50 shades of DNA: genetic engineering of the penis

Alexander Panchin, "Biomolecule" 

Have you ever wondered (and in general, were you aware?) why chicken–like birds have a small penis, and goose-like birds have a big one? Confess! No? But some scientists have thought and even found the answer to this question. 

And they also thought about much more pragmatic things: whether it is possible to improve the regeneration of the mammalian penis, slow down its aging and maintain an erection, or change the size with the help of DNA molecules and proteins encoded by them. Today we will talk about what modern molecular genetics can say about this.

In the film "Idiocracy", scientists, instead of trying to make a person smarter, directed their efforts to increase the volume of the female breast and the size of the male penis, as well as the development of means to restore the lost functions of this most important organ. Scientists can understand: there has always been and will be a commercial demand for such developments, but that is why they could not save humanity falling into the abyss of stupidity and ignorance, not thinking about anything but reproduction. Alas, judging by some real-world news, even director James Cameron can't stop our fall to the bottom. Therefore, as the saying goes: if you can't win, join us!

Let's start with a general question: is it possible to change the genetic material of an adult for any purpose? It will not work to change the DNA of each of his cells * (it was necessary to edit the DNA of the sperm, egg or embryo from which the person turned out), but this is not necessary. If someone suffers from hemophilia – a hereditary disease in which blood clots badly – you don't need to correct the DNA in the cells of their eyes, skin or nervous system. It is necessary to correct exclusively liver cells – that is where most of the blood clotting factors are produced, which means that the genes encoding them work there [1]. In the framework of modern gene therapy, we can send a neutralized virus carrying corrected or additional copies of a gene, specifically to liver cells or some other tissue. It remains only to figure out which gene and where to turn it on or off in order to rid a person of a particular disease, but if you return to the topic of the article – something to increase it.

The use of genetic engineering to change the genitals of animals has been going on for a dozen years. In 2004, an article was published in the American Journal of Pathology, the authors of which wanted only to increase the density of the hair of mice. They managed to do this by enhancing the activity of the gene regulating the work of BMP proteins - growth factors that play an important role in the formation of bones, cartilage and some other tissues [4].

The resulting genetically modified mice had many anomalies: a reduced eye slit, thickening of the skin, the transformation of sebaceous glands opening at the edges of the eyelids into hair follicles, and some limb changes. But one result was downright surprising: the mice increased the size of their genitals. Judging by the photos given in the article, the length of the penis of mutant mice (Fig. 1) has approximately doubled. It is worth noting that the mice were fertile!

Figure 1. Penis enlargement in transgenic mice. 

Figure b shows a genetically modified organ (GMO). Figure from [4].

I think that the majority of the male population of the planet is not yet ready to get covered with hair in unexpected places for the sake of a large penis size, but the value of this study is not in the discovery of a dubious method of increasing the size of the penis (especially since this method will not help adult men). This study is another brick of the "puzzle" that sheds light on the mechanisms of formation of tissues and organs, including the penis.

The authors suggest that this genetic modification could affect the concentration of one of the growth factors – BMP4, active at the tip of the growing penis. If this is the case, then by purposefully changing the work of the gene encoding this growth factor exclusively in the tissue we need, and not in the whole body, we will be able to "eat a cherry and not choke on a bone." That is, to avoid the mentioned side effects and get only the growth of the penis.

However, it is not yet known whether it will be possible to do this on adult organisms. So far, another growth factor has found effective use in rodents, which, as it turned out, improves the regeneration of the nerves of the penis when they are damaged [5]. Yes, it is precisely such medical technologies that condemn our civilization to the path of Idiocracy: you damaged your penis by accidentally putting it in a coffee grinder or blender, and they cured everything for you! You can continue to breed and educate idiots. (In fact, this is an important technology that can help people who have undergone surgery to remove part of the prostate, for example, in the case of cancer.)

As for the BMP4 gene, it turned out to be the answer to such a burning question about the significant differences between the sizes of penises in different groups of birds. In 2013, an article appeared in the journal Current Biology revealing this mystery of nature [6]. It turned out that the chicken has all the genes necessary for the development of a normal, full and long penis. They even have a fully developed rudiment of this organ, however, due to the excessive work of the BMP4 gene during development, the cells of this unprepared penis decide to commit suicide (this is called apoptosis), which leads to a decrease in the size of the organ. If you suppress the work of BMP4, you can protect the cells of the penis from such a sad fate and preserve its size. Similarly, in goose-like animals, it is possible to reduce the size of the penis by activating BMP4. The question remains unanswered as to whether cocks want their penises enlarged? Maybe they have completely different values?

Well, now we come to the most interesting. In 2015, Swiss scientists constructed and transferred into the erectile tissue of rats a gene encoding a protein whose activity depends on the level of illumination. Such rats get an erection if blue light is directed at their genitals [7]. Just imagine the potential of such an approach to the treatment of impotence!

Specially developed by Swiss scientists, a variant of the photosensitive protein called "erectile optogenetic stimulator", or EROS, triggered certain cascades of chemical transformations in the cells of the erectile tissue of rats, which eventually led to an erection. The beauty of the approach is that this technology can be transferred to adults in the future, if they are not afraid of such a kind of enlightened "Viagra". It is worth noting that unlike classical proteins used in optogenetics*, EROS is not a channel, but an enzyme found in bacteria. Its photosensitivity has been improved in the laboratory by mutagenesis.

Classical photosensitive channels were initially found in algae. In response to the ingress of light, the channels open, passing positively charged sodium ions into the cell. If you transfer the gene of such a channel into a nerve cell, then in response to light exposure it is activated, generating a nerve impulse. Such an optogenetic approach allowed the Japanese scientist Susume Tonegawa and his colleagues to edit the memory of rodents [11], instilling in them fear of a room in which nothing bad happened to them, but this is a separate story.

The disadvantage of the optogenetic approach when working with a large penis (and even a small human penis is larger than a rodent penis) is that it is difficult to enlighten it completely, through and through! Therefore, it is possible that EROS for humans will have to be refined by moving from optogenetics to thermogenetics [12]. Similarly to the existence of proteins activated by light, there are proteins that are activated when heated. If the genes of such proteins are embedded in the nerve cells of the body, then the nervous function can be controlled by changing the temperature. Thus, with the help of thermogenetics, it was possible to influence the behavior (including sexual) of fruit flies [13]. Theoretically, it is possible to set up thermogenetic control of erection. Taking a hot shower before sex is already a good idea, but it will be twice as useful this way!

By the way, there is another promising approach not to the treatment, but to the prevention of age-related erectile dysfunction, based on gene therapy. In some cases, this disease is associated with an increase in the amount of reactive oxygen species that damage cells and disrupt the functioning of blood vessels and smooth muscles in the erectile tissue of the penis. In 2003, scientists succeeded in slowing down the aging of the penis in rats, which were injected with a specially designed virus with the gene of an enzyme that neutralizes reactive oxygen species [14].

In the same year, it was possible to improve the erectile function of rats by activating the physiological mechanism through which the same "Viagra" works. Only this time with the help of gene therapy [15]. The gene transferred to the penis tissue encoded NO-synthase, an enzyme responsible for the production of nitric oxide. Nitric oxide activates the enzyme guanylate cyclase, which produces cyclic GMF. An increase in the concentration of cyclic GMF in smooth muscle cells leads to their relaxation, vasodilation, erection. There are several ways to increase the amount of cyclic GMF in cells. "Viagra" protects cyclic GMF from destruction, and NO-synthase increases the synthesis of GMF. NO-synthase already works in the tissues of a normal penis, but additional copies of the corresponding gene increase the concentration of the enzyme. The advantage of gene therapy over the drug is that the latter has a lot of side effects associated with its effect on other human tissues and organs. Gene therapy can act locally, exactly in the tissues where we injected. In addition, the therapeutic effect will be long-term.

The results of the first human trial of gene therapy for erectile dysfunction were published in 2006 [16]. By injection, patients were injected into the tissues of the cavernous body of the penis with a plasmid (a ring DNA molecule) carrying the potassium channel gene. Activation of such channels also promotes relaxation of smooth muscles, which increases blood flow to the penis, causing an erection. The study showed that no negative effects from such a gene modification of penis cells are observed, and the plasmid itself does not enter the seminal fluid, i.e. it is safe for offspring. Patients who received the highest dose of plasmid had an improvement in their condition, but it should be understood that these are, although encouraging, but preliminary results.

Of course, there are still a lot of unsolved mysteries of the penis device, but, as you can see, science does not stand still [17], responding to social requests, among other things. In the future, we will learn how to print genitals on biological 3D printers [18], create penises of the ideal size, shape and sensitivity. Maybe even double, for particularly spicy situations. I think this is another reason to support the development of genetic engineering for both men and women. No one, of course, recognizes this reason as important or relevant, but the statistics of Google queries speak for themselves (Fig. 2). You can't fool her!

Figure 2. Dynamics of the popularity of "penis enlargement" queries 

and "salary increase" according to Google Trends.

There is also a serious scientific approach to determining the optimal penis size. So, in 2015, an article was published in the journal PLoS ONE, the authors of which offered 75 women to choose between plastic phalluses of different sizes printed on a 3D printer. It turned out that women preferred phalluses with an average length of about 16 cm and a perimeter of about 12 cm [19]. In another study, it was shown that women who prefer larger penises are more likely to experience vaginal orgasm [20].

Well, for men who are dissatisfied with their size, scientists from South Park have proposed an alternative solution to the problem of small penises (Fig. 3).

Figure 3. The original solution to the problems of male aggression, 

proposed in one of the series of "South Park".

02.12.2015