A son’s quest
While he won’t be able to cure his dad, a scientist’s gene therapy research may help everyone else with muscle wasting diseases
When Sharif Tabebordbar was born in 1986, his father, Jafar, was 32 and already had symptoms of a muscle wasting disease. The mysterious illness would come to define Sharif ’s life.
Jafar Tabebordbar could walk when he was in his 30s but stumbled and often lost his balance. Then he lost his ability to drive. When he was 50, he could use his hands. Now he has to support one hand with another.
No one could answer the question plaguing Sharif and his brother, Shayan: What was this disease? And would they develop it the way their father had?
As he grew up and watched his father decline, Sharif vowed to solve the mystery and find a cure. His quest led him to a doctorate in developmental and regenerative biology, the most competitive ranks of academic medical research, and a discovery, published in September in the journal Cell, that could transform gene therapy — medicine that corrects genetic defects — for nearly all muscle wasting diseases. That includes muscular dystrophies that affect about 100,000 people in the U.S., according to the Muscular Dystrophy Association.
Scientists often use a disabled virus called an adeno-associated virus, or AAV, to deliver gene therapy to cells. But damaged muscle cells like the ones that afflict Sharif Tabebordbar’s father are difficult to treat. To get the virus to those muscle cells, researchers must deliver enormous doses of medication. Most of the viruses end up in the liver, damaging it and sometimes killing patients. Trials have been halted, researchers stymied.
Tabebordbar managed to develop viruses that go directly to muscles — very few end up in the liver. His discovery could allow treatment with a fraction of the dosage, and without the disabling side effects.
Dr. Jeffrey Chamberlain, who studies therapies for muscular diseases at the University of Washington and is not involved in Tabebordbar’s research, said the new method “could take it to the next level,” adding that the same method also could allow researchers to accurately target almost any tissue.
Dr. Francis Collins, the director of the National Institutes of Health, which helped fund the research, said in a blog post that it holds “potential for targeting other organs,” thereby “possibly providing treatment for a wide range of genetic conditions.”
At Tabebordbar’s office at the Broad Institute of MIT and Harvard, he works typically 14 hours a day, except on the days when he plays soccer with a group at MIT. While he works, he listens to Persian music, podcasts or audiobooks. He loves biographies, and made mention of a passage he found meaningful in an autobiography of English soccer player Michael Owen.
Owen writes that when he learned he had been voted European soccer player of the year, his reaction was muted. “All I wanted to do was score the next goal, the next hat-trick and lift the next trophy,” Owen wrote. “Looking back, I was relentless in that respect, and I’ve no doubt that that mindset was key to my success.”
“That is like me,” Tabebordbar said. “It is amazing that we achieved this but now” — he snaps his fingers — “we need to get to work. What’s next?”
At the University of Tehran, he majored in biotechnology. After 4 ½ years, he had a master’s degree but began applying to Ph.D. programs at universities doing research on muscular dystrophies, hoping that would lead to a discovery that could help his father. He ended up at Harvard.
All along the question hovered over him: What caused his father’s illness?
When his father came to Harvard to attend the 2016 graduation ceremony, Tabebordbar seized the moment to have Jafar’s genes sequenced and figure out the mystery. No mutations were found.
More detailed and sophisticated testing finally revealed the answer: His father has an extraordinarily rare genetic disorder, facioscapulohumeral muscular dystrophy or FSHD, that affects an estimated 4 to 10 out of every 100,000 people. It is not caused by a mutation in a gene. Instead, it is caused by a mutation in an area between genes, resulting in the excretion of a toxic chemical that kills muscle cells. To Tabebordbar’s horror, he learned that he had a 50-50 chance of inheriting the mutation from his father. If he had it, he would get the disease.
He was tested by a friend, who called him with the result. Tabebordbar had inherited the mutation but — amazingly — the mutated gene was missing the last piece of the toxic DNA, which prevented the condition from emerging.
In the Harvard lab, Tabebordbar worked on muscular dystrophy, using CRISPR, the gene editing technique. He attempted to use AAV to transport the CRISPR enzymes to muscle cells where it might correct the mutation. As others found before him, that was not so simple.
Tabebordbar’s project at Harvard suffered from the high dose problems, too. Although he managed to correct muscular dystrophy in mice — a feat reported at the same time by two other labs — that was no guarantee the gene therapy would work in humans. Different species can have different responses to the same gene therapy.
After he graduated from Harvard, Tabebordbar thought he had a chance to develop a gene therapy for muscular dystrophy at a biotech company. But after about a year, the company announced there was going to be a reorganization and the muscular dystrophy program was being dropped. Tabebordbar got a position in the lab of Pardis Sabeti at the Broad Institute and set to work. His plan was to mutate millions of viruses and isolate those that went almost exclusively to muscles.
The result was what he had hoped — viruses that homed in on muscle, in mice and also in monkeys, which makes it much more likely they will work in people.
As scientists know, most experiments fail before anything succeeds and this work has barely begun.
“I will do 100 experiments and 95 will not work,” Tabebordbar said.
But he said this is the personality that is required of a scientist. “The mindset I have is, ‘This is not going to work.’ It makes you very patient.”
He hopes his work will spare others from suffering. Yet his father’s fate hangs over him. Jafar Tabebordbar has missed the window when it might still be possible to help him.
“He was born too soon,” his son said.