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THE
EVOLUTION OF BIOTHERAPY
LEECHES, MAGGOTS, WORMS, RATS AND DOGS:
PARASITES OR COLLEAGUES?
John C T Church MD FRCSE
IN the
evolution of scientific discovery, and its exploitation, over the past
two centuries, physics and chemistry can be said to have dominated the
scene. By contrast, the twenty-first century is already being identified
as the Biological Century.1
The scientific emphasis throughout has been reductionist, but with no
end in sight as the complexities of quantum
physics and the genome unfold. By contrast again, natural biological evolution
is holistic. A multiplicity of unicellular organisms interact, giving
rise to a staggering diversity of multi-cellular organisms, all in their
turn altering the environment and creating ecosystems which are ‘fuzzy’.
‘Biotherapy’ can be defined as ‘the use of living organisms
in medicine’. Most of the natural biological ‘research and
development’ in this arena has occurred over formidably long periods.
Thus, for instance insects and mammals have been interacting for over
200 million years. Host/parasite interactions, whether symbiotic or hostile,
are highly sophisticated and complex, perhaps nowhere more so than in
the interplay of their respective immune systems. Dogs and men have lived
together since the earliest days of their respective evolution. The relationships
that can develop between sentient individuals of difference species, such
as dog and man, can be quite as complex as those between individuals of
the same species. None of these interactions lend themselves readily to
scientific measurement.
For the greater part, ‘Biotherapy’ involves the use of normal
healthy organisms, so managed that natural aspects of their behaviour
are appropriately utilised. Leeches (hirudotherapy), maggots (maggot débridement
therapy, MDT), and scavenger fish (ichthyotherapy), all have had a place
in traditional medicine. In the ‘evolution’ of medical practice,
all these branches of ‘Biotherapy’ are now being incorporated
into modern medical practice, in a variety of ways, albeit mostly in a
somewhat unstructured environment. To this list we can now add helminths
(helminotherapy), and, in the recognition of disease, ‘sniffer’
rats and ‘cancer sniffer’ dogs (biodiagnostics).
Hirudotherapy
The use of leeches in medicine, for bloodletting, dates back to the ancient
civilizations of India and Egypt. Bloodletting in ancient Greece was used
to restore the balance of the four humors: blood, lymph, black bile and
yellow bile.
Throughout history the use of leeches this way has waxed and waned. In
medieval Europe, religious and superstitious ideas caused a surge in the
popularity of bloodletting. In 1833 alone France had to import ‘over
40 million leeches’!2
With the development of microsurgical techniques leeches now have a vital
place in plastic and reconstructive surgery, particularly where venous
congestion hinders healing (Plate 1).
Plate 1: Leeches on a leg flap with venous congestion.
An excellent
example of this is the following case report: A patient was admitted to
a plastic surgical unit having had his ear bitten off by a dog. The dog
was caught and the ear retrieved. The ear was then taken to hospital with
the patient. Its surgical reattachment included finding a small divided
arteriole and suturing it to restore arterial blood flow into the ear.
But no veins of sufficient size could be found for such suturing. This
left a precarious situation which, if left that way, would have led to
engorgement of the re-attached ear and failure. But leeches were applied
to the rim of the ear for a sufficiently long period to allow capillary
re-growth across the wound, with ultimate restoration of normal circulation
(Plate 2). So this patient regained his ear, by dint of prompt
action at the roadside, meticulous micro-vascular surgery, and the judicious
application of hungry leeches.3
Plate 2: 2(a) Detached ear, due to a dog
bite; (a) and (b) pre-op; 2(c) fully recovered.
Modern
hirudotherapy includes the use of leeches over arthritic joints, in venous
ulcers, in a variety of ophthalmic and neurological conditions.4 A number
of physiologically active biochemical agents in the leech saliva have
been studied in the search for mechanisms for the beneficial effects of
this treatment in these conditions. A word of caution must however be
added. In spite of meticulous culture in dedicated laboratories it is
impossible to fully eradicate bacteria from leech secretions, and appropriate
antibiotic cover is advised during hirudotherapy.
Maggot Débridement Therapy (MDT)
‘Harvested’ maggots have been used for centuries as cleansing
agents in open wounds. They were first cultured in dedicated laboratories,
for clinical use, in the 1930s.5 With the advent of antibiotics maggot
therapy almost disappeared. But with the renaissance of this treatment
by Sherman in the 1980s6, and in the UK in 19957, Maggot Débridement
Therapy (MDT) has now not only been accepted internationally but has in
many centres become an integral part of modern wound care (Plates 3a–3d).
This development, however, is by no means uniform, due in part to negative
or
Plate
3: 3(a) Gangrene of great toe in a diabetic, aged 55. 3(b) Post disarticulation,
but still infected.
3(c) Wound after one application of maggots. 3(d) Closed wound, proceeding
to full healing.
cautious
attitudes of health care pro-fessionals and managers. It is also due to
the difficulties of adequately monitoring and regulating the production
and use of maggots this way. After extended deliberation FDA approval
in the USA was granted in January 2004, and maggots have been available
on prescription in the UK from February 2004.
Maggot feeding activity in wounds is characterised by at least the following
factors:
- Enzymatic
digestion of decomposing organic material.
- Antibacterial
action, in the wound and in the maggot gut. This includes the destruction
of bacterial biofilm, and suppression of its formation.
- Enhancement
of granulation tissue, presumably by the action of cytokines.
- Mobility.
Maggots are dynamic and respond actively and appropriately to changes
in the wound environment.
- pH.
Maggot alkaline exo-secretions reverse acid wound pH.
- Wound
warming. Maggot metabolism is exothermic, particularly so when they
are closely packed, in group feeding.
- Enzyme
‘shelf life’. Maggot exo-secretions have a zero ‘shelf
life’, being secreted directly from the salivary glands into the
wound.
A number
of prospective studies have been undertaken or are under way, comparing
MDT with other wound care products. However, this whole exercise, though
essential for proper scientific assessment, presents considerable intrinsic
challenges. There is no single manufactured product available that can
simultaneously deliver all the factors listed above, and thus be compared
with maggot activity. Equally, it is impossible to separate or isolate
these various factors when healthy maggots are allowed to feed normally
in open wounds.
Ichthyotherapy
This can be defined as the use of fresh water or marine organisms as agents
of wound cleansing. The history of such treatment in traditional medicine
is sparsely documented. In a museum near the River Kwai, recording the
privations of prison camps, a sketch drawn by a prisoner showed him up
to his waist in water, but with small fish attending to his leg ulcers.8
There is widespread use of such fish in India, particularly in rural areas.
In Kerala State Professor Padmanabham PhD studied this phenomenon in detail.9
During the sixth International Biotherapy Conference in Turkey, in June
2003, the Kangal Balikli spa was visited. Warm water pools are stocked
with three species of small fish that scavenge lesions of the skin, particularly
psoriasis.10 (Plate 4.)
Plate 4: Scavenger fish, Kangal Spa, Turkey,
cleaning psoriasis plaques.
Helminthotherapy
A number of diseases are associated with auto-immunity dysregulation.
Typical of these are Crohn’s disease and ulcerative colitis. Acting
on the hypothesis that the autoimmune response in these patients is due
to lack of helminth antigenic stimulus in the alimentary tract, studies
have been conducted giving such patients doses of helminth eggs
orally. The chosen helminth, porcine whipworm, Trichuris suis, is not
pathological to man, but has a positive effect on the host immunity, with
reversal of symptoms.11 This work opens up a further horizon on the potential
to use living organisms that interact with each other, particularly through
immunological reactions, thereby maintaining healthy co-existence.
Biodiagnostics
Biodiagnostics can be defined as the use of living organisms in the detection
of disease. Although modern medical screening systems are thorough, they
are not universally available, and they are often still far short of requisite
levels of sensitivity and specificity. There are still no reliable tests
for the early detection of most cancers. National screening in the UK
is currently only available for breast and cervical cancer.
Trained sniffer-dogs are now used extensively in the detection of drugs
and explosives, in forensic work, and in a variety of other ways such
as the detection of dry rot and termites in houses. Anecdotal stories
have been published of pet dogs that have apparently caused their owners
to seek advice, and have an early cancer diagnosed and treated, with good
results.12,13 A controlled pilot study has shown that dogs can be trained
to recognise cancer of the urinary bladder.14 (Plate 9.) A certain species
of rat in Tanzania has been trained to recognise tuberculosis in samples
from patients afflicted with this disease.15
Plate 5(a) - left. Cocker spaniel with
a line of samples.
Plate 5(b) right. Cocker spaniel indicating a cancer
sample.
This presents us with an extensive field for similar studies, using any
species with a well developed olfactory system that can be trained to
recognise disease at high levels of specificity and sensitivity.
The future of ‘Biomedicine’
Nature provides us with an almost limitless array of species that respond
to chemical or other signals in their environment. There is thus a vast
potential to harness or control such behaviour to give us models for the
early recognition of disease, perhaps most readily when it is characterised
by volatiles expressed by the patient. Working well with living organisms
is exacting. It demands an understanding of their biology, and enough
control of their ‘working’ environment to result in ‘optimal’
behaviour. Their use in the clinical arena is thus an art. With skilful
and appropriate use, excellent clinical results can be obtained.
It must be expected that all this ‘fuzzy-edged’ activity will
become progressively more integrated into modern clinical practice. This
already presents its own array of challenges for its requisite monitoring
and evaluation and the assessment of clinical outcomes, but guidelines
for all this activity are being established.
References:
1. Benford G. The Biological Century
http://reason.com/9511/BENFORDfeat.shtml
2. El-Awady A. Maggots and leeches make a comeback. Science in Africa
July–Aug 2003.
http://www.scienceinafrica.co.za/2003/july/leech.htm
3. Teo TC. Personal case. Sherman RA. Maggot Therapy – The Last
Five Years. ETRS Bulletin Vol 7 Issue 3. 2000.
4. Gilyova O. Modern Hirudotherapy – a Review. http://www.scienceinafrica.co.za/2003/july/leech.htm
5. Lederle – Surgical Maggots. Council of Pharmacy and Chemistry.
New and non-official remedies. JAMA 1932; 98: 401.
6. Pechter EA, Sherman RA. Maggot therapy: the surgical metamorphosis.
Plast Reconstr Surg 1983; 72(4): 567–570
7. Church JCT. ETRS working party consensus paper on wound debridement.
Surgery 1995;13(10):228c-d
8. JCTC. Personal observations, April 1998.
9. Cohen J. Feeding the fish. BMJ 2000; 320: 181
10. Church JCT. 2003 Report on the Sixth International Biotherapy Conference,
Turkey
http://biotherapy.
md.huji.ac.il/newsletter07.htm
11.Weinstock J, Summer WR. Will Helminths Become the Future Treatment
for Inflammatory Bowel Disease? http://www.uihealthcare.com/news/currents/
vol2issue1/1helminths.html
12.Williams H, Pembroke A. Sniffer dogs in the melanoma clinic? Lancet
1989; 1: 734.
13. Church J, Williams H. Another sniffer dog for the clinic? Lancet 2001;
358: 930.
14.Willis CM, Church SM, Guest CM, Cook WA, McCarthy N, Bransbury A, Church
MRT, Church
JCT. Olfactory detection of human bladder cancer by dogs: proof of principle
study. BMJ 2004, 329: 712.
15. Balile D. Tanzania trains rats to detect tuberculosis. Science and
Development Network 28 December 2003 http://www.scidev.net/Newsindex.cfm?fuseaction=readNews&itemid=1169&language=1
Acknowledgments
The author is grateful to Mr T. C. Teo for Plates 1 and 2; Mr A. Jarvis
for Plates 3 and 4; and to the
Medical Illustration Department, Wycombe General Hospital, for Plate 5.
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