April 2019, ScientificAmerican.com 61chenne muscular dystrophy. This is a slow, degenerative muscle-
wasting ailment, quite distinct from the sudden damage of a
heart attack. Our preliminary data indicate that MSI-1436
prompts enough cell regeneration to keep skeletal and heart
muscles ahead of the wasting. It does not stop the disease, but it
may mitigate its effects.
ON FROM ANIMALS
what bodes well for humans is that the compound stimulates
tissue regeneration in both zebra fish and adult mice. These ani-
mal species are separated by approximately 450 million years ofevolution. Because MSI-1436 works on such distinct creatures,
the compound most likely targets cellular pathways that have
been strongly conserved, or reused, by evolution in organism
after organism. It increases the chances that such pathways
exist in people and can be manipulated in a like fashion.
Testing drug candidates in a diverse population of humans,
however, is very different from tightly controlled lab animal stud-
ies. The potential for failure in clinical trials is high. And although
there are good reasons to be optimistic about MSI-1436, the real-
ity is that we will not really know if it is effective in treating heart
attacks until we try it in human patients. As a first step in that
direction, we have begun National Institutes of Health–funded
tests of this drug candidate in a pig heart attack model. The pig
heart is remarkably similar to the human heart, and the size of
the animal allows us to mimic a human heart attack and its
early-stage treatment much better than we can in mice. If the pig
trial results are positive, we will be well positioned to seek per-
mission from the fda to conduct clinical trials.
In our studies, we are also going to be watching out for signs
of cancer. A concern in regenerative medicine is that treat-
ments to stimulate tissue growth and repair may trigger uncon-
trolled cell proliferation, which is the biological hallmark of a
cancerous cell. We believe that this concern is lower with MSI-- The extensive toxicity testing already done on the com-
pound during its earlier incarnation as a diabetes and obesity
drug was designed to identify problems such as cancer. None
were found, and the fda deemed MSI-1436 safe to use in studies
of human patients. Limiting the presence of PTP1B also seems
reasonably safe. The gene responsible for making it was first
knocked out in mice in 1999. These mice have been studied
extensively. They showed no signs of overt tumor growth, which
suggests that even long-term inhibition of PTP1B does not
cause cancer. Plus, treatment using MSI-1436 to stimulate tis-
sue regeneration would likely last only a few weeks or months.
Finally, our own experiments indicate that MSI-1436 acts only
at an injury site and does not send cells in normal tissue into a
kind of cancerous overdrive. In zebra fish and mice, we did not
observe tissue overgrowth or abnormalities in tissue and organ
shapes (a sign of growing malignancy) when injured animals
were treated with the compound. We tested this idea in one-cell
zebra fish embryos, a highly sensitive point in the development of
the fish. Embryos injected with the com-
pound for 14 straight days developed into
normal adult animals. Going from a single
cell to a full-blown animal is, obviously, a
complex process that requires tremen-
dous cell proliferation and differentiation.
Many drugs and environmental factors
easily send it wildly off-kilter when given
at such an early stage. It is reassuring that
MSI-1436 does not.THE NATURAL ADVANTAGE
perhaps animals respond well to the com-
pound because it evolved in animals in the
first place. It was not identified in a geneti-
cally engineered lab mouse or in cells
grown in a dish at a medical center or from
a screen of tens of thousands of synthetic
chemicals at a drug company. Our findings came out of lessons we
learned from dolphins, sharks and zebra fish. MDIBL, where we
took advantage of those lessons, was founded to do exactly that.
Our institution began as a marine re search station on the coast of
Maine in 1898, when biologists wanted an immediate connection
to the natural world they were trying to understand.
This link is, unfortunately, something that the larger biomed-
ical research enterprise, and the pharmaceutical industry in
particular, has drifted away from. There is an important role for
computer-de signed molecules, of course. But regenerative med-
icine biologist Alejandro Sánchez Alvarado of the Stowers Insti-
tute for Medical Research, who is not involved in our research,
has told us that MSI-1436 is “a great case study of what happens
when scientists choose to walk away from the familiar and
search nature for answers to vexing biomedical problems.”MORE TO EXPLORE
Observations on the Remarkable (and Mysterious) Wound-Healing Process of
the Bottlenose Dolphin. Michael Zasloff in Journal of Investigative Dermatology,
Vol. 131, No. 12, pages 2503–2505; December 2011.
Rethinking Differentiation: Stem Cells, Regeneration, and Plasticity. Alejandro
Sánchez Alvarado and Shinya Yamanaka in Cell, Vol. 157, No. 1, pages 110–119;
March 27, 2014.
The Protein Tyrosine Phosphatase 1B Inhibitor MSI-1436 Stimulates Regeneration
of Heart and Multiple Other Tissues. Ashley M. Smith et al. in npj Regenerative
Medicine, Vol. 2, Article No. 4; March 3, 2017.
FROM OUR ARCHIVES
A Change of Heart. Ferris Jabr; April 2013.
scientificamerican.com/magazine/saPerhaps animals respond well
to MSI-1436 because it evolved
in animals in the first place. It
was not identified in a genet ic ally
engineered lab mouse or from
tens of thousands of synthetic
chemicals at a drug company.