Hawkins and Clare Robertson have been studying the prospects of children
who survive cancer. They found that children diagnosed with cancer after
1971 who survived the first five years, had a 92 per cent chance of surviving
the following ten years without the disease returning – which is effectively
a cure. After ten years the chance of the cancer recurring is ‘vanishingly
small’, says Hawkins.

However, they also found a small but significant number of deaths that
appeared to be associated with the treatment the children had received.
For example, some children treated with powerful chemotherapy developed
heart disease and died before they reached thirty.

The researchers want detailed records of chemotherapy and radiotherapy
kept for the patient’s lifetime. ‘We will only see the full effects of treatment
when we have a much longer follow-up,’ says Robertson.

But the Department of Health guidelines say that once child cancer patients
reach the age of 25 the records of their treatment can be discarded. This
makes any long-term study of survivors virtually impossible. ‘We cannot
say that after 20 years there will be no problem because we don’t know that,’
says Gordon McVie, scientific director of the Cancer Research Campaign.

Only a decade ago, children with cancer were either not expected to
reach 25, or if they did they were considered to be cured. But now, so many
children survive cancer that the effects of their treatment on health in
later life must be considered. The body can ‘remember’ treatments, says
McVie, and react to certain drugs in potentially fatal ways, so the type
of therapy used in early life can be important in deciding how to treat
disease later.

This trait is also present in most people who develop Creutzfeldt-Jakob
disease (CJD) spontaneously. Researchers now say it is highly likely that
their disease is triggered by a fault in the brain rather than an infection.

CJD is a rare, fatal form of dementia related to bovine spongiform encephalopathy
(BSE) or mad cow disease. In Britain there are about 50 new cases a year.
In a small number of families CJD is inherited but, until recent years,
most cases developed for reasons that were unclear.

The BSE epidemic raised fears that some sort of infectious agent is
at work in diseases such as BSE and CJD. And these worries have been fuelled
by cases of people who have contracted CJD after medical treatments. Some
received injections of pituitary hormones, to treat growth and fertility
problems, that were taken from the dead bodies of people who had suffered
from CJD (This Week, 10 October 1992). Last month, the Department of Health
in London announced that others had developed the disease after receiving
grafts of a brain membrane, called the dura mater, during brain surgery.
Some of this material also came from people with CJD.

Goldfarb told last week’s meeting that one particular genetic trait
– an abnormality in the gene that codes for a substance called prion protein
– was present in 86 per cent of those who caught CJD from dura mater transplants,
a significantly higher proportion than in the general population. ‘This
is very unusual,’ said Goldfarb. The trait ‘can be considered as a predisposing
factor’ he added.

According to Robert Will, head of the National CJD Surveillance Unit
in Edinburgh, the majority of people who develop the sporadic disease have
the same genetic trait as the dura mater cases. ‘What this suggests is that
the sporadic CJD is likely to be a genetic effect rather than environmental,’
he says.

A large proportion of people who developed CJD after receiving hormone
injections, where the contaminated material entered the body through the
bloodstream, have a different abnormality in the prion gene. While it is
unclear exactly what is going on, Will says it appears that the two genetic
traits predispose people to CJD in two different ways.

There is now considerable evidence that defective prion protein is the
‘infectious agent’ in CJD and BSE, not a living organism as some have suggested.
Nobody knows what the usual role of prion protein is, but normally it is
produced and broken down in a short space of time.

Mutation of the prion gene can, however, produce a form of the protein
which is hard for brain cells to break down. This abnormally shaped protein
begins to accumulate and ‘encourages’ normal prion protein to change to
its shape by acting as a template. As protein levels increase, cells begin
to malfunction and the symptoms of the disease appear.

TB is caused by the bacterium Mycobacterium tuberculosis. By transplanting
sections of its DNA into E. coli, Lee Riley and colleagues at Cornell University
Medical College, New York, identified one stretch that gives E. coli the
power to invade and survive in human cells. ‘This is really the essence
of how (M. tuberculosis) causes infection in humans,’ says Riley.

M. tuberculosis avoids attack in the body by invading the scavenger
cells, called macrophages, that are part of the immune system. Normally,
macrophages absorb microorganisms and break them down with powerful enzymes.
But M. tuberculosis penetrates the outer membranes of macrophages and can
survive inside for years.

The researchers chopped up DNA from M. tuberculosis, put the pieces
one at a time into E. coli, and then mixed them with human cells. E. coli,
which lives in the human gut, does not usually invade cells. But one piece
of transplanted DNA gave it the ability to do so. The altered strain of
E. coli also invaded macrophages and survived inside them, says Riley in
the latest issue of Science.

The researchers then made shorter and shorter versions of the DNA strand
and found that under a certain length, E. coli stopped being invasive. They
also found that the shorter the transplanted DNA, the more likely E. coli
were to be ‘digested’ by macrophages. It seems that Riley’s stretch of
DNA contains genes that help M. tuberculosis both to invade macrophages
and survive inside them.

The researchers also believe they have identified the protein that is
produced from the stretch of DNA. They think the protein appears on the
surface of invasive strains of E. coli and acts as a ‘key’ to give it entry
into macrophages.

The next step is to see if ‘masking’ the protein with an antibody will
stop these strains invading cells. If so, it may be possible to design a
vaccine that stops M. tuberculosis infiltrating macrophages. By attaching
the protein to antibiotics, it might be possible to direct drugs into infected
macrophages.

(see Graphic)
Uncertain is a word well suited to the future of health care in Britain and,
by association, the future of medical research. Since April 1991, the
government’s attempts to create an internal market in health services, by
allocating money to patients and forcing hospitals to compete for their
trade, has created turmoil in hospitals up and down the country. Many of
those hospitals are also transforming themselves into independent ‘trusts’,
to operate on commercial lines.

In London, the dust from these reforms was still rising when William
Waldegrave, then the health secretary, announced plans for a sweeping
review and reorganisation of medical care in the capital. Since then have
come at least seven reports from government-appointed teams on different
aspects of health care provision in London.

Last month, on top of this pile landed another report into eight of the
country’s most prominent research hospitals which have the status of special
health authorities (see Map). It is the first of the reports to concentrate
on the quality of research being carried out in hospitals and has
implications for the country as a whole. As well as contributing to the
London reorganisation, the report forms part of a review of Department of
Health research spending being carried out by Michael Peckham, the
department’s director of research and development.

Similar assessments will be carried out across the country, and the results
used to determine which research should be protected from the ravages of
the internal market and which left to founder. The key issue of how that
decision will be made now rests with the present health secretary, Virginia
Bottomley.

The SHAs are unique in Britain, and researchers are watching how they are
treated as a model for how the department intends to support medical
research in future. Each health authority is allied to a research
institute: so, for example, the Hospital for Sick Children in Great Ormond
Street is linked to the Institute of Child Health. In 1974 the hospitals
were awarded extra funding in recognition of the large amount of research
and specialist care they carry out.

Caring for patients in a research hospital often demands more time from
medical staff, more expensive equipment and treatments, and longer stays
than usual. Because of this, the DoH provides ‘support’ money to make up the
shortfall. The SHAs, for example, receive £120 million a
year to support research. On top of this, they receive money for specific
research projects from organisations such as the Medical Research Council,
drugs companies, medical charities and the NHS.

The government intends the eight hospitals to become trusts in April next
year. They will then have to compete with other hospitals for patients and
the funds that go with them. Because of their higher treatment costs, no
research hospital could survive in a market where low cost as well as high
quality are paramount. In part, the review of the SHAs was intended to
determine what, if any, of their research should receive funding to protect
it from market forces. The report also makes suggestions for Bottomley on
how the hospitals and institutes should be reorganised to optimise their
contribution to London’s health care system.

The brief of the SHA review team, which was made up of academics and NHS
managers from outside London, has caused some concern. It seems reasonable
that Peckham should assess research that the NHS pays for – in the same way
that the MRC or medical charities assess research they fund. But the review
team looked at all research at the hospitals. To some extent, all these
projects benefit from the department’s support money. But should the DoH be
rigorously looking into research funded principally by others?

The reviewers also assessed the relevance of research to the NHS. A possible
consequence of this is that the department will stop supporting research
which it considers irrelevant to the health service, leaving other funding
bodies to pay support money along with the costs of research projects.

‘I don’t see how highly rated medical research cannot be of value to the
NHS. What they mean is that it does not fit in with current NHS priorities,’
says Diana Garnham, head of the Association of Medical Research Charities.
The association does not believe it should be forced to pay the costs of
basic health care.

‘The charitable sector cannot and will not accept the further burden of
funding the infrastructure which underpins research and which it believes
should be funded from Treasury sources,’ the association wrote in June to
the House of Lords Select Committee on Science and Technology.

‘I’m not sure that you can rigidly divide research into what is of use to
the NHS and what is not. It is naive and dangerous to do that,’ says David
Weatherall, head of the Institute of Molecular Medicine in Oxford. He warns
against pulling well-rated research groups apart in order to expedite health
care, but adds that ‘it should not be beyond the wit of man’ to come up
with a satisfactory solution.

How the government intends to use the information from its review to arrive
at that solution is still unclear and is worrying researchers whose careers
are at stake. When the SHA review was conceived, senior figures in the eight
hospitals expected the government to take their support money and distribute
it to research groups in hospitals across the country. But they now believe
the DoH has dropped this plan, in part because of the damage that would be
done by loss of support money just as the SHAs were being thrust into the
health care market.

In addition, the government no longer favours its system for sharing out
support money to teaching hospitals other than the SHAs because it fails to
recognise the quality of research. SIFTR, or the Service Increment for
Teaching and Research, is paid to hospitals according to how many medical
students they have.

In its place, the DoH is expected to set up a central pool of funds, made up
of the research support money from the SHAs and SIFTR payments, for which
researchers would bid in the same way they do for research funds. The money
would be allocated on merit and, possibly, relevance of research to the NHS.
Provided this fund is of a reasonable size, most researchers at the SHAs
have no objection.

Doubts persist, however, over the timing of any changes in the way the
department distributes its funds – both support money and NHS research
funds. Peckham is almost certain to include assessments of research around
the country in his national review, based on experience gained from the SHA
investigation.

But decisions over the SHAs and London’s other hospitals will have been made
before the national review is completed. ‘This (review process) is said to
be about science and its importance to the health service. What we have is a
judgment on a few hospitals in London,’ says Philip Poole-Wilson, research
director at the Royal Brompton National Heart and Lung Hospitals, one of the
SHAs.

Judging the relevance or significance of research to the NHS as a whole is
next to meaningless unless it is known what groups outside the SHAs are
doing. ‘You’ve got to ask how much research of a comparable standard is
going on elsewhere,’ says Adam Sillito, research director at the Institute
of Ophthalmology, which is tied to another SHA, Moorfield’s Eye Hospital.
‘That has not been done.’

One fear is that the DoH will withdraw support money for research below a
certain rating. The use of such measurements in isolation is inadequate,
says Colin Dollery, Dean of the Royal Postgraduate Medical School, in
London. Rather, these ratings should be a starting point for discussion.
Important research can become bogged down for a number of reasons and,
consequently, given a low rating. But this does not mean that a project is
at a dead end and should be stopped.

‘If you only fund highly rated research, it will mean a steady downward
progress because you are not funding research that will grow,’ says Dollery.
This applies to NHS research funds as well as the department’s support
money. The NHS will spend £316 million on research this
year. The real value of this money lies in the fact that it has often been
used to develop projects to the point where they attract funding from the
MRC or the charities.

At St Mary’s Hospital in Manchester, for example, a group led by geneticist
Andrew Read received NHS funding to collect data and DNA samples from
families with certain genetic disorders. From that work came sufficient
data on Waardenburg’s syndrome, a rare hearing disorder, to attract money
from the Hearing Research Trust. Soon afterwards, the gene was identified
and the MRC and the Wellcome Trust took the research further.

Regardless of the ‘rules’ the government decides on for distributing its
funds, the future shape of medical research will obviously depend on which
hospitals survive. Ministerial decisions, attrition in the marketplace and
the location of remaining hospitals could all make a big difference to
research.

What form the SHAs and other London teaching hospitals will take in future
is now being decided by Bottomley. Other cities such as Birmingham,
Manchester, and Sheffield all have teaching hospitals with patient
populations too small to attract enough money under the new market rules to
support their work. Although they may be under no immediate threat, some
researchers acknowledge that they are working in ‘miniature Barts’ – a
reference to St Bartholomew’s Hospital in London, which Bottomley is almost
certain to close.

One fear within the medical charities, which place their research in the
best hospitals with the most appropriate patient groups, is that Bottomley
will make no decisive changes in London. They are concerned that rather than
close teaching hospitals or break up respected research teams, Bottomley
will let the priorities of the market hold sway.

The vagaries of that system were stressed in July when Camden and Islington
Health Authority said it wanted to terminate its contract with University
College Hospital and buy emergency services for its patients elsewhere. This
would make a big dent in the hospital’s bank balance, and several of the
reports on Bottomley’s desk have singled out this hospital as a potential
centre of research after London’s reorganisation. The DoH responded by
saying that Camden and Islington was correct in looking for the best deal
for its patients, but that there might have to be more consultation on the
matter. It is this creeping indiscriminate change that the charities are
afraid of.

There are other ways that research can be lost or its quality degraded.
People move, for example. Some will retreat abroad or to the universities,
fed up with the politics of it all. Both the SHA institutes and the Cancer
Research Campaign are already having problems recruiting researchers
because of uncertainty in London. Much clinical research is also tied to
hospitals and cannot be divorced from particular groups of their patients.
If they disappear, then so will their research.

In all this change it is easy to forget that the government has given an
undertaking to increase the amount of money the NHS spends on research from
1.1 per cent to 1.5 per cent of its budget. There is also an opportunity to
streamline and improve research. But in making her decisions about London –
and later the rest of the country – if Bottomley fails to understand the
impact on research of prolonged uncertainty and hospital closures, what she
sees as good for the health service may be bad for research.

Ian Mundell is a freelance reporter who specialises in science and medicine.

Resistance to the poison warfarin has been known since the 1960s, but there
was always thought to be some price to pay. Warfarin-resistant rats are
usually smaller and lighter than susceptible rats from the same populations.
This meant that while the resistant rats have the advantage in the survival
stakes when warfarin is being used, when there is no poison around they lose
out because social dominance – and success in feeding and breeding – depends
largely on size and weight.

However, researchers from the Universities of Reading and Oxford have found
some rats that seem to suffer none of the disadvantages that usually
accompany the gene for resistance, and may even have an advantage over the
susceptible animals. The researchers have built up a colony from wild rats,
some resistant to warfarin, some susceptible. In two years, the colony has
become dominated by successful, heavy, warfarin-resistant rats. The
researchers have also been able to produce rats with these characteristics
in the laboratory by selective breeding.

One strategy for dealing with warfarin resistance is to periodically stop
using the poison until the bigger, susceptible animals predominate again.
Because they are the most successful breeders, the gene for resistance
almost disappears from the population. The new finding suggests that this
may not be a useful a strategy in the future, because if the resistant rats
hold their own or become dominant, the gene for resistance will not
disappear.

This is not the only cause for concern. Resistance to warfarin is related to
resistance to newer poisons, so its spread could rule out a whole battery of
weapons in the anti-rat arsenal.

Warfarin is a coumarin derivative that disrupts the blood clotting
mechanism. The rats die from internal bleeding a few days after eating
poisoned bait. More potent coumarins were developed as a response to
warfarin resistance in the mid-1970s and are now more widely used than
warfarin, but it is not uncommon for the warfarin resistance gene to mutate
further so that the rats become invulnerable to these chemicals too. If rats
with this degree of resistance suffer no disadvantages, then the resistance
gene will spread and coumarin-derived poisons will become increasingly
useless.

‘If we continue to find situations where there are benefits (for resistant
rats) in the absence of pesticide, let alone with it present, then we are
going to have to come up with a new approach,’ says Peter Smith, from
Reading, who now works for the Central Science Laboratory of the Ministry of
Agriculture, Fisheries and Food.

What the world lacks is another good, slow-acting rat poison. If a poison
acts too quickly, within 5 to 16 hours, then the rats will learn not to eat
certain sorts of food bait. Rat ‘psychologists’ – scientists who have
studied rat feeding patterns – are able to outwit the rodents as much as 70
per cent of the time, but few people routinely using rat poisons can get
close to this.

The report presents data from environmental monitoring in the three months
since the accident. ‘Initial results suggest that populations of fish,
plants and birds were not affected, even locally, to a degree which might
have threatened their survival,’ it says.

Around 1500 dead seabirds were recovered in January, but this is a low toll
compared with other major oil spills. The spill seems to have had no effect
on sea mammals. However, the group acknowledges that three months is a short
time: ‘The ecological implications of a spill of this magnitude are unlikely
to be transitory, and monitoring over a longer period will be needed before
the full range of effects of the oil spill can be determined.’

The oil spilt from the Braer did not form a slick, but was dispersed by the
violent mechanical action of the waves. According to the report, around 30
per cent of the oil has been deposited in the sediments of two basins,
around 10 500 tonnes to the west of the South Shetland peninsula and around
12 500 tonnes to the southeast of Fair Isle. This oil will slowly break
down, but little is known about the ecological implications of this process.

The group is also puzzled about why a fine spray of oil fell over the island
in the early days of the spill, and it recommends research into how the
spray could have formed. It concludes that the level of air pollution after
the spill was extremely low despite the oily mist. Friends of the Earth
Scotland dispute this. It says there is some contradiction in the figures
and that the island was poorly equipped to monitor atmospheric pollution.

William Waldegrave, the science minister, has given Phillips until 16 July
to decide which research councils should pay for what under the new scheme
of things laid down in the White Paper. The tight deadline placed on what is
one of the review’s key policy decisions leaves no time for anything other
than token consultation outside the research councils.

The White Paper splits the Science and Engineering Research Council into the
Engineering and Physical Sciences Research Council and the Particle Physics
and Astro-nomy Research Council. Work on the life sciences paid for by the
SERC will transfer to the new Biotechnology and Biological Sciences Research
Council, while responsibility for Earth observation satellites will be taken
over by the Natural Environment Research Council.

Phillips’s ‘boundary survey’ is an essential step in the implementation of
Waldegrave’s restructuring of British science. Until the councils know the
extent of their financial and organisational responsibilities, they cannot
begin planning for next year. The reformulated councils are scheduled to
start operating in April 1994.

In a letter from Phillips to Mark Richmond, chairman of the SERC, which was
leaked to the IPMS, the trade union that represents scientists in the civil
service, Phillips says he intends to hold private meetings this week with
each of the heads of the existing research councils to thrash out the new
boundaries. Outstanding difficulties will be discussed at joint meetings
next week.

According to the letter, a draft proposal will then be sent by the Office of
Science and Technology to chief scientists at government departments and to
‘well – informed scientists, engineers and industrialists selected from the
communities who will be most directly affected by the transfer of
responsibilities’. These experts have just a week to reply, but are in
effect being asked only to say whether the plans will meet the aims already
set out in the White Paper.

Among the toughest decisions to be made will be how responsibility for the
SERC’s Daresbury and Rutherford Appleton laboratories will be split. The
work carried out at these laboratories will fall under the auspices of a
number of the new research councils. The IPMS says experienced teams might
be broken up. Alternatively, excessive charges might be imposed on
researchers using the laboratories’ services.

PCBs stem from industrial components such as transformer coolants and jet
engine lubricants, and reach the environment as mixtures of up to 209
different compounds known as congeners. Most are considered harmless, but
about a dozen appear to be toxic: there is evidence that they damage the
immune system and cause cancer in animals, although the effects on humans
are disputed.

The usual methods of detecting PCBs measure the total amount present, but do
not show the relative amounts of the individual compounds. In the
‘fingerprinting’ technique, developed at the University of Liverpool’s
Industrial Ecology Research Centre, the concentrations of each congener is
first measured by high-resolution gas chromatography. These results are then
separated into 92 analytical domains, some with single congeners, others
with several. Each source of PCBs produces a distinctive pattern of amounts
of congeners in each domain. This would allow a pollution sample to be
matched with reasonable certainty to its source, or possibly show that the
pollution did not come from another source. ‘We now should be able to group
samples into sites,’ says Rick Leah, one of the researchers.

The team found distinctive patterns in samples from three sites – one in
Cheshire contaminated by PCB waste, another near an incinerator owned by
Rechem used to dispose of PCBs, and another by an incinerator near
Southampton that does not burn PCBs. Those could be due to background
deposits or a by-product of chemical processes at the incinerator.

The method also allows a PCB mixture to be followed as it is assimilated in
the environment. If a PCB solution is released from an industrial site, some
congeners will be taken up by plants, some will bind strongly to soil, and
others will remain in the liquid. The researchers think it will eventually
be possible to reconstruct the processes in a computer model. This will be
important if the toxic congeners are found to be accumulating in particular
media or in animals.

The first structures using the concrete, which is also stronger and more
flexible than the normal form, should be built in the next year or so.

Previous forms of ‘smart concrete’ had to have electric stress sensors
embedded in the building material, or optical fibres threaded through the
structure itself. Changes in stress then showed up as either changes in
resistance or in the quality of the light transmitted through the fibres.

In the new product, the monitoring mechanism consists of short pieces of
carbon fibre 10 micrometres in diameter and a few centimetres long. These
are simply mixed into the concrete as it is made. Although they form only a
small part of the mix – 0.2 per cent by volume – the fibres increase its
conductivity by a factor of 10. Changes in stress, or fractures, show up as
changes in the concrete’s electrical resistance, which can be measured with
a conventional resistance meter and two electrodes. Permanent monitoring
points can be set up, and spot checks can also be made by placing electrodes
anywhere on the concrete because the fibres protrude microscopically,
allowing good electrical contact.

Most concrete structures use prestressed steel rods to hold the set concrete
in compression. (Concrete is stronger under compression than tension.)
These rods also increase conductivity, but this does not vary significantly
with stress. According to Deborah Chung, one of the project researchers,
adding carbon fibre makes it possible to detect the separation of steel and
concrete that is an early indicator of structural damage.

One factor that might complicate the use of smart concrete is the natural
variation of the concrete’s inherent conductivity. This is an electrolytic
effect, caused by water trapped in the pores of the concrete, and varies
according to temperature, pore size and the amount of water present. Though
the researchers have yet to test this, they hope the effect will be
negligible.

Although this approach to smart structures is relatively novel – because it
involves so little effort to make the material, yet is so flexible – Chung
expects the construction industry to adopt the concrete for its physical
properties alone.