Checking Benedict’s Facts

In the “Acknowledgements” of Mendel’s Dwarf, Simon Mawer explicitly states that any molecular biology errors in the book are the fault of Benedict Lambert. So I have to wonder — just how accurate is Dr. Lambert? It would take weeks to fact-check every scientific reference made throughout the novel, so I decided to focus on the biology related to Achondroplasia.

Achondroplasia is a disorder of bone growth that derives from a complication in converting cartilage to bone. It affects roughly 1 in 20,000 babies and is the most common cause of dwarfism. The average adult male affected with the disorder grows to a height of four feet, four inches. Though the disorder can cause health problems such as difficulty breathing, obesity, and lower back pain, people with achondroplasia have normal intelligence.  The disorder is merely physical, not mental.

The disorder is caused by a mutation in the FGFR3 gene.  This gene provides the instructions to make the FGFR3 protein, which is fully referred to as the fibroblast growth factor receptor 3.  The FGFR3 protein is used during the development and maintenance of bone and brain tissue.

The protein limits formation of bone from cartilage, especially in long bones. (The process of converting cartilage to bone is called ossification.) In other words, it regulates growth to prevent uncontrolled bone formation.  The FGFR3 protein is positioned across the cell membrane, with one end on the inside of the cell, and one end on the outside of the cell. The end that is outside the cell is able to interact with growth factors, which give it signals to control growth.  When growth factors attach to the protein, the protein triggers chemical reactions inside the cell, which lead to certain changes.

The mutations that cause achondroplasia provoke the protein to be overly active. So the protein’s receptor will be overly active, receiving too many signals and therefore triggering chemical reactions too often. This will signal bone formation to be limited more than normal.

A DNA molecule is comprised of a sequence of amino acid bases that provide instructions to make proteins. A mutation in the DNA changes the instructions that are given to form proteins. So a different protein in formed. In the case of Achondroplasia, a protein is formed that is overly active. It receives too many signals to limit bone growth.

This mutation in the actual FGFR3 gene causes a change in the amino acid sequence of the protein. At position 380, the amino acid arginine (A) is inserted where a glycine (G) should be. The change in amino acids is responsible for the over-activity of the receptor, which leads to disturbances in bone growth. Two known mutations in the gene can lead to the same change in amino acid sequence. Therefore, two genetic mutations are known to cause achondroplasia, though they lead to the same mutation at the protein level.

The mutated gene is inherited in an autosomal dominant pattern, so one copy of the altered gene will cause the disorder.  Inheriting two of the gene (one from each parent) often leads to death during infancy. However, about 80% of people with the disorder have average-size parents.  These cases are the result of a new mutation that was not inherited, but rather happened at random during DNA formation.

This picture shows a simplified diagram of the chances Benedict and Jean's child would have had of being affected by anchondroplasia.

Lambert’s description of the gene and its mutation in the chapter “Nonsense” (pages 195 – 198 in my book), coincides very well with the scientific information. He says that 90% of cases are the result of sporadic or chance mutations, while the US Library of National Medicine said this is true for only 80% of cases, but that difference may be due to changes since the book was published in 1998.  Lambert explains that the mutation is in the gene that codes for fibroblast-growth-factor receptor 3, and the gene is expressed in cartilage-forming cells. (To be expressed means to be active, so the gene is active in cartilage formation.)  He also shows that the mutation results in an amino acid change from G to A.  All of his descriptions of the disorder that I can find agree with the information I found from researchers.

Therefore, the science behind the explanation of the achondroplasia gene in the novel is correct. I am by no means a genetic, or even biology, expert, but I have taken classes on the basics of DNA formation, transcription, and translation. As far as I can tell, Lambert got his facts right.

Mawer, on the other hand, indulged in some historical embellishments. The FGFR3 gene was not actually discovered by a dwarf.  Rather, it was discovered by John Wasmuth and his team in 1994. Wasmuth also discovered the gene that causes Huntington’s disease.

So while the science is real, the story of Mendel’s Dwarf is still a work of fiction.

-Laura Dolbow

~ by lauradolbow on April 8, 2010.

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