Moving the Needle for Amyloidosis Patients
Deborah Dormady Letham, PhD

Moving the Needle for Amyloidosis Patients

From petunias to worms to people. How a genetic experiment’s surprising turn led to a breakthrough drug

Edelweiss is a rare flower and a great symbol for Rare Disease Day when we raise awareness and hope for over 300 million people affected by 6,000 plus rare illnesses, most of them (72%) caused by a genetic issue.

What is not rare is the hope in science and the drive to find cures and understanding, which is so essential to patients who are racing against time to survive.

My friend Cristina, whom I wrote about recently, has a very rare, debilitating disease called Amyloidosis. Her muscles are literally wasting away. She is hoping to slow the disease with the first-ever approved siRNA medication. A BBC podcast on amyloidosis and a novel medication infusion recently triggered another flower memory for me: white petunias.

In the 1990s, researchers at DNA Plant Technology in California attempted to genetically transform purple petunias into an even deeper shade of purple by overexpressing chalcone synthase genes. Instead, they turned the flowers white, and opened the door to a medical breakthrough that is helping my friend Cristina and others like her. The researchers stumbled upon a mechanism they called co-suppression—mechanisms and techniques now called siRNA (silencing RNAs) or RNAi (RNA interference) – where proteins are not made after both the inherent and transferred RNA molecules are both rendered inactive.

This white petunia story is embedded in my memory. While studying for my Plant Molecular Biology PhD at Cornell I was part of an early 1990’s journal club class. After seeing the “Cossack Dancer” and other images of white and variegated purple and white flowers, we listened to theories by the presenter and then debated them. This data was novel—this data was UNEXPECTED.  The overexpression of genetic materials to enhance purple color had actually shut down expression of similar native (homologous) genes, blocking anthocyanin production, resulting in white flowers, or splashes of purple and white combinations. Confirmation of the genetic cause of the phenomenon was verified by crossing these flower lines back to parental lines; the purple returned. Wouldn’t Gregor Mendel and his wrinkled pea experiments be so EXCITED!

That day in the journal club we could scoff at speculated rare reasons and we could debate mechanisms. As I recall, my thoughts were on the horticultural advantages of selling new flower patterns.

More than debates, these petunia results triggered revelations in the thoughts of many scientists - who are always building upon the past with new ideas. These researchers included Fire and Mello who won the 2006 Nobel Prize for Medicine for untangling the mechanism of RNA interference using C. elegans, a worm deeply studied for its genetic material. Fast forward 30 years and we have the first approved medication using a siRNA mechanism to treat none other than amyloidosis, which is diagnosed in 4,500 people a year.

Form petunias to worms to people. Amazing.

Debbie Dormady Letham, left, with Cristina and her daughter Sophia.

When the amyloidosis drug was approved, then FDA Commissioner Scott Gottlieb, M.D. noted that  “new technologies like RNA inhibitors, that alter the genetic drivers of a disease, have the potential to transform medicine, so we can better confront and even cure debilitating illnesses.” 

As for my friend Cristina, we had a moment to visit at a Girl Scout camping event recently. I was finishing up my chores and thinking (as a scientist and a mom) about the amazing thinking that leads scientists to discoveries, and about getting my dishes done so I could share some science experiments with the Girl Scout troop that has become a second family to me.

That is when the thought popped into my head to ask Cristina if she wanted to ride along to the campsite for dinner. This is the same crew of dedicated parents and girls who were instrumental in rallying around Cristina’s daughter Sophia two years when she underwent back-to-back liver transplants. Taking Cristina and one of her other daughters to camp made us all very happy.

Despite this rare disease, Cristina works really hard as a mom, while battling intense pain. Knowing how precious time is, she and her family strive to continue making memories together. She encourages us all to continue to spread awareness of amyloidosis and to keep hope alive for treatments for all those who battle a rare disease.