‘A monumental example of translational science’

Paris, 1972: At a scientific conference, Dr. Bibudhendra (Amu) Sarkar strikes up a conversation with a paediatric neurologist from Australia, Dr. David Danks, who shares an unexpected story not about patients, but about livestock.  

Australia’s wool industry had been hit hard after large flocks of sheep produced fleece described as “kinky” that was not soft. The phenomenon reminded Danks of children born with Menkes disease, a genetic disorder causing severe neurological decline, which is marked by thin, kinky hair. At the time, no child with Menkes lived past the age of three.  

Sarkar hadn’t heard of that condition (discovered just 10 years earlier) and was instantly intrigued. The sheep had been grazing land with low levels of copper, and he was an emerging expert in copper deficiency. Danks was likewise intrigued and decided to study this possible link, publishing his findings later that year in The Lancet.  

“Copper deficiency has been demonstrated in seven babies with Menkes' kinky-hair syndrome,” begins the abstract. “Treatment of Menkes' syndrome may become possible as a result of these findings.” 

A historic copper discovery 

Eight years earlier, in 1964, Sarkar had joined SickKids as its first basic scientist. Focusing on translational research, he was fascinated by biophysics and inorganic biochemistry and especially drawn to how metals interacted in the human body.  

Copper, he knew, was essential to our health yet highly toxic in excess. Sarkar set out to understand its properties in detail, including how copper binds to proteins in the blood. It wasn’t long before he made a breakthrough. 

In 1965, Sarkar discovered that a trace amount of copper bound to an amino acid called histidine — results that formed the basis of his first publication, in Biochemistry of Copper, the next year.   

“This was quite unexpected, so I was very excited,” says Sarkar, now Senior Scientist Emeritus in Molecular Medicine. “As a chemist, I thought right away about the functional groups involved. Something important was happening here.” 

The finding sparked what quickly became a passion pr

oject for Sarkar, who believed the copper-histidine complex could have medical relevance. While it would take decades for him to decode exactly how copper bound to histidine, only a few years later the conversation in Paris would give his work new urgency.  

First patient with Menkes at SickKids 

In 1976, SickKids doctors diagnosed their first newborn with Menkes disease. The infant was premature and severely copper deficient. 

“Treatment with copper chloride didn’t work, so doctors approached me for ideas,” Sarkar recalls. “I proposed they administer copper-histidine.”   

With no alternatives available, the hospital’s ethics committee approved this experimental therapy. With the family’s consent, doctors administered the compound through a subcutaneous injection (under the skin), which succeeded in bringing the infant’s copper and ceruloplasmin (a copper-carrying protein) to regular levels.  

Soon after, a second newborn with Menkes was treated the same way, with similar success. 

Over the following years, seven more babies were diagnosed with Menkes at SickKids. Two received copper-histidine shortly after birth and went on to develop without intellectual challenges. Five were treated after two months of age, and experienced progressive neurologic deterioration. (Sarkar documented this in a 1993 Journal of Pediatrics article.)  

“Based on the science and on these clinical experiences, it was clear to me that copper-histidine must be given subcutaneously, rather than orally as Menkes patients do not absorb copper from the gut,” Sarkar says. “And it was critical that newborns receive it as soon as possible.” 

Decoding a protein puzzle  

In the 1990s, Sarkar finally crystallized the copper-histidine complex and solved the structure. It was a five-coordinate complex with a distorted square pyramidal shape that pinpointed where the metal and amino acid bound together.   

He had found that histidine boosted the uptake of copper in cells yet further research showed that albumin (the most abundant protein in our blood) stopped that uptake. From there, Sarkar looked more closely at the albumin, discovering it had a strong copper-binding site which he named the “ATCUN motif”.  

To decode this puzzle, Sarkar spent years studying this in depth using a wide variety of approaches, from molecular design to protein sequencing to electron spin resonance and X-ray crystallography. In doing so, he found that copper transfers from copper-histidine to albumin through a rapid reaction via the specific intermediary ternary complex albumin-copper-histidine.  

“It was clear that albumin acts as a buffer for copper,” he says. “All this information became very useful during the application of copper-histidine for the treatment of Menkes disease.” 

It also drew the world’s attention: a resulting study in Accounts of Chemical Research in 1997 became his lab’s most-cited paper.  

Sharing knowledge to help others 

Mostly due to administrative barriers, copper-histidine was never patented. But rather than restrict access, Sarkar made a deliberate choice to share his finding as widely as possible. He published a detailed protocol for preparing the injectable formulation, enabling others to reproduce it.  

Requests soon arrived from around the world. Working with SickKids Pharmacy, Sarkar ensured the full procedure was shared free of charge with physicians, hospitals and pharmacies around the world, a practice that continues today.  

“I couldn’t patent it, so I thought, why should I keep it to myself?” Sarkar says. “Just on compassionate grounds, I owed this to so many families.”  

Dr. Roman Melnyk, Program Head and Senior Scientist in Molecular Medicine, adds that the Canadian ecosystem for translating discoveries to patients at the time was poles apart from what it is now.  

“If this discovery were made today, it would likely follow a very different path to reach patients,” Melnyk says. “What’s remarkable is how quickly Dr. Sarkar’s discovery went from bench to bedside. For families, his hard work and generosity were invaluable. He didn’t stop at discovery but worked through the problem in order to translate it all the way to patients.” 

For pioneering this treatment, Sarkar was named to the Order of Canada in 2024. 

FDA approves treatment for Menkes disease 

In January 2026 — half a century after the first SickKids patient received copper-histidine — the U.S. Food and Drug Administration approved the first official treatment for Menkes disease. It is the very same copper-histidine formulation that Sarkar developed decades earlier. 

With the FDA approval, this story concludes as one of the earliest examples of bench-to-beside research at SickKids. 

“I’m happy SickKids will go down in history as the place where this copper-histidine therapy was discovered and developed to treat Menkes disease,” Sarkar says.

For Melnyk, the approval represents long-overdue validation. “It is a testament to the rock-solid biochemistry and beautiful work by Dr. Sarkar that made all this possible. He was there from the earliest discovery all the way through to the patient impact, which is incredibly rare. It is a monumental example of translational science.”  

‘I’ve done my job’ 

Over time, researchers have identified genes responsible for Menkes disease, enabling prenatal diagnosis of a condition that must be treated within weeks of birth. Copper-histidine has since been used worldwide, helping children live longer lives. 

Sarkar recalls giving a lecture in Tokyo in 1999 where he met two brothers who both had Menkes disease. One was about five years old and had to be carried by his parents; his younger brother — who was genetically screened and received copper-histidine treatment at birth — ran freely around the room. 

“It’s amazing to think I would ever see something like that in my lifetime,” he says. “I’ve been blessed by so many people in SickKids, worked with so many of my students and postdocs, supported by so many who were my close friends, my family. I’m very grateful.   

“I’ve done my job.”