CAMBRIDGE — 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.
اضافة اعلان
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 younger
brother, Shayan: What was this disease? And would they develop it the way their
father had?
As he grew up and watched his father gradually 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 United States, 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. Forty
percent of the body is made of muscle. 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, including brain cells, which are only beginning to be considered as
gene therapy targets.
And 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.”
Tabebordbar’s small office at the Broad Institute of MIT and
Harvard has a glass door that opens directly to his lab bench. It is not homey.
There are no photos, no books, no papers strewed about on the white counter
that serves as a desk. Even the whiteboard is clean. There, fueled by caffeine,
he works typically 14 hours a day, except on the days when he plays soccer with
a group at MIT.
“He is incredibly productive and incredibly effective,” said Amy
Wagers, who was Tabebordbar’s Ph.D. adviser and is a professor and co-chair of
the Department of Stem Cell and Regenerative Biology at Harvard. “He works all
the time and has this incredible passion and incredible dedication. And it’s
infectious. It spreads to everyone around him. That is a real skill — his
ability to take a bigger vision and communicate it.”
Tabebordbar and his wife live in Cambridge, Massachusetts. He
likes to cook Persian food and hosts a feast in his small apartment every
Thanksgiving for about a dozen friends. While he works at his lab bench he
listens to Persian music, podcasts or audiobooks. He loves biographies, and
made mention of a passage he found meaningful in an the autobiography of one of
his heroes, English soccer player Michael Owen.
Owen writes that when he learned he had been voted European
soccer player of the year in Europe, 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 1/2 years, he had a master’s degree but began applying to Ph.D. programs at
top international universities doing research on muscular dystrophies, hoping
that would lead to a discovery that could help his father. He ended up in
Wagers’ lab 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.
“How is that even possible?” Tabebordbar asked.
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 four
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.
“You are the luckiest guy among the unlucky,” he recalled his
friend saying.
In Wagers’ 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 — even different strains
of mice — can have different responses to the same gene therapy. And the AAV
doses were perilously high.
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 called everyone into a conference room to
tell them there was going to be a reorganization and the muscular dystrophy
program was being dropped. Tabebordbar knew he had to go somewhere else.
He 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’d 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.
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