BRITISH MEDICAL JOURNAL
VOLUME 290
15 JUNE 1985
The report describes the arrangements made for clinical
work, supervision, prescribing, teaching, and also the
administrative problems. The general practice house officer
worked alongside the general practice trainee in certain
respects and seems to have had an ample experience of acute
and chronic illness, and some experience of preventive
approaches, to have learnt to work in a multidisciplinary
fashion, and to have been properly supervised from both
legal and educational standpoints. The experiment has been
monitored by the regional postgraduate dean, and the
complementary medical and surgical house officer posts were
solidly embedded in the teaching hospital.
Yet after all these years only one such apparently successful scheme seems to exist. This may reflect resistance to
change and to the idea itself (though there are clearly also
problems in switching to four monthly from six monthly
rotational schemes) and the report from Harris and his
colleagues is opportune (p 1811). Influenced perhaps by its
new mood of introspection as well as manpower problems,
pressure from the juniors, and public opinion, the medical
profession seems now to be thinking that "general clinical
training" may no longer be encompassed simply by working
within the hospital system in medicine and surgery. Means
may need to be devised which will not lengthen training but
will nevertheless permit exposure at this stage to subjects
such as general practice, obstetrics and gynaecology, laboratory clerkships, psychiatry, and community medicine. This
is quite evident from the profession's response to the
proposals of the GMC's education committee on basic
specialist training, which called for broadening of that next
phase.6
The education committee is currently looking at general
clinical training. Any effective proposals for change will have
to be practicable in statutory terms as well as acceptable in
educational and professional ones. More adequate supervision and guidance may also be necessary during this period.
Such supervision might protect the house officer from
defensive blunting of his sensitivity to human problems,
which may otherwise sometimes be the price to be paid for
the traumas of the initiation rite, and which others have
perhaps wrongly attributed exclusively to deficiencies of
undergraduate training.2
The recent tendency has been to blame undergraduate
education for inadequacies such as alleged deficiencies in
clinical skills when it may be that the preregistration and
early specialist training phases are more culpable. With
better supervision for preregistration training (and there are
resource implications in this) this phase can perhaps become
a properly coordinated part of medical education and practice. For instance, at present the trainee starts with a clean
sheet on graduation and then finds an abrupt change of
responsibility for his medical education at the point of
registration; this change may be a block to the idea of
continuity in the educational process. It is the GMC's
education committee which, since 1978, has been given
statutory responsibility for coordinating all stages of medical
education. If this can be done then perhaps the undergraduate
course may finally be liberated from its present overriding
commitment to detail in its many compulsory course units.
The detail is often said to stultify creative thinking and
problem solving skills, but one of the essential steps in
training young doctors is helping them to understand the
relation of the minutiae to the whole-an understanding vital
to the later tasks of medical practice in both its specialist and
generalist forms and presumably also to the ability to adopt
when necessary an holistic approach. Yet as things stand at
1765
present the young doctor is required to be "complete" by the
time of full registration, for this step gives a legal right to
practise independently.
A H CRISP
Professor of Psychiatry,
University of London, and
Chairman,
Education Committee,
General Medical Council
1 Himsworth H. Address at the opening of the 1953-54 session of the faculty of medicine, University
of Birmingham. Lancet 1953;iu:789.
2 Horder J, Ellis J, Hirsch S, et al. An important opportunity. An open letter to the General Medical
Council. Br Med 7 1984;288:1507-1 1.
2a Dornhorst AC. Shanrng the Secrets. Harveian Oration 1984. London: Royal College of Physicians,
1984.
3 General Medical Council Education Committee. Recommendations on basic medical education.
London: General Medical Council, 1980.
4 Anderson J, Roberts FJ. A new look at medical educaton. London: Pitman Medical Publishing,
1965.
5 Comnmittee of Inquiry into the Regulation of the Medical Profession. Report. London: HMSO,
1975. (Crnnd 6018.) (Chairman A W Merrison.)
6 General Medical Council. Basic specialist training. A discussion document frotm the GMC Education
Committee. London: General Medical Council, 1983.
Unconventional viruses or
prions?
In his recent book Late Night Thoughts Lewis Thomas made a
list of "Seven Wonders of the Modern World."' His fourth
wonder is the infectious agent commonly known as scrapie
virus, which produces a fatal degenerative disease of the
central nervous system in sheep and goats-as well as in
several laboratory animals such as mice and hamsters.
Thomas's decision to place the scrapie agent among his
wonders is based on the fact that no nucleic acid has yet been
found among the infectious material. Indeed, it has been
suggested that the agent may be composed entirely of
protein. To quote Thomas, "looked at this way, the scrapie
agent seems the strangest thing in all biology. ..."
The disease of sheep, now termed scrapie, was described
in the scientific literature of the last century in a Note sur les
lesions nerveuses de la tremblante du mouton by Besnoit
and Morel.2 Only in the past few decades has the agent
responsible for the transmission of the disease been recognised as being odd or unconventional.35 Numerous attempts
have been made to define the scrapie agent in terms of its
chemical composition and place it alongside other infectious
agents such as the viruses ofanimals and man or the viroids of
plants. To date, all efforts to show the presence of a nucleic
acid (either DNA or RNA) have completely failed. The agent
has proved resistant to all nucleases, to irradiation with
ultraviolet light, to divalent cation hydrolysis, to chemical
inactivation with agents such as hydroxylamine, and to
psoralen photoinactivation.' These are all agents which
modify nucleic acids. Most viruses, especially those whose
genetic information is contained within relatively low
molecular weight DNA or RNA, may prove recalcitrant to
one or more of these processes, but no virus has ever before
proved resistant to all of them. In this regard the scrapie agent
is unique. On the other hand, its infectivity has been shown
to be susceptible to numerous processes which inactivate
proteins-for example, the hydrolytic activity of trypsin.
Experiments such as these have provided the basis for the
suggestion that a protein, or proteins, may be exclusively
required for infectivity and led to the suggestions of Prusiner
that the scrapie agent may be better defined not as a virus but
1766
as a proteinaceous infectious particle, or prion (pree-on).7
This term is not, however, readily accepted by all.89
Were scrapie a disease with no kinship to other disorders it
might not have received so much recent attention or be so
contentious a subject. Prions, or prion like agents, have,
however, been suggested to play some part in many diseases,
including such ill understood human syndromes as senile
dementia (Alzheimer's disease), multiple sclerosis,
rheumatoid arthritis, Parkinson's disease, diabetes, lupus
erythematosus, and even neoplastic disorders.'° Clearly, if
even a few of these conditions can be traced to proteinaceous
infectious particles these agents must take high priority in
medical studies. On a more modest level six rare diseases
have been tentatively or otherwise ascribed to prion
infections, three of animals (scrapie, transmissible mink
encephalopathy, and the chronic wasting disease of deer and
elk) and three of man (Kuru, Creutzfeldt-Jakob disease, and
Gershmann-Straussler syndrome).6 These six diseases have
many features in common, all being confined to the central
nervous system, having prolonged incubation periods, and
being inevitably fatal. (The agents responsible for these
diseases have been sometimes called "slow viruses" and the
diseases themselves "slow diseases.") Only in the case of
scrapie has the infectious agent been highly purified, though
still not to homogeneity, and partly characterised. 12A prion
aetiology for the other diseases is deduced from their
resemblance to scrapie.
Most of the recent advances in our knowledge of the
scrapie agent comes from the work of Prusiner and his
colleagues in San Francisco. For example, they have recently
identified a major sialoglycoprotein(s), of apparent molecular
weight 27 000-30 000, which is present in the brain cells of
hamsters infected with scrapie but absent or undetectable in
brain cells of normal hamsters.'3'-5 This protein population,
designated PrP, has been partly sequenced and also has been
used to elicit antibodies in rabbits. Purified preparations of
prions have been found to contain rod shaped structures,
composed of PrP proteins, that resemble amyloid bodies
(giving green birefringence after staining with Congo red).'4
Using antibodies raised against PrP in rabbits they have
recently identified similar cross reacting rod shaped particles
in the brains of two patients with diagnosed CreutzfeldtJakob disease.'6 Thus the evidence that supports a relation
between Creutzfeldt-Jakob disease and scrapie becomes
more compelling.
Clearly prions are very unconventional agents. Whether
they are viruses at all depends on the definition one chooses
for a virus. The concept of a transmissible pathogen which
will pass through a bacteria proof filter, and for replication
and survival depends on its host, is, I believe, generally
accepted. 7 Further, viruses are classified by the size of their
genetic information and whether this resides within DNA or
RNA. If prions possess either DNA or RNA they must be
protected to an unusual degree by the PrP proteins or
alternatively be so small as to elude all agents that have been
used in the deliberate attempts to destroy them. Although
being cautious, the Prusiner school favours the notion of
an agent with no nucleic acid and an infectious protein
molecule.'3 Negative evidence is always less satisfying, and
indeed less reliable, than positive data, and others prefer the
concept of a subviral size for the putative nucleic acids of
prions. In a long letter to Nature Rohwer, for example,
reinvestigated this topic and showed how difficult it is to
destroy completely the infectivity of very small viruses; he
concludes from his study that "the scrapie agent, while
perhaps representing a new taxon, is nevertheless, a small
BRITISH MEDICAL JOURNAL
VOLUME 290
15
JUNE 1985
virus with conventional sensitivities to heat and numerous
chemical inactivants."'" The question will clearly not be
convincingly resolved until highly purified particles become
available. '9
If there really is no DNA or RNA associated with prions,
many questions arise with regard to the mode by which
the agent manages to replicate and survive. Numerous
hypotheses could be invoked to answer this question,
including the idea that PrP might bind to a specific host DNA
sequence and activate its own expression from a host cell
gene. This model depends on the concept that preprion genes
may exist in normal cells. (The techniques of modern
molecular biology should allow the latter point to be settled
in the near future, since oligodeoxyribonucleotides corresponding to the known PrP protein sequences may be
synthesised and employed as nucleic acid hybridisation
probes to search for putative genes in DNA from uninfected
host cells.) Alternatively, prions may violate the central
dogma of molecular biology which holds that genetic information flows from nucleic acids to proteins.&3 Before
discarding this notion entirely it may be salutory to remind
ourselves that it was not so many years ago that three
scientists upset the central dogma by showing that in the case
of some viruses, now called retroviruses, genetic information
is transcribed from RNA to DNA rather than the other way
round, which is the conventional manner.20 2 Whatever
transpires from studies in the next few years with regard to
these remarkable unconventional agents they will be of
considerable medical and scientific relevance.22
It seems appropriate to end this brief commentary on what
may prove to be one of nature's wonders by reminding
ourselves that it may not be unique. Lewis Thomas's second
wonder concerns a thriving colony of bacteria that has
reportedly been isolated from open vents in the deep
sea bottom where temperatures in excess of 300 degrees
centigrade exist.' No replicative proteins or nucleic acids
as we know them would be expected to survive such
temperatures, and yet these bacteria apparently reproduce
themselves.
BEVERLY E GRIFFIN
Director and Professor of Virology,
Royal Postgraduate Medical School,
London W12 OHS
1 Thomas L. Seven wonders. In: Late night thoughts. Oxford: Oxford University Press, 1984:55-63.
2 Besnoit C, Morel C. Note sur les lesions nerveuses de la tremblante du mouton. Revue Veterinaire
Toulouse 1898;23:397-400.
3 Parry HB. Scrapie: a transmissible and hereditary disease of sheep. Heredity 1%2:17:75-105.
4 Pattison IH. Resistance of the scrapie agent to formalin. J Comp Pathol 1965;75:159-64.
5 Alper T, Cramp WA, Haig DA, Clarke MC. Does the agent of scrapie replicate without nucleic
acid? Nature 1967;214:764-6.
6 Prusiner SB. Prions: novel infectious pathogens. Adv Virus Res 1984;29:1-56.
7 Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982;216:136-44.
8 Kimberlin RH. Scrapie agent: prions or virions? Nature 1982;297:107-8.
9 Liberski PP. Virion or prion? Reflections on the physicochemical structure of the scrapie agent.
Neurol NeurochirPol 1984;18:51-6.
10 Gaidusek DC. Unconventional viruses and the origin and disappearance of Kuru. Science
1977;197:943-60.
11 Prusiner SB, Bolton DC, Groth PF, Bowman KA, Cochran SP, McKinley MP. Further
purification and characterisation of scrapie prions. Biochem'istry 1982;21:6942-50.
12 McKinley MP, Bolton DC, Prusiner SB. A protease-resistant protein is a structural component of
the scrapie prion. Cell 1983;35:57-62.
13 Prusiner SB. Prions. ScientificAmerican 1984 Oct:48-57.
14 Bendheim PE, Barry RA, DeArmond SJ, Stites DP, Prusiner SB. Antibodies to a scrapie prion
protein. Nature 1984;310:418-21.
15 Bolton DC, Meyer RK, Prusiner SB. Scrapie PrP 27-30 is a sialoglycoprotein. 7 'irol
1985 ;53: 596-606.
16 Bockman JM, Kinsbury DT, McKinley MP, Bendheim PE, Prusiner SB. Creutzfeldt-Jakob
disease prion proteins in human brains. N Englj Med 1985 ;312:73-8.
17 Waterson AP. The name and nature of viruses. Nezvcastle Medical3ournal 1971;31:183-94.
18 Rohwer RG. Scrapie infectious agent is virus-like in size and susceptibility to inactivation. Nature
1984;308:658-62.
19 Masters C. Perspectives on prions. Nature 1985;314:15-6.
20 Baltimore D. Viral RNA-dependent DNA polymerase. Nature 1970;226:1209-11.
21 Temin HM, Mizutani S. RNA-dependent DNA polymerase in virions of Rous sarcoma virus.
Nature 1970;226:1211-3.
22 Prusiner SB. Some speculations about prions, amyloid, and Alzheimer's disease. N EnglJ Med
1984;310:661-3.