Paracelsus‘ homunculus, the result of complicated alchemic recipes, is an allegorical figure that fascinated the collective uncoscious for centuries. Its fortune soon surpassed the field of alchemy, and the homunculus was borrowed by literature (Goethe, to quote but one example), psychology (Jung wrote about it), cinema (take the wonderful, ironic Pretorius scene from The Bride of Frankenstein, 1935), and the world of illustration (I’m thinking in particular of Stefano Bessoni). Even today the homunculus hasn’t lost its appeal: the mysterious videos posted by a Russian youtuber, purportedly showing some strange creatures developed through unlikely procedures, scored tens of millions of views.

Yet I will not focus here on the classic, more or less metaphorical homunculus, but rather on the way the word is used in pathology.
Yes beacuse, unbeknownst to you, a rough human figure could be hiding inside your own body.
Welcome to a territory where the grotesque bursts into anatomy.

Let’s take a step back to how life starts.
In the beginning, the fertilized cell (zygote) is but one cell; it immediately starts dividing, generating new cells, which in turn proliferate, transform, migrate. After roughly two weeks, the different cellular populations organize into three main areas (germ layers), each one with its given purpose — every layer is in charge of the formation of a specific kind of structure. These three specialized layers gradually create the various anatomical shapes, building the skin, nerves, bones, organs, apparatuses, and so on. This metamorphosis, this progressive “surfacing” of order ends when the fetus is completely developed.

Sometimes it might happen that this very process, for some reason, gets activated again in adulthood.
It is as if some cells, falling for an unfathomable hallucination, believed they still are at an embryonic stage: therefore they begin weaving new structures, abnormal growths called teratomas, which closely resemble the outcome of the first germ differentiations.

These mad cells start producing hair, bones, teeth, nails, sometimes cerebral or tyroid matter, even whole eyes. Hystologically these tumors, benign in most cases, can appear solid, wrapped inside cystes, or both.

In very rare cases, a teratoma can be so highly differentiated as to take on an antropomorphic shape, albeit rudimentary. These are the so-called fetiform teratomas (homunculus).

Clinical reports of this anomaly really have an uncanny, David Cronenberg quality: one homunculus found in 2003 inside an ovarian teratoma in a 25-year-old virginal woman, showed the presence of brain, spinal chord, ears, teeth, tyroid gland, bone, intestines, trachea, phallic tissue and one eye in the middle of the forehead.
In 2005 another fetiform mass had hairs and arm buds, with fingers and nails. In 2006 a reported homunculus displayed one upper limb and two lower limbs complete with feet and toes. In 2010 another mass presented a foot with fused toes, hair, bones and marrow. In 2015 a 13-year-old patient was found to carry a fetiform teratoma exhibiting hair, vestigial limbs, a rudimentary digestive tube and a cranial formation containing meninxes and neural tissue.

What causes these cells to try and create a new, impossible life? And are we sure that the minuscule, incomplete fetus wasn’t really there from the beginning?
Among the many proposed hypothesis, in fact, there is also the idea that homunculi (difficult to study because of their scarcity in scientific literature) may not be actual tumors, but actually the remnants of a parasitic twin, incapsulated within his sibling’s body during the embryonic phase. If this was the case, they would not qualify as teratomas, falling into the fetus in fetu category.

But the two phenomenons are mainly regarded as separate.
To distinguish one from the other, pathologists rely on the existence of a spinal column (which is present in the fetus in fetu but not in teratomas), on their localization (teratomas are chiefly found near the reproductive area, the fetus in fetu within the retroperitoneal space) and on zygosity (teratomas are often differentiated from the surrounding tissues, as if they were “fraternal twins” in regard to their host, while the fetus in fetu is homozygote).

The study of these anomalous formations might provide valuable information for the understanding of human development and parthenogenesis (essential for the research on stem cells).
But the intriguing aspect is exactly their problematic nature. As I said, each time doctors encounter a homunculus, the issue is always how to categorize it: is it a teratoma or a parasitic twin? A structure that “emerged” later, or a shape which was there from the start?

It is interesting to note that this very uncertainty also has existed in regard to normal embryos for the over 23 centuries. The debate focused on a similar question: do fetuses arise from scratch, or are they preexistent?
This is the ancient dispute between the supporters of epigenesis and preformationism, between those who claimed that embryonic structures formed out of indistinct matter, and those who thought that they were already included in the egg.
Aristotle, while studying chicken embryos, had already speculated that the unborn child’s physical structures acquire solidity little by little, guided by the soul; in the XVIII Century this theory was disputed by preformationism. According to the enthusiasts of this hypothesis (endorsed by high-profile scholars such as Leibniz, Spallanzani and Diderot), the embryo was already perfectly formed inside the egg, ab ovo, only too small to be visible to the naked eye; during development, it would just have to grow in size, as a baby does after birth.
Where did this idea come from? An important part was surely played by a well-known etching by Nicolaas Hartsoeker, who was among the first scientists to observe seminal fluid under the microscope, as well as being a staunch supporter of the existence of minuscule, completely formed fetuses hiding inside the heads of sperm cells.
And Hartsoeker, in turn, had taken inspiration precisely from the famous alchemical depictions of the homunculus.

In a sense, the homunculus appearing in an ancient alchemist’s vial and the ones studied by pathologists nowadays are not that different. They can both be seen as symbols of the enigma of development, of the fundamental mystery surrounding birth and life. Miniature images of the ontological dilemma which has been forever puzzling humanity: do we appear from indistinct chaos, or did our heart and soul exist somewhere, somehow, before we were born?

Little addendum of anatomical pathology (and a bit of genetics)
by Claudia Manini, MD

Teratomas are germ cell tumors composed of an array of tissues derived from two or three embryonic layers (ectoderm, mesoderm, endoderm) in any combination.
The great majority of teratomas are benign cystic tumors mainly located in ovary, containing mature (adult-type) tissues; rarely they contains embryonal tissues (“immature teratomas”) and, if so, they have a higher malignant potential.
The origin of teratomas has been a matter of interest, speculation, and dispute for centuries because of their exotic composition.
The partenogenic theory, which suggests an origin from the primordial germ cell, is now the most widely accepted. The other two theories, one suggesting an origin from blastomeres segregated at an early stage of embryonic development and the second suggesting an origin from embryonal rests have few adherents currently. Support for the germ cell theory has come from anatomic distribution of the tumors, which occurs along the body midline of migration of the primordial germ cell, from the fact that the tumors occur most commonly during the reproductive age (epidemiologic-observational but also experimental data) and from cytogenetic analysis which has demonstrated genotypic differences between omozygous teratomatous tissue and heterozygous host tissue.
The primordial germ cells are the common origins of gametes (spermatozoa and oocyte, that are mature germ cells) which contain a single set of 23 chromosomas (haploid cells). During fertilization two gametes fuse together and originate a new cell which have a dyploid and heterozygous genetic pool (a double set of 23 chromosomas from two different organism).
On the other hand, the cells composing a teratoma show an identical genetic pool between the two sets of chromosomes.
Thus teratomas, even when they unexpectedly give rise to fetiform structures, are a different phenomenon from the fetus in fetu, and they fall within the scope of tumoral and not-malformative pathology.
All this does not lessen the impact of the observation, and a certain awe in considering the differentiation potential of one single germ cell.

References
Kurman JR et al., Blaustein’s pathology of the female genital tract, Springer 2011
Prat J., Pathology of the ovary, Saunders 2004