San Francisco Chronicle | By Erin
Allday
It began over a glass of good red wine. Paul Muchowski thought he'd found a molecular compound that could slow down
the damage done in the brains of people with neurodegenerative diseases. But he
didn't know how to get his hands on the compound, which was made by a major
pharmaceutical and wouldn't be loaned out without a lot of cost and hassle.
So one night, after a family dinner at his parents' home in Sunnyvale, he
asked his dad for help. "Paul says, 'Do you think you could make this compound?' And I said
any competent chemist could do it," said Joseph Muchowski, now 75, who had
decades of experience making drugs and is far beyond "competent" in
chemistry.
"I made him just under 50 grams in a week," Muchowski said,
"and that's how the relationship started."
The relationship is a rare one in science: a father and son, one a highly
credentialed chemist, the other an up-and-coming biologist, working together on
a new drug that, if it works, could be among the first to treat terrible brain
diseases such as Alzheimer's and Huntington's.
The pair are working at the Gladstone Institutes, an independent research
group affiliated with UCSF. Paul Muchowski, 40, is a full-time investigator at
Gladstone. His father, now retired from the Swiss drug maker Roche, splits his
time between a lab at Gladstone and his current home just east of Vancouver in
British Columbia.
Their compound - called JM6 because it came from page 6 of a journal in
which Joseph Muchowski kept his notes - inhibits an enzyme that when left
unchecked, allows a toxic chemical to build up in the brain.
In a mouse study, results of which were published in the journal Cell last
summer, the Muchowskis found that the compound prevented memory loss and
preserved synaptic connections between brain cells in mice afflicted with
Alzheimer's disease. The compound also protected synaptic connections in the
brains of mice with Huntington's disease, in addition to extending their life
by a few months.
Too early to tell
It's far too early to say whether the compound will be successful in
protecting human brains, say both of the Muchowskis and their third partner, a
researcher at the University of Maryland. The three men hope to start human clinical trials in two
years to make sure the drug is safe.
Both Alzheimer's and Huntington's disease are notorious not just for their
devastating effects on the brain, but for the lack of successful treatments for
those afflicted with them. Alzheimer's disease, which affects more than 5
million people in the United States, is the most common form of dementia in the
elderly. Huntington's disease is an inherited brain disorder that afflicts
30,000 people, damaging their ability to move and think.
"It's astounding, in this day and age, to not have any single drug
that slows down these brain diseases," Paul Muchowski said.
Compound discovered
As a professor at the University of Washington in the early 2000s, Paul
Muchowski was studying Huntington's disease when he stumbled across the early
version of the compound he would later develop with his father.
He was screening a wide variety of compounds already in existence to see if
any would have an affect on the enzyme, called KMO, that promotes toxic
buildups in the brain. He got one big hit: a compound from Roche, where his
father was working.
It turned out that the Muchowskis couldn't get the compound from Roche, but
that's where Joseph Muchowski stepped in. Later, when Paul Muchowski took his
job with Gladstone, he asked his dad to join him as a consultant.
In the world of developing new drugs for humans, having a chemist around is
critical, said Robert Schwarcz, a biochemist at the University of Maryland
School of Medicine, who discovered the KMO enzyme and works with both of the
Muchowskis.