Imagine a house, but not just any house. It’s a house made entirely of Lego bricks: Everything from the walls, to the doors, your bed, kitchen, shower head, even the glass of the light bulbs.
This isn’t some extravagant creation, but rather a useful analogy to understand proteins and how they work to, well, keep you alive.
And, perhaps unsurprisingly, Danish protein chemist Malene Brohus turns to her nation’s most popular cultural export when explaining the role these crucial materials play in bringing the world to life.
Brohus has reached a degree of notability far from her homeland. A research paper on which she was the lead author triggered a second inquiry into the convictions of Kathleen Folbigg. The inquiry before former NSW Supreme Court Chief Justice Tom Bathurst KC began in Sydney this week and runs for three weeks.
The ‘Brohus article’ has been consistently referenced by expert witnesses during the inquiry. They include her Aalborg University colleagues Michael Toft Overgaard – the paper’s senior author – and Mette Nyegaard, who presented evidence of their functional protein tests and genetic analyses.
And while Brohus herself is not appearing, she followed the proceedings in November, and has again this week, at home in Denmark.
Her research – both contributing to the paper that led to the inquiry and day-to-day – looks at how genes code for “functional proteins”: molecules that perform specific roles in the body.
“Genes themselves do not perform a function, they are just a recipe for the proteins and the proteins are, as I like to explain, the workhorses of our cells,” Brohus tells Cosmos.
“The proteins are the molecules that have the functions that makes life and then constitute life. Without proteins, there would be no cell, and without a cell, there would be no human being, or no organism.”
Proteins matter because they are the building blocks of life
A long strand of human DNA contains around three billion base pairs – linkages of corresponding nucleotide molecules that contribute to tens of thousands of genes.
Grouped in threes, these nucleotide triplets (called codons) transcribe specialised instructions to produce any of 20 amino acids. A complete sequence of aminos, produced by a gene, fold together to form a unique protein.
You can think of these genetic instructions a bit like the booklet that comes in your new box of Danish building blocks.
Brohus imagines a full-sized house made of Lego.
Our amino acids – which come in all shapes and sizes – are the pieces you shake out of your Lego box to build parts of your house: your fridge, your shower, your bed, your desk: all objects that perform very specific roles.
And just as those objects make a house work and make it comfortable, proteins are what makes the human body tick along nicely.
But if your set has a piece missing, or the wrong piece, your final creation might not be quite what you imagined.
We’re not talking a piece that’s, say, the wrong colour. We’re talking about the wrong shape altogether. Brohus’s colleagues have argued in their evidence during the inquiry that this has resulted in a damaging loss of protein function.
The amino acid glycine is a tiny Lego piece…
“You can fit it anywhere in your big Lego house,” Brohus explains to Cosmos.
But if a genetic mutation changes that glycine to a larger amino you might have a problem, especially if it’s part of a protein performing a specific, essential function.
That’s the crux of what is being argued in the second inquiry into the convictions of Kathleen Folbigg.
Studying the way that amino substitutions in proteins like calmodulin change the body’s functioning have driven Brohus’s career for the last decade, but her contribution to what this inquiry has dubbed ‘the Brohus article’ was almost something that didn’t happen.
Cosmos explainer: What is calmodulin?
It was a chance encounter in Aalborg’s chemistry and biosciences department that led to her being placed first on the list of authors.
“I’ve been working with Michael, and on the calmodulin related project, for the past 10 years,” Brohus says.
“We identified the first ever mutation in calmodulin back in 2012.
“It was quite surprising when I casually met Michael in the hallway back in the summer of 2019 and he said he had this request from Carola Vinuesa [another senior author on the study], asking if we could contribute to producing some data for this specific case, an almost 20-year-old murder case from Australia.”
Working out how proteins work for people
Brohus spends her days investigating the way proteins work, and how gene changes impact function.
Right now, she’s examining the molecular processes by which brown bears hibernate for half a year without any ill effect: no loss of muscle mass, no change in bone density. A bed-ridden human would experience both phenomena, and worse. Her research identifies specialised proteins that are expressed during hibernation to the benefit of the sleeping bear.
“We hope to be able to figure out the molecular triggers that prevents the bear from developing these different kids of diseases,” Brohus says.
“The bigger picture is we wish to understand how the bear – or it could be another model organism – [has these] extraordinary resistance mechanisms to a lot of diseases. Our hope is that the knowledge we can gain … can be applied back to humans to help develop some therapeutics that can be used for obesity, for osteoporosis, atherosclerosis, muscle loss and diabetes.”
In the meantime, Brohus is closely following the Folbigg inquiry.
While questions about the research with her name on it have – and will – be raised by other experts during the inquiry, she is confident in her findings, while acknowledging that scientists often disagree on some of the details.
“We know how it looks, we know that these mutations in calmodulin encoding genes,” she says.
“So whenever we see them, our first expectation is they’re pathogenic, it’s not the other way around for us. Our assumption is they are pathogenic [so] let’s check whether they are or not.
“It’s so rare to have these mutations in calmodulin encoding genes.”
For some, the seemingly simple substitution of a glycine amino acid for arginine may not mean much. Some experts presenting in the inquiry are unconvinced that ensuing mutation significantly explains the deaths of the Folbigg daughters.
For Brohus, and the other authors of her article, it’s the equivalent of replacing a tiny Lego piece in the human gene box, with a much bigger, unwieldly and unsuitable brick.
Matt Agius has been reporting on the inquiry into Kathleen Folbigg and the deaths of her four children.