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Mutations
and Revelations
It is not
uncommon for a protein to carry out the same biological
task in a fruit fly as in a fish as in a human. Evolution
really happened! Thank you, Charles Darwin.
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How
do we get our hands on these 2400 genes? We use a special
technique we devised here in my lab at MIT about two years
ago called insertional mutagenesis. The approach allows you
to do essentially just what I said- take away one gene at
a time and see what happens. We bombard the DNA of the cells
that will become the fish's future sperm or eggs with a substance
that causes mutations. In this way, we can damage the genes
one at a time and also mark the DNA with a tag at the site
where the mutation occurred. Each fish may carry only a single
mutated gene. So if by chance we damage any one of the 2400
genes that are essential for development to occur normally
then when we breed fish that carry these potential time bombs
their offspring inherit a developmental defect so that this
program goes noticeably wrong. Then we know we have removed
one of the genes we are after.
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A
normal fish (left) and a mutant (right). The mutant
lacks normal pigmentation and has smaller eyes.
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We
have also compared a number of fish genes to human genes.
Human and fish genes are 90% identical! See, I told you we
could study human genes by studying fish genes. Is it amazing
that these genes are so similar between fish and human? This
incredible conservation of genes is a surprising and profoundly
important finding of modern developmental biology. We know
for example that humans and chimpanzees share 99% of their
DNA. In fact we're having trouble figuring out what's different
between a human and a chimpanzee. Perhaps even more amazing,
we find that the proteins that are encoded by genes are incredibly
conserved not only in their structure but also in what they
do. It is not uncommon for a protein to carry out the same
biological task in a fruit fly as in a fish as in a human.
Evolution really happened! Thank you, Charles Darwin.
Only about 2400 genes are essential
to development. Take any one of those 2400 away and something
goes wrong.
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So,
we damage the genes one at a time and study the result. But
if there are 50,000 genes and we work on them one at a time,
doesn't that mean we have to work with an awful lot of fish?
The answer is yes. Over the next two years, we expect that
about 1 million fish will pass through our lab! Don't we need
a lot of fish tanks? The answer is yes. We have 4,592 of them.
Not only is this a big experiment, it was also a big risk.
We didn't even know for sure how well this experiment is going
to work. It took five years to develop the method, a year
to get ready to scale up to do it, and three years and ten
months to complete. What drives people to keep going even
in the face of possible failure?
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Not
all mutations are fatal. This mutant below grew to adulthood
with its extra long fins.
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There
are two reasons. One is practical; one is more mysterious.
First, people pay us to do this research because it can have
a significant impact in medicine and human health. We believe
that when we and others finish this huge project, we will
know which genes are required to make each organ in a vertebrate
animal. Up on the shelves of our lab will be bottles filled
with genes. Over here, the perhaps 187 needed to make an embryo's
brain, on this shelf, the 75 genes needed to make a heart
and so forth.
That
kind of information is potentially very useful. The most successful
biotech company in the US, a big supporter of our research
program, sells a protein that is the product of a single human
gene. When injected into humans, this protein causes a large
increase in the number of red blood cells in the body. People
undergoing treatment for cancer and other diseases often need
more red blood cells fast, and this is how they can get them.
But that's just one gene. 
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Photos: Hopkins' Lab, MIT
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