A major cause of biodiversity is biodiversity itself (Feder, J. (2018). As new species form, they can generate niches that others may exploit, which can catalyse a sequence reaction of speciation events across trophic levels (smith, J. (2018). They conducted experiments and tested for sequential radiation in the apple maggot fly, Rhagoletis pomonella complex, an insect which confers sympatric speciation in the absence of geographic isolation due to host plant shifting. This species is attacked by three species of braconid wasps such as Diachasma alloeum, Utetes canaliculatus and Diachasmimorpha mellea (Wharton and Marsh, (1978).
There are two questions that must be asked in this case study, does the wasp species D. alloeum form ecologically and genetically differentiated incipient species in response to their diversifying Rhagoletis fly hosts and does the same host-plant-related adaptations that serve as ecologically-based gene flow barriers between flies have also evolved to reproductively isolate the wasps (FORBES, A. (2010). As a result of specialising on variable fly hosts, including the apple infesting race R. pomonella shows that the parasitic wasp Diachasama alloem formed new developing species. Furthermore, the case study displayed traits that differentially adapt R. pomonella flies to their host plants have rapidly evolved and therefore are served as biological barriers for reproduction which in turn isolates the wasps (Smith, J (2018). In conclusion, speciation cascades as the effects of new niche construction move across trophic levels (Forbes, A. (2018).
D. alloeum is in the genus Diachasma which also belongs to the ferrugineum species as well as D. ferrugineum and D. muliebre which are widespread in North America (Wharton, 1997). Surveys of D.alloeum (Stelinski et al, 2004) shows that the Diachasma species can attack a subsection of R. pomonella sibling species complex. Furthermore, R. pomonella, both hawthorn and apple fly races, is parasitized by D. alloeum, R. mendax (blueberry maggot) and R. zephyria (snowberry maggot) are also parasitized by D. alloeum. However, D. alloeum does not take place on R. pomonella’s entire environmental range, the wasp is situated in the north-eastern and Midwestern portion of R.pomonella’s distribution in the U.S.A (Rull et al., 2009). The parasitic wasp D. alloeum was tested for sequential radiation by examining if wasps attacking the derived R. pomonella and the ancestral hawthorn, and their closely related sibling species which are R. mendax and R.zephria show forms of host related genetic variation (Feder, J. (2018).
They also investigated if wasps varied from the same host plant, which showed genetic differentiation in the D. alloeum population, which appeared to be similar in the fly species R. pomonella. Mitochondrial DNA (mtDNA) cytochrome oxidase I (COI) sequences displayed only modest host related differentiation of wasps (Smith, J. 2018). Which concludes that apple, hawthorn, blueberry and snowberry wasps are of recent origin which in turn do not have highly genetically diverged cryptic sibling species (Forbes, A., Powell (2018). Instead, these taxa of recent origin have different haplotype frequencies. D. ferrugineum, D. alloeum and D. muliebre are distinguished by ?5% mtDNA divergence (Feder, J. 2010). We can argue that in snowberry wasps, they found mtDNA haplotype that is not present in any of the other wasp populations. In addition, the mtDNA haplotype found in blueberry, apple and hawthorn wasps was not present in the snowberry wasp, which tells us that the snowberry wasp was offset from the other taxa (Feder, J. (2018). Apple, blueberry, hawthorn and snowberry fly populations of D.alloeum show genetic differentiation for 9 of 21 microsatellite loci was scored across sympatric sites in the U.S.A (Forbes et al., 2009). Neighbour-joining trees for the microsatellites separated blueberry and hawthorn wasp populations at different ends of the networks (Feder, J. (2010). Blueberry wasps were most closely related with snowberry wasps, whilst the apple wasps were in between hawthorn and blueberry populations.
Similar host-related adaptations that naturally isolate R. pomonella flies seems to play a huge role in genetically differentiating D. alloeum wasps. Field studies were formed of D. alloeum which showed that adult wasps use host fruits as a site of mating which is similar to the flies. They also displayed similar discriminatory behaviour for host fruit volatiles to Rhagoletis flies in Y-tube olfactometer assays (Forbes et al., 2010). In the case study they found that the hawthorn, apple, snowberry and blueberry wasp populations all positively slanted towards the arm of the Y-tube which contained their natal fruit odour and were also antagonised by non-natal volatiles (forbes et al., 2010). The finding of avoidance behaviour in D. alloeum is very interesting as R. pomonella flies are also deterred by non-natal volatiles (Forbes et al., 2005). Because the F1Rhagoletis hybrids between hawthorn and apple flies fail to respond to any fruit volatiles (Linn et all., 2004). They have hypothesised that the evolution of avoidance to alternate hosts may cause olfactory incompatibilities and constitute a previously unrecognised post zygotic barrier in flies of mixed ancestry (hybrids are partly ‘behaviourally sterile’ due to a reduced chemosensory ability to find host fruit for mating and laying eggs (Feder
Development of Genetically Engineered Pig Organs
In the United States, an average of 21 people die per day waiting for a transplant 1. Due to the shortage of human organs, biotechnology companies have been looking for alternatives. Xenotransplantation, the process of transplanting tissues or organs of different species into humans, is one of them. Revivicor is focusing on genetically engineering pigs for xenotransplantation.
The main barrier for xenotransplantation is rejection. One cause of rejection is due to alpha 1,3 galactosyltransferase, an enzyme present in most animals except for humans and primates. When a tissue containing this enzyme is grafted into a human, the body’s immune system signals an attack causing a hyperacute rejection 2. To overcome this barricade, Revivicor knocks out the gene that produces alpha 1,3 galactosyltransferase then clones pigs from the modified cells.
Figure 1. Revivicor’s xenograft process. [http://www.revivicor.com/technology.html]
Formed in 2003 by David Ayers and based in Virginia, Revivicor is a regenerative medicine company that concentrates on genetically modifying pigs to be used as a tissue source for treatment of degenerative diseases in humans. The company is a spin-out of PPL Therapeutics, a UK company that produced Dolly the Sheep: the first cloned animal. Revivicor built upon the PPL Therapeutics’ technology and became the first company to clone a genetically-engineered pig.
In 2009, a study was run on primates induced with diabetes to test the viability of hCD46 transgenic porcine islets, acquired from Revivicor. After a 3-month follow-up, four of five monkeys experienced graft survival and insulin‐independent normoglycemia. The fifth monkey, selected at random and studied for more than a year. … The study marked the first time a functional islet xenograft in a diabetic monkey survived over a year3. The pigs that produced the hCD46 transgenic porcine islets had CD46 added and the pig gene alpha-GAL deleted. CD46 is a protein produced by a human gene, that aids in suppressing an immune attack on the transplanted cells4. Alpha-GAL epitopes trigger an immune response that results in rejection of the transplanted organ or tissue into primates. By removing alpha-GAL, the transplant is less likely to be rejected as well as degrade5.
Revivicor was purchased for approximately $8 million in 2011 by United Therapeutics Inc., and now operates as a subsidiary under the company. United Therapeutics is a biotech company that focuses on aiding rare and life-threatening diseases. The company was founded by Martine Rothblatt, who strives to create an endless supply of transplantable organs6. In 2014, $50 million was invested in Synthetic Genomics by Rothblatt. The company designs and inserts genetic add-ons into pig cells, which Revivicor uses cloning to produce pigs from the cells 6.
The National Heart, Lung, and Blood Institute in Bethesda, Maryland implanted a pig kidney, genetically engineered by Revivicor, into a baboon.
Revivcor is still in business today but faces stiff competition: eGenesis, a company using CRISPR/Cas9 to genetically modify pigs for xenotransplantation. This technology allows eGenesis to more quickly and precisely edit the genes. The Cambridge, MA company is working on two different designs that they plan to combine into one pig cell, a pig with a humanized immune system and a pig wiped of viruses 7. The cell will then be cloned into a pig, the same process used by Revivicor.
The Food and Drug Administration (FDA) may cause some setbacks to Revivicor as well. At the moment, the FDA suggests that xenotransplantation only be available to individuals with life-threatening diseases. With a majority of serious epidemics initiating from animal pathogens that have jumped to humans, the FDA is concerned with the possibility of disease from PERVs in the transplanted animal organs and tissues. Aside from the concern for disease, another hurdle to face is the regulations on genetic engineering. For a pig organ or islet to be able to go to market, the process in which the animal was genetically engineered must be approved8.
Even with these roadblocks, the CEO of United Therapeutics is pushing Revivicor to engineer transplantable pig lungs and have plans in the pipeline to create xenotransplantable kidneys, hearts, and lungs by 2029.
1. Hansman H. The Future of Animal-to-Human Organ Transplants. 2015. https://www.smithsonianmag.com/innovation/future-animal-to-human-organ-transplants-180956402/. Accessed November 12, 2018.
2. Phelps CJ, Koike C, Vaught TD, et al. Production of alpha 1,3-galactosyltransferase-deficient pigs. Science (New York, NY). 2003;299(5605):411-414.
3. Van der Windt DJ, Bottino R, Casu A, et al. Long-term controlled normoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009;9(12):2716-2726.
4. Roth M. Can pig pancreas help cure diabetes? 2009. http://old.post-gazette.com/pg/09338/1018307-114.stm#ixzz0mOsOvbzG. Accessed November 11, 2018.
5. Park S, Kim W-H, Choi S-Y, Kim Y-J. Removal of alpha-Gal epitopes from porcine aortic valve and pericardium using recombinant human alpha galactosidase A. Journal of Korean medical science. 2009;24(6):1126-1131.
6. Regalado A. Surgeons Smash Records with Pig-to-Primate Organ Transplants. 2015. https://www.technologyreview.com/s/540076/surgeons-smash-records-with-pig-to-primate-organ-transplants/. Accessed November 7, 2018.
7. Weintraub K. CRISPR May Speed Pig-to-Human Transplants. 2017. https://www.technologyreview.com/s/603857/crispr-may-speed-pig-to-human-transplants/. Accessed November 13, 2018.
8. Reardon S. New life for pig-to-human transplants. Nature News. 2015;527(7577):152.