“I CAN’T really understand a molecule until I look at it,” says Pamela
Bjorkman, an immunologist at Caltech in Pasadena, California. “After that I can
ask questions about how it might work.”
Bjorkman’s favourite molecules to gaze at are those that trigger immune
reactions against foreign organisms, called major histocompatibility complex
(MHC) molecules. These same molecules are also responsible for rejecting
transplanted organs and for the graft-versus-host disease that may result when
white cells are carried from the donor in a transplanted liver or bone marrow.
Bjorkman’s insights into the structure of MHC molecules, arrived at mostly by
X-ray crystallography, have revealed surprises about how they function, and
inspired new avenues of drug design.
MHC molecules dwell on the surface of nearly every cell in the body. They
pick up and display peptides— fragments of proteins—from viruses,
bacteria and parasites to passing T cells. These in turn trigger an immune
response against that particular organism. Based on the work of Bjorkman and
others, scientists are now designing vaccines they believe will bind to MHC
molecules and trigger stronger immune responses.
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But to really understand how immune responses are triggered will require new
techniques. X-ray crystallography works with pure substances or a mixture of
two, but with any more than three the combination becomes impossible to purify.
To see how MHC molecules combine with T-cell receptors and other proteins to
trigger an immune response, other techniques will need to be developed.
“One of the things I’m really excited about for the future is cryo-electron
microscopy,” Bjorkman says. This technique, which is still under development in
other laboratories, freezes cells at different time points and then uses
electron microscopy to produce a 3D image. Employing beams of electrons rather
than an ordinary light microscope gives a magnification of up to a million-fold,
rather than the few thousand achievable with a light microscope.
It may one day even be possible to see molecules interacting over
time—the biological equivalent of the movies. “The next step is going to
be snapshots of dynamic processes,” Bjorkman says. “The whole thing with
electron microscopy is that since you don’t need crystals you could take
snapshots as fast as you can freeze.” A sequence of still pictures taken
sufficiently close together could give a moving image of real-life events.
Bjorkman has also taken a close look at the so-called MHC-like molecules.
While these are closely related to regular MHCs, they have evolved for entirely
different purposes. For example, one MHC-like molecule transports antibodies
across the placenta from a mother to her baby during pregnancy. In adults this
molecule, known as FcRn, prolongs the lifetime of antibodies, leading to a more
robust immune system. Bjorkman’s crystal images of this molecule have suggested
ways to design drugs that persist for longer in the bloodstream.
“What fascinates me about this MHC family is the diversity of function that
it can take on,” Bjorkman says. “The question is, what was the primordial
function of these molecules?” She suspects it was something more basic to life,
such as fat or iron metabolism, and that the immune function arose much later.
If this can be worked out, she says, the evolutionary history of MHC proteins
should shed light on our distant past.
