Mutation researchers affirm their science at inquiry

The Folbigg inquiry has again put the methods and opinions of scientists under the microscope on the fifth day of hearings in Sydney. 

Professor Carola Vinuesa, the immunologist who initiated research into an ultra-rare calmodulin variant possessed by Folbigg and her two daughters, backed her science against the suggestions by the inquiry that her public comments about Folbigg’s conviction affected her objectivity.

These are legitimate lines of questioning for the inquiry to take, as expert witnesses are barred from taking positions of advocacy.

The inquiry also quizzed Vinuesa and her former colleague Professor Matthew Cook about suggestions directed at them by other expert witnesses (who will appear and be questioned later) that their research was compromised by “circular reasoning”.

Both rejected those suggestions.

Wednesday was Vinuesa’s first opportunity to present her prepared evidence to the inquiry. In it, she emphasised her view that variation to CALM genes is “not benign”.

Kathleen Folbigg and her daughters possess a unique variant to the CALM2 gene dubbed G114R.

Video: What is calmodulin?

Cook and calmodulinopathy expert Professor Peter Schwartz backed those assertions, which were also expressed by Professor Mette Nyegaard on Monday.

Other scientists expressing expert opinions that disagree with that view will appear over coming days.

Vinuesa provided new detail about the glycine amino acid produced at position 114 on the CALM2 gene. She said that nature resists any genetic variation at this position. Only two mutations have been identified here. The other is in a variant known as G114W, which is considered disease-causing and was deemed the cause of death in a four-year-old American girl, and cardiac arrest in her brother aged five.

“G114 is not only conserved in all vertebrates, it’s conserved in all plants, it’s conserved in yeast, and as Professor Nyegaard pointed out, this points to it being a critical amino acid for the function [of calmodulin]. It cannot be substituted,” Vinuesa said.

In Kathleen Folbigg and her daughters, DNA at the 114 location mutated to produce arginine instead of glycine. This appears to result in a loss of the final protein’s function regulating a sodium ion channel in heart cells.

Because the three CALM genes are small, there are fewer opportunities for them to mutate compared to larger ones, which have hundreds of variations and, in some cases, tens of thousands of carriers.

Can the law keep up with science?

Vinuesa said the ultra-rare nature of calmodulin variations makes it difficult to ascertain how calmodulinopathy – the disease caused by these mutations – would appear.

“The clinical spectrum is expanding, but there are such small numbers – only 132 cases in the world – that we probably need hundreds, if not thousands of more cases to understand the full spectrum,” she said.

“G114R has not been found in another individual [outside of the Folbiggs]; it’s intolerant to substitution, and causes a unique alteration in function.”

Inquiry suggests tweets show advocacy

Counsel assisting the inquiry, Sophie Callan SC, continued several lines of questioning from Tuesday, particularly as to how Vinuesa researched information relating to Folbigg’s medical history, and to her willing participation in media commentary after the release of the report of the first inquiry.

“If I’m convinced of my science, then the logical thinking about this is that she shouldn’t be in prison.”

Carola Vinuesa

Callan presented several of Vinuesa’s tweets to the inquiry, and suggested these showed a form of public expression of advocacy for Folbigg, a line of questioning also pursued by Dean Jordan SC for the DPP.

Vinuesa agreed her public tweets showed she perceived Folbigg to be innocent of murder and manslaughter, but she said she formed that view because of her research.

“If I’m convinced of my science, then the logical thinking about this is that she shouldn’t be in prison. That’s what I can say,” Vinuesa said.

“Biology is complicated”

Professor Matthew Cook, who worked with Vinuesa at ANU but is now employed at an institution in the United Kingdom – was also grilled on his assessment of the G114R variant. In his evidence, he dismissed suggestions his team had only relied on the deaths of the Folbigg girls to determine the variant’s pathogenicity.

Callan raised a report submitted by Sydney-based experts Edwin Kirk and Michael Buckley, who argue the deaths cannot be considered evidence of a pathogenic gene in isolation. To do so, they argue, would be a “logical fallacy of circular reasoning”.

“Absence of a clear cause of death means the presence of this mutation is a very valid explanation.”

Peter Schwartz

In response, Cook cited the low number of benign calmodulin variants, knowledge of the rare G114R variant in the Folbigg girls, the existence of the similar pathogenetic G114W variant and “multiple lines of computational evidence” as evidence enough to consider the Folbigg mutation as pathogenic.

Professor Peter Schwartz, who’s considered the leading authority on calmodulin-related illnesses, expressed his view during his evening appearance via video link that while these illnesses are few in number, they are increasing.

In response to questions that the absence of a definitive reason for the girls’ deaths in forensic pathology reports was suggestive of a genetic cause, Schwartz replied: “Absence of a clear cause of death means the presence of this mutation is a very valid explanation.”

More on the Folbigg inquiries

• Scientists grilled on advocacy and accuracy
• Calmodulin variants “not benign” say Danish experts
• Can the law keep up with science?
• Video explainer: What is Calmodulin