60 Scientific American, April 2019CHRISTINA A. DYKEMAN AND YIN LABORATORYMDI Biological Laboratoryand there is probably an animal that can
readily regenerate it.
Even humans are not out of this regrow-
and-repair game completely. Our capability
appears more limited, but our skin, blood
and gut cells regenerate constantly. Muscle
can add new cells after some small injuries.
And like Prometheus of Greek legend per-
petually regenerating his liver, ours, too,
can regrow after limited injury. So our cells
have these abilities, but they get dialed
down and switched off, especially as we
grow older. Yet because they exist in the
first place, we thought it might be possible
to turn them back on with the proper
molecular signal. But of course, we first
had to find that signal. The fast-healing
animal world was the logical place to look.
Zasloff, in his prospecting for antibiot-
ics in animals, had come across a class of
molecules called aminosterols—MSI-1436
is one of them—that also had the poten-
tial to stimulate regeneration because
they could regulate cell activities such as
growth. We decided to test their capaci-
ties using zebra fish. As vertebrates, the
fish have many of the same major organs that people do, and
about 70 percent of their genes have human counterparts. They
are transparent as embryos, making it easy to study changes in
anatomy. We wanted to see if any of the aminosterols made the
fish’s ability to regrow tissue happen faster and better.
We started with a simple amputation test, cutting off part of
the tail and adding various aminosterols to the water in the fish
tanks. Nothing happened. That changed, however, when we got
some help from Helen Roberts, a recently graduated high school
senior working as an intern in Yin’s laboratory. Roberts developed
methods to inject substances directly into the zebra fish rather
than adding them to the water. When she did this with MSI-1436,
it stimulated the rate of tail fin regeneration by more than 300
percent. Instead of taking 10 to 12 days to regenerate, the fin took
only three to four days, and there were no signs of abnormal
growth. We had Roberts and a lab technician independently re -
peat the experiments, comparing different compounds, and made
sure they did not know which one they were injecting into the fish.
MSI-1436 worked in each situation; other compounds did not.
This was stunning and prompted some exclamations of ex -
citement in Strange’s office that are not appropriate to repeat here.
How did MSI-1436 stimulate regeneration in such a dramatic
fashion? Some scientists had studied its effects on cells, and after
we did more experiments, the answer seemed pretty clear: MSI-
1436 hobbled an enzyme named protein tyrosine phosphatase 1B
(PTP1B), which has several jobs in the body, one of which is to
regulate the growth of new cells. That is an important occupation
because widespread uncontrolled growth can make an organ
malfunction or become cancerous. PTP1B is essentially a brake
on cell regeneration. Our compound released that brake but only
at injury sites, in a very local, focused and controlled way.
When PTP1B brakes, it does so by interfering with a crucial
class of cell proteins called receptor tyrosine kinases, or RTKs.
RTKs are embedded in cell membranes and form parts of signal-
ing pathways that start outside the cell and lead inside; the sig-
nals the path carries tell a cell to grow and divide. To become
active and pass those signals along, RTKs need to be bound to
another type of molecule, called a phosphate group. PTP1B gets in
the way because it cuts phosphate groups away. No phosphate, no
RTK signaling and no cell regeneration. But our compound, MSI-
1436, disables PTP1B’s phosphate-cutting ability. And with these
brakes disabled, RTKs and cell regeneration run happily along.HEART DISEASE AND HEART ATTACKS
in addition to regrowth of the zebra fish tail fin, we found that
our PTP1B blocker stimulates regeneration of the zebra fish
heart. That is quite important because while humans may not
have a tail fin, we do have a heart, and it often needs help. Cardio-
vascular disease is the leading cause of death worldwide, killing
about 18 million people every year, and 85 percent of those
deaths are caused by heart attack and stroke. Heart muscle cells
that die in an attack do not regenerate but instead form a scar
that increases the chances of another attack. A 45-year search for
treatments, including stem cell transplants, to help the heart
repair itself has failed.
So when we saw that MSI-1436 helped fish, we moved on to
test it in mice, an animal model widely used in heart disease
research. We induced heart attacks in the rodents and then
injected them with MSI-1436 every three days over a span of four
weeks. The blood-pumping ability of the organ improved by
more than twofold, the amount of scar tissue was reduced by
50 percent, and heart muscle cells at the injury site proliferated
by nearly 600 percent. MSI-1436 is the only small molecule
known to have this effect.
Recently we began testing the compound in mice with a
completely different kind of disease: a rodent version of Du -ZEBRA FISH HEART, damaged and then dosed with the compound MSI-1436,
quickly regrew muscle and regained blood-pumping ability.