My name is Wei Wang.
I am postdoc at the Stowers Institute for
Medical Research.
I work with Dr. Alejandro Sánchez Alvarado,
and I study tissue regeneration.
Regeneration is a long standing question in
biology.
It has attracted biomedical interest because
of the potential of replacing damaged organs
with new ones.
Currently, there are still a lot of fundamental
questions that have not been addressed
in the field of regeneration.
For example, why some animals such as fish
and salamanders regenerate extensively, while
others such as humans regenerate poorly is
not well understood.
The essential goal of my research is to understand
the genetic mechanisms underlying such broad
disparity of regenerative capacity in vertebrates.
Currently, the most popular regeneration model
with powerful genetic tools are zebrafish
and mouse, which diverged 450 million years
ago.
Because of the large phylogenetic distance
and differences in tissue composition, a direct
comparison between these two species is very
difficult.
Therefore, we took an alternative strategy
by introducing a more closely related species:
the African killifish Nothobranchius furzeri
that is capable of regeneration.
In this way, we can reduce the phylogenetic
distance from 450 million years to 230 million
years and compare regeneration in tissues
with similar composition.
The direct comparison between the African
killifish and zebrafish regeneration has allowed
us to identify both similarities and differences
in the genetic response to amputation.
Although both are bony fish, we were very
surprised that we observed twice more genes
activated in zebrafish regeneration compared
with African killifish regeneration.
And without such comparison, we would not
be able to discover such dramatic differences,
and we would not be able to discover or distinguish
the species-specific response and shared genetic
response between the two species.
So, our comparative studies have identified
conserved regeneration responsive genes and
regulatory DNA, and we also call this regulatory
DNA: enhancers.
And we found that these regeneration responsive
genes and regulatory DNA are also present
in the human genome.
And I cloned the human-derived regulatory
DNA and put it in African killifish genome,
and surprisingly, I found they are also able
to respond to amputation, but in a very different
way compared with the same African killifish
DNA.
The activation was delayed and was in the
wrong place, and because of such change, the
human-derived regulatory DNA cannot activate
regeneration in African killifish.
So, this result suggests that the human regulatory
DNA has repurposed its function during evolution,
and we call this “enhancer repurposing”.
And we think that such enhancer repurposing
could be an important mechanism underlying
the loss of regenerative capacity in mammals,
including humans.
Because of the presence of a large amount
of species-specific genetic response, my work
suggests that in the future, comparative studies
should be considered in regeneration studies
in order to identify and investigate conserved
mechanisms underlying regeneration.
Although currently we are still unable to
let humans regenerate, my work provides new
insights into why humans lost regenerative
capacity of many organs.
