In my role as a PhD student in the OPIG group, I integrate and analyse data from various biological, chemical and data sources. As I am interested in the intersection between chemistry, biology and daily life, it seems suitable that my next BLOPIG posts will discuss and highlight how biological phenomena have either influenced law or history.

Connection between Law and Biology – The Curious Case Of A Human Chimera
Our scene opens in a dark lab, where a scientist injects himself with an unknown substance. The voice over notes that they created a monster named “Chimera” while searching for their hero “Bellerophon”.  This scene is the famous opening scene of the movie “Mission Impossible II” , where we are introduced to the dangerous bioweapon “Chimera”, a combination of multiple diseases. As “Chimera” is a mythological beast from Ancient Greek mythology, with a lion’s head, a goat’s body, and a serpent’s tail, the naming of this bioweapon seems appropriate.

What does this dangerous mixture of multiple diseases, an ancient mythological monster and the promised connection between law and biology have in common?

Apart from a really bad joke, the term “Chimera” is an actual term in biology to describe a biological entity of multiple diverse components, e.g. a human organism, whose cells are composed of distinct genotypes.
In case of tetragametic chimerism, human chimeras thus possess forty-six chromosome pairs instead of the “usual” set of twenty-six chromosome pairs, and as such, their organs and tissues are constructed according to the DNA outlined in the respective organ or tissue.
Tetragametic chimerism occurs by the fertilization of two ova by two spermatozoa, which develop into zygotes. These zygotes then subsequently fuse into one organism, which continues to develop into an organism with two sets of DNA.^1-2

But how did such a biological phenomenon like a chimera enter the court of law?

The Romans famously defined that the mother of a child is the one who gives birth to it (Mater sempre certa est, which can be translated as “The mother is always certain”).  I would like to point out that in the times of in-vitro fertilization, this principle is no longer viable, since a child can now have both a genetic mother and a birth mother.³
This Principle was disproved in 2002, when Lydia Fairchild applied to receive Welfare for her two children and her third, unborn child, from the US State. Paternity tests were conducted on all children to prove her ex-partner’s paternity. While the tests proved the paternity of the father without a doubt, Lydia was shown to be no genetic match to her children.

Accused of being a “wellfare fraud” or a surrogate, the judge ordered that Lydia Fairchild had to give birth to her third child in front of witnesses. Immediately blood samples were taken, which revealed that Lydia Fairchild also did not share DNA with this child, despite giving birth to it. Now accused of being a surrogate, Lydia’s case looked dire.
Fortunately, Lydia’s lawyer read a journal article about a similar case involving a woman named Kareen Keegan.^{2, 4-5} Karen, a 52-year old woman, had renal failure. As she needed a kidney replacement, Karen’s sons underwent the histocompability process to test for donation.Yet the genetic tests showed that only one of her three sons was related to her.¹ Material from her entire body was tested for genetic matches to her sons’ DNA, but only genetic material of her thyroid matched her sons.²
Ultimately, the researchers concluded that Karen was a tetragametic chimera, born of the fusion of her zygote and her twin sibling in her mother’s womb. As Dr. Lynne Uhl, a pathologist and doctor of transfusion medicine at Beth Israel Deaconess Medical Center in Boston, said:
“In her blood, she was one person, but in other tissues, she had evidence of being a fusion of two individuals.”⁶

Subsequently, scientists collected Lydia’s cell material from various body parts and tested for a genetic match with her children. The DNA from her cervical smear was found to be a match, while the DNA collected from her skin and hair was not. Additionally, DNA samples from Lydia’s mother matched her childrens’ DNA. ^4-5

Interestingly, while both Lydia and Karen were carrying two sets of DNA as a result of prenatal fusions with their twins, they didn’t show any phenotypic sign of being a chimera, e.g. different skin types or the so-called Blaschko lines.^7-8

1. https://www.scientificamerican.com/article/3-human-chimeras-that-already-exist/
2. To, E. & Report, C. LEADING TO IDENTIFICATION OF TETRAGAMETIC CHIMERISM. 346, (2002).
3. https://en.wikipedia.org/wiki/Mater_semper_certa_est
4. https://pictorial.jezebel.com/one-person-two-sets-of-dna-the-strange-case-of-the-hu-1689290862
5. https://web.archive.org/web/20140301211020/http://www.essentialbaby.com.au/life-style/nutrition-and-wellbeing/when-your-unborn-twin-is-your-childrens-mother-20140203-31woi.html
6. http://abcnews.go.com/Primetime/shes-twin/story?id=2315693
7. https://jamanetwork.com/journals/jamadermatology/fullarticle/419529
8. http://biologicalexceptions.blogspot.co.uk/2015/09/when-youre-not-just-yourself.html

All links were last viewed on the 24.04.2018.

My next blog post: Can a mismatch in maternal DNA threaten a government? How Biology can Influence History.

What is the “biological space” and why is this space so important for all researchers interested in developing novel drugs? In the following, I will first establish a definition of the biological space and then highlight its use in computationally developing novel drug compounds and as a starting point in the experimental exploration of biological systems.

While chemical space has been defined as the entirety of all possible chemical compounds which could ever exist, the definition of biological space is less clear. In the following, I define biological space as the area(s) of chemical space that possess biologically active (”bioactive”) compounds for a specific target or target class¹. As such, they can modulate a given biological system and subsequently influence disease development and progression. In literature, this space has also been called “biologically relevant chemical space”².

Only a small percentage of the vast chemical space has been estimated to be biologically active and is thus relevant for drug development, as randomly searching bioactive compounds in chemical space with no prior information resembles the search for “the needle in a haystack”. Hence, it should come as no surprise that bioactive molecules are often used as a starting point in in-silico explorations of biological space.
The plethora of in-silico methods for this task includes similarity and pharmacophore searching methods^3-6 for novel compounds, scaffold-hopping approaches to derive novel chemotypes^7-8 or the development of quantitative structure-activity relationships (QSAR)^9-10 to explore the interplay between the 3D chemical structure and its biological activity towards a specific target.

The biological space is comprised of small molecules which are active on specific targets. If researchers want to explore the role the role of targets in a given biological system experimentally, they can use small molecules which are potent and selective towards a specific target (thus confided to a particular area in chemical space)^11-12.
Due to their high selectivity ( f.e. a greater than 30-fold selectivity towards proteins of the same family¹²), these so-called “tool compounds” can help establish the biological tractability – the relationship between the target and a given phenotype – and its clinical tractability – the availability of biomarkers – of a target¹¹. They are thus highly complementary to methods such as RNAi, CRISPR¹² and knock-out animals¹¹. Consequently, tool compounds are used in drug target validation and the information they provide on the biological system can increase the probability of a successful drug ¹¹. Most importantly, tool compounds are particularly important to annotate targets in currently unexplored biological systems and thus important for novel drug development¹³.

1. Sophie Petit-Zeman, http://www.nature.com/horizon/chemicalspace/background/figs/explore_b1.html, accessed on 03.07.2016.
2. Koch, M. A. et al. Charting biologically relevant chemical space: a structural classification of natural products (SCONP). Proceedings of the National Academy of Sciences of the United States of America 102, 17272–17277 (2005).
3. Stumpfe, D. & Bajorath, J. Similarity searching. Wiley Interdisciplinary Reviews: Computational Molecular Science 1, 260–282 (2011).
4. Bender, A. et al. How Similar Are Similarity Searching Methods? A Principal Component Analysis of Molecular Descriptor Space. Journal of Chemical Information and Modeling 49, 108–119 (2009).
5. Ai, G. et al. A combination of 2D similarity search, pharmacophore, and molecular docking techniques for the identification of vascular endothelial growth factor receptor-2 inhibitors: Anti-Cancer Drugs 26, 399–409 (2015).
6. Willett, P., Barnard, J. M. & Downs, G. M. Chemical Similarity Searching. Journal of Chemical Information and Computer Sciences 38, 983–996 (1998)
7. Sun, H., Tawa, G. & Wallqvist, A. Classification of scaffold-hopping approaches. Drug Discovery Today 17, 310–324 (2012).
8. Hu, Y., Stumpfe, D. & Bajorath, J. Recent Advances in Scaffold Hopping: Miniperspective. Journal of Medicinal Chemistry 60, 1238–1246 (2017)
9. Cruz-Monteagudo, M. et al. Activity cliffs in drug discovery: Dr Jekyll or Mr Hyde? Drug Discovery Today 19, 1069–1080 (2014).
10. Bradley, A. R., Wall, I. D., Green, D. V. S., Deane, C. M. & Marsden, B. D. OOMMPPAA: A Tool To Aid Directed Synthesis by the Combined Analysis of Activity and Structural Data. Journal of Chemical Information and Modeling 54, 2636–2646 (2014).
11. Garbaccio, R. & Parmee, E. The Impact of Chemical Probes in Drug Discovery: A Pharmaceutical Industry Perspective. Cell Chemical Biology 23, 10–17 (2016).
12. Arrowsmith, C. H. et al. The promise and peril of chemical probes. Nature Chemical Biology 11, 536–541 (2015).
13. Fedorov, O., Müller, S. & Knapp, S. The (un) targeted cancer kinome. Nature chemical biology 6, 166–169 (2010).