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| The award of this year's chemistry Nobel prize to Robert Lefkowitz (left) and Brian Kobilka |
The first Nobel in chemistry for two MDs?
David Kroll, a blogger at Terra
Sigillata, believes this may be the first Nobel prize in chemistry
awarded to two medical doctors.
I asked David Phillips (see interview below) about the biological
emphasis of this year's Nobel prize in chemistry. Here's what he makes
of it:
The field of chemical biology is burgeoning because at its heart, at the heart of certainly cell biology, is an understanding at the molecular level of what's going on and that's chemistry essentially. So other sorts of chemistry are still going on and still very important, but this level of understanding which has been made possible by advances in techniques over the last 20 years or so is crucial to mankind. I'm not worried at all that many of my colleagues are working in what is essentially a biological field, because I think it's so crucial that we understand the molecular processes that are going on in cells in animal and human bodies.
In our eyes, nose and mouth, we have sensors for light,
odours and flavours. Within the body, cells have similar sensors for
hormones and signalling substances, such as adrenalin, serotonin,
histamine and dopamine.
As life evolved, cells have repeatedly used the
same basic mechanism for reading their environment:
G-protein–coupled
receptors. But they remained hidden from researchers for a long time.
In a human, tens of thousands of billions of cells
interact.
Most of them have developed distinct
roles. Some store fat; others register visual impressions, produce
hormones or build up muscle tissue.
In order for us
to function, it is crucial that our cells work in unison, that they can
sense their environment and know what is going on around them. For this,
they need sensors.
Sensors on the cell surface are
called receptors. Robert J. Lefkowitz and Brian K. Kobilka are awarded
the 2012 Nobel Prize in Chemistry for having mapped how a family of
receptors called G-protein–coupled receptors (GPCRs) work. In this
family, we find receptors for adrenalin (also known as epinephrine),
dopamine, serotonin, light, flavour and odour.
Most
physiological processes depend on GPCRs. Around half of all medications
act through these receptors, among them beta blockers, antihistamines
and various kinds of psychiatric medications.
Knowledge
about GPCRs is thus of the greatest benefit to mankind. However, these
receptors eluded scientists for a long time.
An elusive enigma
At the end of the 19th Century, scientists began
experimenting with adrenalin’s effects on the body. They soon realised
that it does not work via nerves in the body and they concluded that
cells must have some kind of receptor that enables them to sense
chemical substances — hormones, poisons and drugs — in their
environment.
But when researchers attempted to find
these receptors, they hit a wall. They wanted to understand what the
receptors look like and how they convey signals to the cell. The
adrenalin was administered to the outside of the cell, and this
led to changes in its metabolism that they could measure inside the
cell.
Each cell has a wall: a membrane of fat
molecules that separates it from its environment. How did the signal
get through the wall? How could the inside of the cell know what was
happening on the outside?
The receptors remained
unidentified for decades. Despite this, scientists managed to develop
drugs that specifically have their effect through one of these
receptors.
In the 1940s, the American scientist
Raymond Ahlquist examined how different organs react to various
adrenalin-like substances. His work led him to conclude that there must
be two different types of receptors for adrenalin. He called the
receptors alpha and beta.
Such drugs
undoubtedly produced effects in the cells, but how they did so remained a
mystery. We now know why the receptors were so difficult to find: they
are relatively few in number and they also are mostly encapsulated
within the wall of the cell.
It was only at the end
of the 1960s that Robert Lefkowitz enters the history of these
receptors.
Luring receptors
The young top
student has his mind set on becoming a cardiologist. However, he
graduates at the height of the Vietnam War, and he does his military
service in the US Public Health Service at a federal research
institution, the National Institutes of Health. There he is presented
with a grand challenge: finding the receptors.
Lefkowitz’s
supervisor already has a plan. He proposes attaching radioactive iodine
to a hormone. Then, as the hormone binds to the surface of a cell, the
radiation from the iodine should make it possible to track the receptor.
Lefkowitz would also have to show that the hormone’s coupling to the
cell’s outside actually triggers a process known to take place on the
inside of the cell.
Lefkowitz begins working with
adrenocorticotropic hormone, which stimulates the production of
adrenalin in the adrenal gland. As the project enters its second year,
Lefkowitz finally makes some progress. In 1970, he publishes articles in
two prestigious journals where he outlines the discovery of an active
receptor.
He is recruited to Duke University in
North Carolina where he begins working on adrenalin and noradrenalin,
so-called adrenergic receptors.
Using radioactively
tagged substances, including beta blockers, his research group examines
how these receptors work. And after fine-tuning their toolkits, they
manage with great skill to extract a series of receptors from biological
tissue.
Meanwhile, the knowledge about what happens
inside cells has been growing. Researchers have found what they call
G-proteins (Nobel Prize in Physiology or Medicine 1994) that are
activated by a signal from the receptor. The G-protein, in turn,
triggers a chain of reactions that alters the metabolism of the cell. By
the beginning of the 1980s, scientists are starting to gain an
understanding of the process by which signals are transmitted from the
outside of the cell to its inside.
New insights
In the 1980s, Lefkowitz decides that his research group
should try to find the gene that codes for the beta receptor.
This decision would prove to be crucial to this year’s
Nobel Prize. The idea was that if the research group could isolate the
gene and read the blueprint for the beta receptor, they could get clues
as to how the receptor works.
At about the same time,
Lefkowitz hires a young doctor, Brian Kobilka. Kobilka wanted to study
the power of epinephrine in its smallest molecular detail.
Kobilka engages in the hunt for the gene. However, during
the 1980s, trying to find a particular gene in the body’s enormous
genome is a bit like trying to find a needle in a haystack.
However, Kobilka has an ingenious idea that makes it
possible to isolate the gene. With great anticipation, the researchers
begin to analyze its code; it reveals that the receptor consists of
seven long and fatty (hydrophobic) spiral strings — so-called helices.
This tells the scientists that the receptor probably winds
its way back and forth through the cell wall seven times.
Seven times. This was the same number of strings and same
spiral shape as a different receptor that already had been found
elsewhere in the body: the light receptor rhodopsin in the retina of the
eye.
An idea is born: could these two receptors
be related, even though they have completely different functions?
Robert Lefkowitz later described this as a “real eureka
moment”. He knew that both adrenergic receptors and rhodopsin interact
with G-proteins on the inside of the cell. He also knew of about 30
other receptors that work via G-proteins.
The conclusion
The conclusion: there has to be a complete family of
receptors that look alike and function in the same manner!
Since this groundbreaking discovery, the puzzle has been
assembled bit by bit, and scientists now have detailed knowledge about
GPCRs — how they work and how they are regulated at the molecular level.
Lefkowitz and Kobilka have been at the forefront of
this entire scientific journey, and last year, in 2011, Kobilka and his
team of researchers reported a finding that put the crown atop their
work.
Adrenalin effects
After
successfully having isolated the gene, Brian Kobilka transferred to
Stanford University School of Medicine in California. There he set out
to create an image of the receptor — an unattainable goal in the opinion
of most of the scientific community — and for Kobilka, it would become a
long journey.
Imaging a protein is a process
involving many complicated steps.
Scientists use a
method called X-ray crystallography. The first image of a crystal
structure of a protein was produced in the 1950s. Since then, scientists
have X-rayed and imaged thousands of proteins.
However,
a majority of them have been water-soluble, which facilitates the
crystallization process.
Fewer researchers have
managed to image proteins located in the fatty membrane of the cell.
In water, such proteins dissolve just as poorly as oil,
and they are prone to form fatty lumps.
Furthermore,
GPCRs are by nature very mobile (they transmit signals by moving), but
inside a crystal they have to remain almost completely still. Getting
them to crystallize is therefore a considerable challenge.
It took Kobilka over two decades to find a solution to all
these problems. But thanks to determination, creativity and molecular
biology sleight of hand, Kobilka and his research group finally achieved
their ultimate goal in 2011: they got an image of the receptor at the
very moment when it transfers the signal from the hormone on the outside
of the cell to the G-protein on the inside of the cell.
Life needs flexibility
The
mapping of the over one hundred human receptors still presents
challenges to scientists, as their purposes have yet to be figured out.
Researchers have also found that they are multifunctional;
a single receptor can recognize several different hormones on the
outside of the cell. The receptors’ number and flexibility enable the
fine-tuned regulation of cells that life requires.
