Reverse engineering: turning Jurassic Park into reality

By Clarie Lo

In 1990, the science fiction novel Jurassic Park was published. People were fascinated by the idea of constructing a theme park with dinosaurs freely roaming on the island. As a writer with a background in anthropology, Michael Crichton’s attempt in describing how these extinct creatures were cloned from DNA found in mosquitoes preserved in amber was bold. However, the reality is that even if scientists were able to extract blood from insects, all the genetic material of dinosaurs would have degraded1 after 65 million years. In fact, haemoglobin-derived porphyrins2, proteins and even intact cells have been found in dinosaur fossils, just not DNA.

A breakthrough arose from the discovery of birds being a monophyletic group, in which they all share a common ancestor: theropods, which are carnivorous dinosaurs with three-toed limbs3. Genetic calculations also reveal that the majority of dinosaur species have their genes highly conserved throughout evolution, such that the karyotype of chicken, ducks and ostriches closely resembles that of their ancestors.4

The idea of birds being living avian dinosaurs in the modern world inspired attempts to resurrect dinosaurs via reverse engineering. Scientists and palaeontologists like John Horner decide to work backwards from chicken, since their embryos are easily accessible from relatively cheap eggs to the ancient reptiles. To achieve this, the technique of atavistic gene activation is key. Atavistic genes are genes that have been switched off from expression during the course of evolution. Occasional errors in gene regulation results in reappearance of the corresponding genetic traits. Scientists can examine individuals with such aberrations and carry out in-situ hybridisation to identify specific mRNA and hence, the atavistic genes. Activation of the responsible signalling pathway could very likely induce artificial atavism.5

One of the earliest examples is the “Hen’s teeth” experiment conducted by Jean-Yves Sire, whose team tried to reinitiate odontogenesis in a taplid2 (ta2) chicken mutant. Ancient theropods used to have conical teeth that are homologous to that of reptiles, but this phenotype was gradually replaced by the development of beaks at least 80 million years ago. Some suggested the change is to facilitate flying by eliminating the weight of teeth,6 when others think it is to reduce the incubation time of eggs by 60%.7 Regardless of the specific driving force behind natural selection, the gene for tooth morphogenesis became silent due to inactivation of the odontogenic pathway. The dental lamina formed in early stages of embryo development regresses, such that no invaginations are available for tooth formation.8 By reinducing the signalling pathway, pre-dentin collagen matrix deposition was observed in ta2 mutants. Even though these embryos did not manage to survive for hatching,9 these first-generation teeth showcased the potential of reverse engineering.

Apart from the absence of teeth, another obvious anatomical difference between dinosaurs and chickesn is the internal structure of their lower legs. Both are composed of two bones, the outer fibula and the inner tibia. A maturation gene in modern chicken called Indian Hedgehog (IHH) puts the growth of fibula on pause after the initial stage of embryo development, differing from the tubular counterpart in their reptile ancestors, which extended all the way to reach the ankle. The abrupt cease in cell division probably happened at a point when the weight of avian dinosaurs became low enough to be supported by one full bone only. In 2016, a group of researchers led by Alexander Vargas in University of Chile decided to prevent the early maturation of the distal end of fibula by inhibiting IHH. The outcome is just as expected: the splinter-like structure has been transformed to the original form found in dinosaurs.10 The process of evolution was reversed.

After years of experimenting, reverse-engineered chickens now commonly possess dinosaur-like skulls and three fingered hands, while trials for eliminating sternal plates and lengthening arms are still continuous. This is when scientists encountered another major obstacle. Instead of being suppressed from expression, certain genes have completely vanished from the chicken genome through evolution. These include genes that code for enamel9 and lengthened tails, which are crucial dinosaur characteristics to be restored. In this case, transgenic addition of genes that have similar functionalities from another organism could be adopted. The invention of CRISPR-Cas9 gene editing technique also allows researchers to effectively knock out, for example, genes that code for bird tails and introduce genes from alligators instead, which are close relatives of dinosaurs.

Nowadays, many different forms of miniature dinosaur-chicken hybrids have been proposed and illustrated. There have been bioethical concerns regarding scientists’ attempts in playing God, but as what Jack Horner puts it in one of his interviews: ‘Humans have started with a wolf and ended up making a Pekingese with a problematic backbone and problematic legs. If people are fine with it and keep them as pets, then they should not have an issue with the sped up version: the “Chickenosaurus”.’

References:

1.         Griffin DK, Larkin DM, O’Connor RE. Jurassic Park: What Did the Genomes of Dinosaurs Look Like? In: Kraus RHS, editor. Avian Genomics in Ecology and Evolution [Internet]. Cham: Springer International Publishing; 2019 [cited 2022 Feb 28]. p. 331–48. Available from: http://link.springer.com/10.1007/978-3-030-16477-5_11

2.         Greenwalt DE, Goreva YS, Siljestrom SM, Rose T, Harbach RE. Hemoglobin-derived porphyrins preserved in a Middle Eocene blood-engorged mosquito. Proc Natl Acad Sci. 2013 Nov 12;110(46):18496–500.

3.         Xu X, Zhou Z, Dudley R, Mackem S, Chuong C-M, Erickson GM, et al. An integrative approach to understanding bird origins. Science. 2014 Dec 12;346(6215):1253293.

4.         O’Connor RE, Romanov MN, Kiazim LG, Barrett PM, Farré M, Damas J, et al. Reconstruction of the diapsid ancestral genome permits chromosome evolution tracing in avian and non-avian dinosaurs. Nat Commun. 2018 Dec;9(1):1883.

5.         Adams JU, Shaw KM. Atavism: Embryology, Development and Evolution. 2008 Nat Educ [Internet]. 2008; Available from: https://www.nature.com/scitable/topicpage/atavism-embryology-development-and-evolution-843/

6.         Zhou Z, Li FZZ. A new Lower Cretaceous bird from China and tooth reduction in early avian evolution. Proc R Soc B Biol Sci. 2010 Jan 22;277(1679):219–27.

7.         Yang T-R, Sander PM. The origin of the bird’s beak: new insights from dinosaur incubation periods. Biol Lett. 2018 May;14(5):20180090.

8.         Harris MP, Hasso SM, Ferguson MWJ, Fallon JF. The Development of Archosaurian First-Generation Teeth in a Chicken Mutant. Curr Biol. 2006 Feb;16(4):371–7.

9.         Sire J-Y, Delgado SC, Girondot M. Hen’s teeth with enamel cap: from dream to impossibility. BMC Evol Biol. 2008;8(1):246.

10.       Botelho JF, Smith‐Paredes D, Soto‐Acuña S, O’Connor J, Palma V, Vargas AO. Molecular development of fibular reduction in birds and its evolution from dinosaurs. Evolution. 2016 Mar;70(3):543–54.

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