricial (lesser) or precocial (greater) degree of development, humans being a more altricial mammal. The following are the characteristics that the authors believe define the neonate in the mammalian morphotype, based on the evidence found in this study:

1. Low birth weight (<1g)
2. Closed eyes at birth
3. Lack of pelage at birth (naked)
4. Lung at air sac stage at birth
5. Large terminal air sacs at birth
6. Thick double capillary septum at birth
7. Late formation of alveoli

Understanding that these are adaptations for a specified “normal” gestation period gives us perspective on the multiple ways premature infants are ill-prepared for life outside of the womb. Mechanisms of evolution have given monotremes, marsupials and eutherians all adaptation to the many and varied environments that they find themselves in, yet they function at a population level around a statistical mean. In the case of premature human infants we are dealing with the extremes, not the mean. Thankfully, humans have one adaptation that has allowed us to deal with these extremes: science.

If you are interested in more on variable development rates in mammals, take a look at an earlier post of mine discussing bone formation.

(References)

Ferner, K, Zeller, U & Renfree, M, 2008, 'Lung Development of Monotremes: Evidence for the Mammalian Morphotype', The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology, p. NA. 10.1002/ar.20825

Finney, B, del Moral, P, Wilkinson, W, Cayzac, S, Cole, M, Warburton, D, Kemp, P & Riccardi, D, 2008, 'Regulation of mouse lung development by the extracellular calcium-sensing receptor, CaR', The Journal of Physiology, vol. 586, no. 24, pp. 6007-6019. 10.1113/jphysiol.2008.161687