From Wnt7a to Human Wings
or
An Exploration of Embryonic Limb Development
Through a Lens of Mad Science
Another Almandsmith
Preamble:
Man has, in many ways, shapes, and means, always wanted to fly—from the myth of Daedalus and Icarus to the Wright brothers. A whole mythos exists dedicated to winged humans, especially those sprouting bird-like feathered wings from their backs as an extra limb set. While my initial intention was to explore the potential development of such wings on a human, I shifted the focus of the project from feathers to the sensible mammalian option of bat-like webbed wings.
In theory, the process of growing a pair of wings on a human embryo is fairly straightforward (discounting one or two minor complications). Because, essentially, the point is to grow a healthy limb set, little interference in the normal limb development process is needed other than the catalyst events: initiation of two extra limb buds, and signals that shape the new limbs into wings.
Before limb development can happen, though, the embryo has to exist. Embryos can be obtained the usual way, though they must pass through the preliminary stages of zygote and blastocyst first, otherwise known as the “lump of cells” stages. Once in the embryo stage, limbs begin to develop at around five or six weeks of pregnancy, counted from last menstruation, or after seven to eight weeks of gestation (Vorvick, and Storck).
Process:
Limb formation starts with the production of retinoic acid, which activates the morphogenesis-controlling homeobox (abbreviated to hox) genes that designate the placement of limb fields (Gilbert). At least, we’re reasonably sure that’s what’s happening, because blocking it prevents the limb bud from forming (Stratford et al. 1996). In addition, in an experiment where the stumps of tadpoles’ amputated tails were treated with retinoic acid, multiple legs sprouted from the stump, lending credence not only to the theory regarding retinoic acid and limb field designation, but also to the idea that limb fields are easily induced (Mohanty-Hejmadi et al. 1992). This is comforting, as normally vertebrates only develop four limb fields, positioned symmetrically in regards to the developing neural tube (Gilbert). With retinoic acid and extra hox genes, though, designating new limb fields around the future back/shoulder area should be possible.
The next step is for the designated limb fields to become limb buds. Not all of the area of cells that makes up a limb field becomes the limb bud, but if the central portion (the future limb bud) is removed, a limb will still grow from the surrounding limb field cells. Fibroblast growth factor 10 (Fgf10) secreted by the lateral plate mesoderm (a section of the middle germ tissue layer of the embryo) starts the limb bud process. Wnt proteins control Fgf10 concentrations and placement—Wnt2b and Wnt8c, specifically (in chicks, at least) (Gilbert).
Signaled by the Fgf10, mesenchyme tissue accumulates under the ectoderm (outermost germ layer), forming a protrusion: the limb bud. The mesenchyme from the limb field area of lateral plate mesoderm is the limb’s skeletal precursors, while mesenchyme from the somites flanking the length of the embryo’s neural tube is precursor to muscle (Gilbert).
Transcription factors specify (or at least are strongly involved in the specification of) whether the bud becomes a forelimb or hindlimb—Tbx4 (for T-box genes) and Tbx5 are present in the hind and forelimbs, respectively (Gilbert). Specifying the third limb set as wings, or a set of forelimbs from another species, is, perhaps, the most complicated part of the whole process. Because, again, vertebrates develop only two sets of limbs, there is no transcription factor to specify the extra limb buds as “third limb set”. Exposure to or production of Tbx 4 would produce legs, Tbx 5 would produce arms, but there’s no way to know what would induce the limb bud to develop into a third option—especially a third option not normal to humans. If, somehow, an extra set of hox genes resembling those controlling bat morphogenesis were present in the embryo and active in the third limb set, Tbx 5 might do the trick, producing bat forelimbs (wings) instead of human ones (arms).
Let us, then, for the sake of continuing, assume the trick with the bat hox genes worked. Our embryo has six limb buds, primed to develop into two legs, two arms, and two wings. The next stage is the formation of the apical ectodermal ridge (AER) and zone of polarizing activity (ZPA), which define the axes of the developing limb.
Mesenchyme cells in the limb bud and surrounding field secrete Fgf10, which instigates the formation of the AER, a ridge running the tip of the limb bud. The AER secretes Fgf8, which keeps the limb developing and produces a positive feedback loop of Fgf10 and Fgf8. The AER is essential for continued limb development, and controls much of the shaping of the limb (Gilbert). Experiments have shown that removing the AER (or, interestingly, replacing the underlying mesenchyme with non-limb mesenchyeme) halts limb growth, while adding an extra AER produces a split/duplicated limb (Wessells, 1977).
Meanwhile, the protein known as sonic hedgehog homolog, or shh, defines the zone of polarizing activity (ZPA) on the underside of the limb bud. The ZPA, along with the AER, controls the formation of axes in the limb, through positive loops of shh, Fgf’s, and the protein Wnt7a. The anterior/posterior axis (thumb-pinky) is defined by sonic hedgehog, the proximal/distal axis (shoulder-finger, hip-toe) is defined by the Fgf’s, and the dorsal/ventral axis (knuckle-palm) is defined by Wnt7a (Gilbert).
These axes are shaping the growing limb. Hox genes specify what parts of the limb become which limb sections: the stylopod develops first, then zeugopod, and autopod last. The autopod, zeugopod, and stylopod structures are analogous across vertebrates—in forelimbs, the stylopod develops into the upper limb (the humerus), the zeugopod into the lower limb (the radius and ulna), and the autopod into the appendage and digits (Gilbert). Bat wings are no exception to this generalization, and a look at the underlying skeletal structure reveals the similarities to a human arm, with webbing between the “fingers” forming the flight surface of the wing.
When the limb is more or less in a state of completion, BMP proteins shut down the AER’s production of Fgf’s and Wnt7a, signaling what started out as the ZPA to block the AER from cells producing the protein Gremlin, which usually protect it. The BMPs are regulated by the protein Noggin, which can, in excess, block them entirely. The BMPs then start the processes of interdigital apoptosis and necrotic sculpting, which shape the embryo’s now paddle-like appendages into articulated digits via programmed cell death, fragmenting the DNA. While this is a good thing for fingers and toes, we want to keep the webbing between the digits of our burgeoning wings. Fortunately, the process of interdigital apoptosis can be blocked by certain proteins and growth factors, preserving the tissue between digits. This can be seen in ducks’ feet, in which BMPs are completely blocked by the presence of Gremlin (Gilbert). Likewise in bat wings, the webbing is preserved, through a unique process. Unlike in ducks’ feet, where all BMP signaling is blocked, in bat wings the BMPs are still active and signaling, only partially blocked by Gremlin. However, they seem to be rendered ineffective by the expression of Fgf8 in the interdigital tissue (Weatherbee et al. 2006).
The other function of the BMP proteins is the formation of cartilage and joints. Apoptosis and necrotic sculpting happen when BMPs are exposed to Fgf’s from the AER, but when exposed to Wnt proteins, they induce the formation of cartilage, joints, and bone. Noggin, again, acts as a regulator for the BMPs—too much or too little will impair their function (Gilbert).
At this point, the limbs (including the wings) are essentially complete, though they will keep growing with the rest of the embryo, which is rapidly approaching fetus stage (Vorvick and Storck).
Closing Thoughts:
Unfortunately, this investigation did not explore human wings beyond limb development. However, lest all this start to seem plausible, I present a brief, speculative look at the other questions that would need to be considered for human wings to actually function.
First of all, the question of further gestation and birth. How would the wings fold up and fit inside the uterus as the fetus grew? And how in the world would birth work? The latter is simple enough with today’s medicine; a cesarean section would work well enough. As for the former, it’s not necessarily an impossible question, just one that needs considering, especially when taking into account what the wingspan would be.
To actually achieve flight, a fully-grown human, as is, would need a gigantic wingspan. There are calculations that would determine what that wingspan would be, but that doesn’t take into account the skeletal and musculature modifications that would be needed for those wings to function. How beefed up would a person’s upper body need to be to sustain flight? How would the joints work? Would humans need weight redistribution and/or hollow bones to actually achieve lift? And, of course, the center of balance would be thrown completely out of whack.
I could go on (societally, doors would probably need to be wider or taller, and clothes would have to be modified. Buildings would probably include takeoff/landing pads on the roof). The main question I have, though, (after the obvious one of “would it work?”) is this: after all these changes, would humans still be recognizably human?
Works Cited
Gilbert, Scott F. Developmental Biology. 6th e. Sunderland MA: Sinauer Associates, 2001. Print.
“3D Image: Pregnancy Week 5.” Parents Connect. Web. 23 Dec 2010. <http://3dpregnancy.parentsconnect.com/static/pregnancy-week-5.html>.
Vorvick, Linda J., and Susan Storck. “Fetal Development.” Medline Plus. A.D.A.M., 01 Nov 2009. Web. 23 Dec 2010. <http://www.nlm.nih.gov/medlineplus/ency/article/002398.htm>.
Wessells, N. K. 1977. Tissue Interaction and Development. Benjamin Cummings, Menlo Park, CA.
Stratford, T, Horton, C, & Maden, M. (1996). Retinoic acid is required for the initiation of outgrowth in the chick limb bud. Current Biology, 6(9), Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8805369
Mohanty-Hejmadi, P, Dutta, SK, & Mahapatra, P. (1992). Limbs generated at site of tail amputation in marbled balloon frog after vitamin a treatment. Nature, 355(6358), Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1731249
Weatherbee, SD, Behringer, RR, Rasweiler, JJ, & Niswander, LA. (2006). Interdigital webbing retention in bat wings illustrates genetic changes underlying amniote limb diversification. Proc Natl Acad Sci U S A, 103(41), Retrieved from http://www.ncbi.nlm.nih.gov/sites/ppmc/articles/PMC1622783/ doi: 10.1073/pnas.0604934103.
Image Credits
Opening Photo: http://jbwarehouse.blogspot.com/2008_05_01_archive.html
Fig. 1: http://www.ncbi.nlm.nih.gov/books/NBK10003/figure/A3933/?report=objectonly
Fig. 2: http://www.ncbi.nlm.nih.gov/books/NBK10003/figure/A3930/?report=objectonly
Fig. 3: http://reference.findtarget.com/search/Apical%20Ectodermal%20Ridge/
Fig. 4: http://en.wikipedia.org/wiki/File:Bat_mouse_forelimbs.png
Fig. 5: http://momscancer.blogspot.com/2007_07_01_archive.html
Fig. 6: http://www.ncbi.nlm.nih.gov/books/NBK26873/figure/A3246/?report=objectonly
Fig. 7: http://commons.wikimedia.org/wiki/File:Great-Moon-Hoax-1835-New-York-Sun-lithograph-298px.jpg
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