Â鶹´«Ã½

At conception the human body is merely an egg fused with a sperm. Yet
at maturity it contains hundreds of millions of cells. Understanding this
metamorphosis is one of the most challenging and exciting problems in experimental
biology. It is also one that biomedical researchers have grappled with for
decades. Today developmental biology is itself undergoing metamorphosis,
due largely to the impact of molecular genetics. This coming of age is being
celebrated in Cambridge by the opening of a new research centre devoted
to exploring the links between development and cancer.

The core objective of the institute is an ambitious one: unravelling
how an embryo uses its genetic information to turn itself into an adult
animal. Its researchers will be looking at how genes are controlled during
development and what goes wrong with their control in diseases such as cancer
and multiple sclerosis. Worthwhile activities, for sure, but what makes
the centre any different from other academic institutes?

In the first place, it was conceived and funded entirely by medical
research charities, the Wellcome Trust and the Cancer Research Campaign.
This may seem surprising given that the institute will concentrate on basic
science rather than medical research. But the patronage typifies a broad
trend: basic biological research in Britain, once supported almost entirely
by the government, is increasingly being funded by charities. Secondly,
the institute’s organisation comes from a special, almost Utopian, vision
of what a research institute should be. ‘Purpose built’ is a cliche often
applied to new laboratories, but the developers of the Wellcome/CRC Institute
have endeavoured to give the term some substance.

John Gurdon, the institute’s head and a pioneer of developmental biology,
has a clear picture of how good science is done. It is done not from the
top, he says, but in laboratories that are democratic in spirit. He believes
in forging research policy by argument rather than by decree. Accordingly,
he is known as ‘chairman’ not ‘director’ and presides over a governing body
formed of the heads of all the research groups.

Alongside ‘democracy’ the institute’s guiding principle is communication.
For many years developmental biology has been not one but a collection of
subjects, each with its own distinctive methods and theoretical slant. Because
of recent advances in molecular genetics, the subjects are beginning to
converge and borrow each other’s ideas and techniques. At the Wellcome/CRC
Institute the idea is to make that borrowing as easy as possible. For example,
to encourage scientists to walk through each other’s laboratories, the building
was deliberately designed with few corridors. And there are no scientists
there, however good, who are not keen collaborators.

Then there is the question of size. The centre had to be large enough
to provide enough variety of expertise, but small enough to allow research
groups to communicate effectively. The planners finally decided that 100
was the right number, of whom two-thirds are scientists and the rest are
support staff divided among the 16 or so research groups. For Gurdon this
is enough: ‘It is very tempting once you’ve got some good science going
to keep adding other research groups and laboratories in the belief that
they will be able to share in the success. But once it is so big that the
groups are not all talking to each other, there is no real point in having
them under the same roof.’

So much for the organisation, what of the science? Researchers at the
institute will be looking at the three key properties of cells that underpin
development: their ability to proliferate, to differentiate (specialise)
and to move from one part of an embryo to another. All three are controlled
through different sets of genes. But whatever their role, most genes remain
dormant until switched on by a regulatory protein. The timing and spatial
control of such genetic events are crucial to the embryo’s development.

One of the researchers more than any other epitomises the institute’s
aim to bridge subjects. Ron Laskey is a respected biologist who is hard
to pigeon-hole. Of all the scientists who are working at the centre, he
is the furthest from being a developmental biologist. His twin motivations
are a fascination with how single cells work and how cancer can be understood
in cellular terms. The link with developmental biology comes from the cells
he has chosen to work on: frogs’ eggs.

Laskey explains that frog eggs are popular with biologists because they
develop rapidly. Each egg has a large stockpile of material for rapid cell
division. So effective is this stockpiling that in the time a typical mammalian
egg has divided to form two cells, a frog’s egg has already developed into
an embryo of about 20 000 cells – the product of about 16 cellular divisions.
‘It is this exaggerated behaviour of frogs’ eggs that makes them so useful,’
says Laskey.

Laskey and his team hope that frogs’ eggs will lead them to uncover
some of the biological rules governing cell division. One such rule concerns
DNA replication. Before it can divide, a cell must replicate its DNA. But
during each round of cell division, there must be only one replication,
otherwise each daughter cell ends up with multiple copies of genes. The
researchers want to know more about the biochemical machinery, principally
the proteins, that cells use to regulate DNA replication. What happens,
for example, when genetic mutations render these proteins defective?

Questions of this sort are not just academic as unrestrained cell growth
is the hallmark of cancer. Cancer cells multiply in a ‘selfish’ manner,
breaking the rules of cell division.

This delinquency invariably lies in an accumulation of genetic defects.
As cells divide, they accumulate mutations in their genes. This can happen
either spontaneously or in response to such things as radiation or chemical
carcinogens. Usually the mutations are remedied before they can do any harm.
But when the repair mechanism fails, the mutations become ingrained. If
the genes ‘hit’ by such mutations encode proteins that regulate cell division,
the result can be uncontrolled cell growth – and ultimately a tumour. Many
such genes encode proteins that play a part in what are called ‘signal transduction
pathways’, biochemical chains which relay signals from cell membranes to
cell nuclei. The signals are delivered to cells by molecules such as growth
factors, which bind to receptors on cell surfaces. In the last step, proteins
infiltrate the nucleus to regulate genes. It is this step that interests
Laskey.

Laskey’s team is looking at what happens to the structure of the cell
nucleus just before DNA replication begins. By studying a biochemical model
for the cell nucleus, made up of DNA from frogs’ eggs coiled up with proteins
extracted from frogs’ sperm, the researchers are trying to work out which
protein gives the replication signal. The model nucleus has the twin advantages
of obeying the rules of cell division and being easy to study. The researchers
use monoclonal antibodies to trace individual types of protein as they move
in and out of the nucleus.

Tony Kouzarides runs a team researching oncogenes at the institute.
Oncogenes are mutant versions of genes which can promote uncontrolled cell
growth, often by corrupting signal transduction. Some are part of the genetic
weaponry carried by tumour viruses. Kouzarides is particularly interested
in two viral oncogenes, Fos and Jun, which encode members of a class of
proteins known as transcription factors – the molecular keys that unlock
genetic information. Most work by slotting into the grooves of a particular
stretch of DNA and turning on a nearby gene. Researchers are intrigued by
Fos and Jun because they work in concert, interlocking by means of a special
‘zipper’ structure in which amino acids act as teeth. The interlocking seems
to help the proteins to bind to DNA – Kouzarides and his team are trying
to find out how.

Kouzarides is one of the young scientists the institute has attracted
back to Britain from the US. He came back because his new job has two important
ingredients, research money and research freedom. ‘Britain does not have
many attractive jobs to come back to, but the institute matches anything
in the US.’ What does he offer the institute in return? ‘Mainly a different
attitude. Scientists in the US usually show a much greater enthusiasm and
drive than in Britain, and it rubs off.’

Gurdon’s philosophy is that development is as much about cellular specialisation
as proliferation. He views cancer as a tug of war between the two. When
cells differentiate, they stop proliferating so that they can perform a
useful role. Often the most malignant cancers are the ones where the cells
are the least specialised. Hepatomas, cancers involving liver cells, are
a good example. Researchers have tended to look for clues to cancer in the
way cells proliferate, but the molecular steps involved in differentiation
may be equally important.

Gurdon’s main interest is in how cells embark on a particular pathway
of specialisation. In mammals the early embryo is just a ball of undifferentiated
cells. If the cells are all identical how can they influence each other
to become different? The answer seems to lie in how the cells are arranged
spatially. As the embryo forms, two different types of cell emerge: those
on the inside of the growing ball and those on the outside. Researchers
believe that this spatial differentiation is enough to trigger some kind
of chemical signalling between the two cell types. This signalling in turn
triggers the production of a third type of cell.

In frogs development follows a completely different course. The original
egg produces two different cells from its two ends. These cells then signal
each other to produce yet another cell type, and so on. In isolation, one
of the original two cells produces skin, the other gut. The third type of
cell goes on to produce muscle, backbone and internal organs. Gurdon wants
to know how a frog cell can jump from a developmental pathway leading to
skin to a pathway leading to muscle.

All organisms are composed of cells with identical genomes, so specialisation
arises from certain sets of genes being switched on in preference to others.
Gurdon has been trying to find out which of the genes that produce muscle
cells are switched on first. Why? Developmental biologists like to view
cellular specialisation as the outcome of a cascade of genetic events in
which the activation of one gene leads to the activation of another, and
so on. The first gene acts as a switch for the whole cascade. Gurdon’s research
on frog cells shows that the genetic switch in the muscle cascade is turned
on as early as 10 hours after fertilisation, by a protein locking on to
a piece of the gene called the myogenic promoter. Gurdon and other researchers
hope the myogenic promoter will lead them to general rules governing the
workings of gene pathways in development. Yet key questions remain. For
example, how does the promoter work and what is the identity of the protein
that turns it on?

Steve Jackson is also interested in gene regulation. He has just arrived
from the University of California in Berkely, another scientist the institute
has attracted back to Britain. Like many other researchers, he believes
that the most important event in gene regulation is transcription, the copying
of a gene into RNA that is the first step in protein synthesis. Transcription
factors play a key part in controlling the process. Jackson is investigating
the properties of a transcription factor known simply as Sp1. The Sp1 protein
is promiscuous: it binds to many different genes. But gene regulation is
not just about the binding of transcription factors. It also depends on
their potency once they have locked on to their target genes. Jackson’s
main interest is how cells regulate the potency of transcription factors
such as Sp1. Chemical modification, particularly the attachment and detachment
of phosphate groups, seems to be the main way.

Three groups are working on flies and other insects at the centre. On
the face of it this seems surprising. How much can a fruit fly tell you
about the development of mammals? Michael Akam, who runs one of the groups,
explains that the molecular ‘nuts and bolts’ of development are similar
in all organisms. Yet four or five years ago the received wisdom was that
the fruit fly held few clues to the development of vertebrates. The turning
point came in 1989 when Akam made a daring connection between a set of insect
genes known as homeotic genes and genes in vertebrates. Akam argued that
the two sets of genes had parallel roles in development and had evolved
from a group of common ancestral genes.

In the early 1980s, biologists had discovered that homeotic genes have
a profound influence on insect development. The genes, which are clustered
in one part of the chromosome, control the relative positions of the body
segments of the growing insect. Intriguingly, the position of each gene
in the cluster determines where it is active, or ‘expressed’, in the segmented
body: by switching genes on the chromosome, researchers found they could
switch body segments. One celebrated result was a fly with a leg in place
of an antenna.

How do homeotic genes function? What the genes share is a distinctive
stretch of DNA – the ‘homeobox’ – that encodes a transcription factor. The
assumption is that the genes control development by regulating the transcription
of other genes. Akam’s theory is that a cluster of homeobox genes similar
to homeotic genes controls the segmentation that occurs in vertebrates during
development, in the spinal cord and brain, for example. As with homeotic
genes, the position of each vertebrate gene in the cluster determines where
the gene is expressed in the embryo.

Martin Evans, another researcher at the institute, also points out how
closely together genetics and embryology are moving. Biologists can now
design experiments to discover how the developing embryo uses its genetic
information. In the past this was more about luck than design – finding
animals with inherited deformities, maintaining a stock of the animals and
doing experiments to pinpoint the genes responsible. The trouble with this
is that the most important developmental genes evade detection, for any
mutations in these will kill the animal before it is born. Another problem
is that the animal’s appearance might tell you what a particular gene does
when defective, but it says nothing about the function of the same gene
in its undamaged state – a drawback that confounds all studies of natural
genetic defects. One answer is to eliminate the effect of the gene on the
cell altogether. A few years ago this would have been impossible, but recently
molecular biologists have come up with some promising methods.

One of these methods is to target a chromosomal gene with a disabled
version of itself. In some cells the disabled gene will combine with the
functioning gene, rendering it impotent. Evans is using this ‘gene knockout’
approach to establish links between particular genes and animal development.
The institute is also using the technique to develop animal models of human
diseases where the cause is a single defective gene, such as adenine deaminase
deficiency.

Evans’s methods are proving useful to Chris Wylie and Janet Heasman,
who are looking at molecules found on the surfaces of cells from very young
frog embryos. The objective is to work out how the molecules help the cells
to move to the correct place in the embryo. Germ cells, for instance, do
not start out in what develops into the animal’s sex organs. They migrate
there from other parts of the body. The cells appear to ‘know’ where they
are. Indeed if cells from different parts of a frog embryo are mixed, they
are able to sort themselves out. Their ability to do this seems to depend
on proteins called integrins, ‘sticky’ molecules which enable cells to interact
in a specific manner. To find out which integrins are important in development,
Heasman fertilises frog eggs and then blocks particular integrin genes to
see which ones influence the movement of cells in the embryo. The ability
of cells to move in a controlled manner also underlies the development of
the nervous system, and its capacity to repair itself after damage. Multiple
sclerosis is caused by the deterioration of myelin, the sheaths of cells
that insulate nerve fibres. Charles ffrench-Constant, who returned from
the US to join the institute, is trying to work out how the cells that produce
myelin, oligodendrocytes, ‘know’ what direction to grow in. By finding molecular
markers linked to oligodendrocyte growth, he hopes to discover why the cells
fail to regenerate around nerves in people with multiple sclerosis.

Wylie confirms the importance of the closeness of groups with other
expertise: ‘Developmental biology has to be understood and investigated
at many levels from transcription factors through to my own interest, cell
migration.’ This is echoed by Ron Laskey: ‘The field is advancing too fast
for small groups to keep up in isolation. They haven’t the eyes and ears
to keep up with enough other laboratories.’ Laskey is convinced about the
need for research centres like the institute. ‘We have to keep good British
scientists and attract back scientists from abroad.’

Institutes are not, of course, always regarded as an unmixed blessing.
The trouble started with that, possibly apocryphal, crack about the Pasteur
Institute – ‘Pasteur’s enemies clubbed together to buy him an institute’.
The point was presumably that he then spent his time not doing good science
but acting as a tycoon administering a vast and sprawling research empire
with neither the time to be creative himself nor to foster creativity in
the other scientists. Science is often told to be more business-like. But
in today’s science-led economies, it would be nice to think that the Wellcome/CRC
Institute could turn this on its head and say to business, ‘be science-like,
be like us’.

John Galloway works for the Cancer Research Campaign.