Small dose of our own medicine
In the bitter debate over animal experiments,
science often loses out to stunts, writes Robert
Matthews. Anti-vivisection campaigners seized
the headlines in the UK last month after the owners of a farm breeding
guinea pigs for research abandoned the business after the remains
of one of their relatives were stolen from a graveyard.
That same week, pro-vivisectionists went on
the media offensive with a petition backing
animal research signed by more than 500 UK
scientists and doctors – including three Nobel
prizewinners.
This month the US listing of Huntingdon Life
Sciences, the animal testing company, was postponed
by the New York Stock Exchange. The company
has been the target of a long-standing, often
violent, campaign against its activities in
the UK; and extremists had threatened US institutions
involved in the listing.
Such events create an impression of a straight
fight between cool-headed seekers-after-truth
and activists convinced that guinea pigs have
souls. In reality, many campaigners concede
that animal research has led to important breakthroughs
such as transplant surgery and therapies for
premature babies.
At the same time, many scientists admit to
being concerned about the lack of systematic
evidence for the reliability of insights based
on animal testing. And many, if not most, would
prefer to use alternatives – if they were available.
The view that there is no alternative to using
animals is becoming harder to sustain. For while
it attracts little media attention, research
into alternatives is soaring, with impressive
results. In the very week that the guinea pig
farm and pro-vivisection petition were making
headlines, hundreds of scientists gathered
in Berlin for the 5th World Congress on the
use of alternatives to animals in the life
sciences.
The focus was on the so-called “3Rs”: refinement, reduction
and replacement of animals in research. Researchers described progress
towards these goals, using techniques ranging from computer modelling
of how compounds behave in living organisms to “in vitro” studies
of the response of cell cultures to compounds. The predictive value
of such techniques can be high. A review by researchers in the Netherlands
published in the current issue of the journal Regulatory Toxicology
and Pharmacology reports hit rates of 70-90 per cent for some forms
of harmful reaction.
Although the reliability of animal testing
has never been assessed systematically, regulatory
bodies remain chary about accepting alternatives.
One exception is a technique now attracting
huge interest among researchers, pharmaceutical
companies and anti-vivisectionists: human microdosing.
Advocates for replacing animals insist that
tests on animals can never be as reliable as
those on humans. Yet a key problem facing alternatives
such as cell cultures is that while they may
use human tissue, they do not detect “whole body” effects,
which can be crucial.
Tests on animals have long been seen as the
only way of gauging these whole-body effects.
But there is a middle way: exposing humans
to the compound, but at levels too low to cause
health effects. This is the basic idea behind
human microdosing, now being investigated by
a number of companies. The current front-runner
is Xceleron, a company spun out from the University
of York, in the UK, in 1997 to turn human microdosing
into a commercial service.
The core technology is long-established. A
proposed new drug is first “labelled” using an isotope of carbon,
and then injected into volunteers at levels typically about 100 times
lower than the proposed medical dosage.
How the body responds to the drug – for example, its conversion
of the original drug into other molecules, and how long they stay
in the body – is then studied by measuring the level of radioactivity
in blood and waste products. As only microdose levels of the drug
are used, the radiation dose is so low that sophisticated equipment
is required to detect it.
The result is a technique that – in principle – produces
a host of whole-body data about a new drug safely, reliably and without
using animals.
As with any proposed alternative to animal
testing, however, human microdosing has faced
questions about its predictive value. For example,
do results obtained at very low doses reflect
reality at much higher therapeutic dosages?
To answer these, Xceleron has recently taken
part in an independent trial to test the ability
of microdosing to predict the behaviour of
five drugs, each with idiosyncrasies that had
tripped up animal tests. Despite the difficulty
of the test, the results from the microdosing
studies showed a 70 per cent correspondence
with those from full-dose studies. The technique
has received a further boost from regulatory
bodies, including the US Food and Drug Administration,
which have signalled their willingness to accept
human microdosing data.
Several pharmaceutical companies have now begun
their own studies of microdosing. Speedel, a
Basel-based company specialising in therapies
for cardiovascular disease, has used microdosing
to identify promising candidate compounds and
plans to move into clinical trials later this
year. Radiant Research of Seattle, which conducts
clinical trials for many big pharmaceutical
companies, has just completed its first study
of the technique, and expects clients to start
requesting microdosing tests within the next
12 months.
The big pharmaceutical companies will be watching
the outcome of such studies very closely. They
are spending 10 times more in real terms on
research and development than in the early
1980s, yet the number of new drugs winning
approval has remained essentially static.
The failure of much-vaunted genetic medicine
to convert into effective drugs has prompted
the FDA to warn drugs companies to focus less
on blue-sky ideas and more on hard practicalities.
With its potential to speed up drug development
and cut the risk of nasty shocks during clinical
trials, microdosing may be just the tonic that
big pharma needs.
Its impact on the use of animals in testing
remains to be seen. Toxic effects often reveal
themselves only at relatively high dose levels,
and animal testing may still be needed to find
these – at
least for the time being. Even so, the signs are that microdosing
may bring about reductions in the use of animals that no amount of
sick stunts by activists could ever achieve.
The writer is visiting reader in science at Aston University, Birmingham,
UK
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