鈥淭HE nucleus is where my passion is,鈥� says immunologist David Schatz of Yale
University. 鈥淚 love thinking about what happens in the nucleus and how those
chromosomes work.鈥� In particular, he would like to understand how the white
blood cells of the immune system rearrange the DNA in their chromosomes to meet
new infectious challenges. Schatz鈥檚 work has already revealed how two key
enzymes help to generate the diversity needed by our immune systems to combat
disease. His finding may also inspire researchers in the fight against cancers
of the immune system, called lymphomas.
Our immune system can recognise huge numbers of different invaders. Each of
the millions of white blood cells has its own unique protein receptor on its
surface. In B and T cells, the genes that code for receptor proteins are made
from many DNA fragments that lie along their respective chromosomes. During a
cell鈥檚 development, these fragments can be shuffled around and recombined in
endlessly different ways to yield a plethora of different receptor proteins.
With this enormous variety there will always be some cells that can recognise
any invader and trigger an immune reaction.
In 1989, Schatz and Marjorie Oettinger, working in the lab of Nobel laureate
David Baltimore, discovered the enzymes RAG1 and RAG2, which are responsible for
this immune cell recombination. The enzymes recognise where the target fragments
reside and cut the DNA on either side. Other enzymes then paste these fragments
together to produce a new line-up of gene fragments, ready to dictate the
manufacture of a new receptor protein.
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Schatz has since found that the RAG enzymes not only snip out the target DNA
fragments but also move them to new locations. They thus act like transposons,
the mobile 鈥渏umping genes鈥� often found in lower organisms. Schatz believes that
the infinite variety of our own immune system might owe its origins to an
invading transposon that inserted itself into the genome of a primitive
vertebrate (Nature, vol 394, p 744).
Schatz hopes to discover whether the cutting action of RAG1 and RAG2
contributes directly to lymphomas. In many of these tumours, chromosomes have
become attached to one another, possibly as the result of an abnormal attempt at
cutting and splicing receptor genes between two chromosomes. But whether or not
this is due to a malfunction in RAG1 and RAG2 or in some other proteins is not
clear. Schatz hopes that a better understanding of normal rearrangement, and how
it goes wrong in lymphomas, will help to identify which genes get switched on or
off abnormally. 鈥淲e鈥檒l figure out better what makes these tumour cells tick, and
then we鈥檒l get them,鈥� he predicts.
To achieve this goal, scientists will have to start looking directly at
chromosomes in action. One new technology, called spectral karyotyping, uses a
computerised tinting process to display each chromosome in the nucleus in a
different colour, making it easy to see its position. Although the technology is
still in its infancy, within the next few decades Schatz expects that complete
three-dimensional views of what鈥檚 going on in the nucleus will be routine.
鈥淭hen you鈥檒l say, `OK now, go cell, do your thing.鈥� And then you鈥檒l see the
proteins and chromosomes move around,鈥� he says. The only limitations Schatz sees
in achieving this dynamic vision are human. 鈥淚 have no doubt that computers will
be up to it. It鈥檚 just a question of whether biologists and engineers will
figure out ways of gathering that kind of information on that kind of
microscopic scale,鈥� he says. 鈥淚t鈥檚 a bright future, but challenging.鈥�
