The Elucidation of Chronic Diseases Occuring in High Incidence in Primitive and Isolated Populations
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Transcript: English(auto-generated)
00:13
Our German hosts and fellow colleagues and students, I'm very grateful to be with you.
00:22
I'm coming directly from a much warmer climate, about which I hope to speak to you a bit at the end of my lecture. And I'm suffering under the influence of your beautiful weather here. The study of an epidemic of new disease,
00:44
new to Western medicine, and a chronic, progressive, always fatal central nervous system disease in a remote population isolate in people still in a Stone Age culture in the central highlands of New Guinea, who ate their own dead as a right of respect
01:05
and mourning to their nearest kinsmen, has led us to two major discoveries. The first, already mentioned by the over generous introduction, was the discovery that chronic, progressive, even at times
01:25
totally non-inflammatory, and even apparently hereto-familial diseases could be caused by slow-acting virus infections even years and at times several decades
01:41
after original infection and a long, silent incubation period. The second discovery was that of a new group of microorganisms, which cause human diseases and which possess such unusual physical, chemical,
02:02
and biological properties that many of our colleagues prefer that we not call them viruses. They are so very different from all other microorganisms that they clearly represent a new type of replicating agent, which we have tentatively decided
02:22
to call unconventional viruses. The disease in question that led us to these discoveries is called Kuru, a now disappearing plague of the Fauré people and of 10 other cultural and linguistic
02:41
groups in the central highlands of eastern New Guinea who intermarry with them. They all inhabit a high, mountainous interior of the eastern highlands, living from 2,000 to 3,000 meters above sea level. By opening the bodies and the skulls of their dead kinsmen,
03:04
they contaminated the skin and eyes, principally of the women who performed the mourning ritual and of the young children with them. And this led to a fatal brain disease appearing 5, 10, even 20 or 30 years later.
03:21
It became the most common death among them. In fact, it accounted in the first 10 years of our total surveillance of all the population involved for over 50% of all death. And among adult women, 90% of all those
03:44
who died in a 15-year period of surveillance died from Kuru. We have now discovered that the disease first described in Germany a half century ago and named Creutzfeldt-Jakob type of presenile dementia
04:01
after the two German neurologists who first described it is a worldwide disease of at least 10-fold and probably 100-fold the incidence that we attributed to it only a few years ago. It is caused by a virus indistinguishable
04:21
from that of Kuru. But whereas we know the mode of transmission of Kuru from the contamination of the skin and mucous membranes through the ritual rite of cannibalism, we do not know the usual means of transmission of our civilized form of Kuru
04:41
throughout the rest of the world. We now know that these two unconventional viruses of man are similar to two such viruses of animals, Scrapie, Tauberkranghaidoffdeutsch, or Tremblant en Francais,
05:00
and a disease called transmissible mink encephalopathy of mink. We call the group after the nature of its neuropathological lesion, the subacute spongiform virus encephalopathies. Extreme resistance to an activation by ultraviolet radiation of 2,540 angstroms,
05:27
254 nanometers, the wavelength, which is the peak absorption wavelength for RNA and DNA, has led to the prediction that Kuru and CJD, or Creutzfeldt-Jakob disease virus and Scrapie viruses, possess no nucleic acid.
05:43
This heresy has been further promulgated on the discovery that these unconventional viruses also exhibit an enormous resistance to ionizing radiation using either gamma rays from a cobalt-60 source or a neutron beam.
06:01
We're doing this work with Latouge at the Fondation Curie in Paris as well as at Oak Ridge. And we have repeated the work of our British colleagues, Haig and Tigvar-Alpers, and confirm this resistance, which is on the order of 100 to 1,000 times that known for any other microbial system.
06:24
In fact, the equivalent target size for a sphere with such unusual resistance to ionizing radiation as specific or nonspecific, though the damage may be, would be calculated to be under 150,000 daltons, a molecular weight
06:41
which is only 1 10th the size of the smallest genome previously known to virology. Finally, intensive study of these viruses for over a decade has failed to reveal any antigenicity. And in both the natural diseases and the experimentally induced diseases in laboratory animals, there is no evidence
07:03
that the victims develop any immunity or that the immune system plays any role whatsoever in the disorder. The humoral and the delayed hypersensitivity types of immune response, B cell and T cell function remain intact and unstimulated.
07:20
There are no immune complexes formed and no immune complex deposits found on basement glomerular membranes or in the choroid plexus. These, thus, are the first mammalian microbial pathogens which apparently contain no non-host protein in their structure.
07:41
Instead, they seem to be minute messenger RNA-sized pieces of DNA tightly bound to host membrane systems. And indeed, the demonstration that they are, in fact, DNA is very tenuous based on only one unconfirmed,
08:01
very recent experiment now in press. The only structure we are left possible for them at present remains a tightly membrane-bound particle of size no larger than 150,000 dolons, programming probably for none of its own enzymes
08:22
or any core or coat proteins. A virus without core or coat leaves those of us in structural virology most bewildered. It is from recent work in plant virology
08:40
that we find sucur and the hope that we may remain true to our basic tenets of our current DNA-RNA religion and not have to retreat into the previous speculations of replicating membranes devoid of nucleotide structures
09:07
or replicating basic proteins. But I must warn you that the very same workers who with no difficulty whatsoever quickly established the full sequence of PHYX174,
09:20
the smallest virus of bacteria yet sequenced have been six years on this problem from Caltech and North Carolina out and in Germany and in England and have failed yet to establish unequivocally that a nucleic acid is involved in this whole system.
09:41
That we are dealing with viruses and viruses that cause human disease is very clear indeed. They grow in vitro in tissue cultures of infected cells obtained by primary culture of the spleen, liver, lymph nodes or brain of infected animals or primary subhuman
10:02
or animals with the natural diseases. Continuous cell lines such as L cells have been infected in vitro with the need of causing fusion to get the infection started and the perhaps hazardous procedures of transforming both human and animal cell lines
10:23
with the SV40 genome so that they bear the tumor antigen and still carry replicating simultaneously the infected genome of both the Creutzfeldt-Jakob and the Kuru agent in different cell lines and now the Scrapie have all been successfully performed. We are dealing with virus-like agents.
10:43
We are dealing with a new group of microbes which might better be named by another term and as usual, the more fortunate plant virologists have preceded us and found that they must also revise their basic microbial conceptions in a group of agents
11:04
which are the smallest of the plant viruses they prefer to call, following Diener, the man who has defined them most thoroughly, viroids. I will talk about them later and with that introduction, I will start on a series of slides.
11:20
If I get through them on time, I'll then try to take you on a historical travelogue to where this current day molecular biology began. So if I pay somewhat short shrift to the rather lavish and hardly credible claims I have made,
11:42
I beg apologies from my molecular biological colleagues. To make it a little easier to follow the terminology of a discipline, neurology and neuropathology notorious for the use of impossible eponyms and impossible and almost meaningless descriptions
12:01
based on neuropathological lesion, I will leave you rest assured that we have introduced only one new name into medicine, the name Kuru, which is a nice, non-Anglo-Saxon four-letter word, which has even crept into the Webster Collegiate Dictionary
12:20
whereas Louise has yet failed. I am unable to use any other term for Creutzfeld-Jakob disease than the long-established eponym. The disease does run by 17 additional all-longer synonyms in the neurological literature.
12:41
Scrapy is a spontaneous disease of sheep and goats throughout the world, and mink encephalopathy we now have good reason both virologically and epidemiologically to believe is simply the Scrapy infection having spread to mink ranches naturally. In fact, it is known that where it was first seen,
13:01
the carcasses of Scrapy infected sheep have been fed. The next slide, please. This slide simply shows the natural diseases on the left, the experimental diseases in experimentally infected animals after over a year of incubation on the right.
13:23
It shows what is called status spongiosis or spongiform change by the neuropathologist, which simply means a sponge-like, punched-out whole appearance of the gray matter. It is not referring to white matter spongiosis. And although it was previously thought to be edema and intercellular fluid accumulation,
13:44
it is exactly not that. It is a swelling of neuronal and astroglial cells based on a coalescence of minute vacuoles, which can be seen in their origin by electron microscopy long before they are visible to light microscopists. This is Scrapy in sheep and Scrapy in mice,
14:04
Kuru in a child and Kuru in a chimpanzee inoculated with the child's brain tissue, Creutzfeldt-Jakob from a brain biopsy in Oxford, and the same process in the brain two years later of a chimpanzee inoculated with it. Next slide, please.
14:22
The same distribution, Scrapy, natural, and experimental, Kuru, natural and experimental, Creutzfeldt, natural and experimental, demonstrating with a specific stain that shows astroglial cells, the fibrous astrogliosis, which is a dominant part of the pathological picture,
14:42
and about as severe in this disease, in this group of diseases, as in any disease we know. On the other hand, these are the only infections of the brain and I make no exceptions in infections, namely range through the whole range of such things
15:02
as the protozoa through the viruses in which there is no perivascular coughing, no leukocytic invasion of the brain parenchyma, and no sign of a hypersensitivity or a inflammatory response. Next slide.
15:20
For those clinically minded, next slide, please, the phenomenon that these diseases proceed from beginning to fatal outcome with no change in spinal fluid protein and no pleocytosis at any stage of the disease is a further unique finding in fatal CNS infections.
15:41
Now, I'm not going to dwell on the hundreds of studies attempting to purify Scrapy, first using cesium chloride, then using calcium and potassium tartrate, metrizomide, as well as sucrose and sucrose saline gradients have been used.
16:01
And the workers who have done this work are not workers who have difficulty using zonal ultracentrifuges and purifying reverse transcriptases, viral subunits, P30 proteins, polyacrylamide gel, electrophoresing them. But these same workers have been unable to purify
16:23
by these techniques or any other electrophoretic focusing and the like, the Scrapy agent, because no matter what small portion of maximum infectivity at a density of 1.2 to 1.25 they take, it spreads again,
16:42
and electron microscopic control of the re-zonal banding of it simply shows that we are trying to purify soap bubbles. The material obtained with enormously high infectivity is a three-layered bioelectron microscope plasma membrane light structure which fasciculates.
17:03
And the problem is that of concentrating and purifying membranes where the reactive receptor or the reactive macromolecule on the membrane is not known and although we assume it is a small nucleic acid,
17:21
all attempts with hot formaldehyde and with detergents to release this presumed genome have failed to obtain any infectious nucleic acid. Next slide. The most disturbing early data which came first from Compton working on Scrapy,
17:40
then we reconfirmed it in using zonal banded and fluorocarbon cleaned brain suspended Scrapy virus. We obtained linear inactivation curves at ergs per square millimeter times 10 to the fourth. A energy input which if you are not familiar
18:04
with radiation work would not lead you to realize that the most radio resistant forms of life we know to 254 nanometer radiation would intersect here at six. They would be the U1 variant of tobacco mosaic
18:22
and bacillus radiodurans. This was interpreted first as absolute proof that the agents could not contain nucleic acid. In the suspensions, if the argument is that they are dirty, not sufficiently cleaned,
18:41
one puts a large variety of mammalian plant viruses and bacteriophage, these so-called dirty suspensions have no effect on protection at this radiation. Next slide. I'm not going to dwell on the long discussion this might entail but here is the same data you just saw
19:01
but it simply shows that the plant extracts of the plant viroids, these newly described smallest known viruses are even more radio resistant and the purified RNA genome of 115,000 molecular weight of potato spindle tuber virus is of the same order
19:23
of magnitude of radio resistance whereas all conventional viruses fall here. Next slide please. This alone eliminates all other plant and animal viruses from consideration. Studies of very unsatisfactory zonal banding
19:42
into 55 fractions in a sucrosealene gradient but the best anyone has obtained, there's a log scale so it doesn't plot out as well as the earlier ones I showed you, shall have failed to reveal any relation with marker enzyme systems in enzyme activity for three lysosomal membrane bound enzymes
20:04
and one mitochondrial enzyme. Next slide please. I'm now going to rapidly summarize probably as fast as you can read. The much of what I have said simply to drive home the fact that these surely are an unconventional
20:22
type of viral agent. On the physical chemical side, I failed to mention what alone would leave any earlier microbiologist totally skeptical of the integrity of the workers. That a virus or any microbe can be stored in 4% formaldehyde or 10 or 20% formaldehyde
20:43
at room temperature for years without losing titer, namely embalming fluid and that which we use in pathological laboratories to store specimens is blatantly ridiculous. It happens to be the fact. We have isolated Creutzfeldt-Jakob virus from material that has been stored years at room temperature in pathological laboratories
21:03
in formaldehyde. Scrapy and mink encephalopathy have been taken off paraffin embedded blocks which were for two years in formaldehyde before they were sectioned and left several years as blocks and obtained as viable microbes. Beta-propriolactone doesn't touch them.
21:22
Ethylene diamine tetraacetic acid doesn't touch them. Proteases and the nucleases on even the deproteinized fluorocarbon treated zonal band infractions are not effective, nor can we use hot formaldehyde to inactivate them in searching for double or single stranded RNA.
21:42
Heat resistance is not incompatible with the biological experience, but it is incompatible with most virological experience. Up until 80 degrees, we have full stability. At 85 degrees, we begin to inactivate. And as with the hepatitis virus, boiling is not sufficient for hospital sterilization.
22:03
Autoclaving, however, most certainly is. Next slide, please. To go on further, I have already summarized the UV resistance for you. I've mentioned the enormous ionizing radiation resistance. We use ultrasonic energy in such energy input
22:20
that we would be inactivating rapidly polio or flu or most conventional viruses, and all we do is gain in yield, increasing our infectivity tighter. When we do an action spectrum at 2,370 angstroms, the nanometer wavelength of 237, which is much less sensitive for inactivation work
22:45
for most microbes, in fact, all of them, we find six-fold the sensitivity, which is still not very high, of that where it should be in a DNA-RNA system. No one has visualized the agents, and not one, but literally dozens
23:01
of the major structural electron microscopists working on the subunit structure of viruses have been involved for decades in the attempt, and their starting material are either tissue slices containing an infectivity titer of 10 to the ninth per gram or zonal banding material
23:22
even more rich in infectious particles. That they contain no host proteins I mentioned earlier. We doubt this, but it looks as though it may be the case and attempts to immunize animals with material that have infectivity titers as high as 10 to the 11th per gram,
23:42
have produced no neutralizing, no radio-immune assay obtainable, and no cytotoxic antibody that we can with any of the existing systems that work with retroviruses and all other groups of viruses that we can identify. Next slide, please. The pathological lesion is a coalescence of vacuoles
24:05
which have been studied and studied and studied. Their membrane is not very nice to look at. It doesn't look, there's no visible virus-like structure on it, next slide. It expands and, next slide please, it blows up the cell
24:20
and finally we end up with neuronal destruction. A good deal of implanted electrode physiology done at Percy-Kermard and in Marseille with animals inoculated having previously had electrodes implanted has yielded evidence that for literally months and sometimes years
24:41
before neuron death, neuron involvement starts and by controlled, perfused pathological study this can be verified. The first proof that we had an infectious agent here came when chimpanzees succumbed
25:01
to the clinical disease Kuru, a disease which produced a clinical picture which no behavioral analyst had ever seen in zoo or naturally observed chimpanzees or in laboratory subhuman primates. In fact, all the experimental animals develop a disease
25:22
which has never been produced artifactually, which has never had a similar pathological or clinical entity developed spontaneously of unknown or known cause in laboratory animals of the species used. So there is really no control necessary. The next slide, the pathology of these animals
25:43
is identical to that in man with the complex Purkinje cell and molecular cell loss in the cerebellum. I'm not going to expand the pathological discussions. The chimpanzee, interestingly enough, develops a drooping lip months before our clinical neurologist and veterinarians are aware
26:01
that the disease is there. Our keepers by personality change and facial expression are aware of the disease long before hard neurological signs appear, months before. This is true, of course, with Kuru in New Guinea and where even child patients recognize
26:20
their fatal disorder before any physician or their parents are aware of it. Next slide. The analysis of cinema at a stage too early for our neurological astute colleagues to detect the disease does reveal restricted forelimb movement patterns
26:40
as opposed to the normal walking pattern, which coincides with the drooping lip and the keeper's note of personality changes. Next slide. This added matter is of incredible interest if one realizes that during the two and four years of silent incubation in cats and in many species of old world monkeys,
27:03
when these animals would be said to be normal and when their neuropathologically studied brain by conventional means would be said to be normal, we now know that there are vast disturbances from implanted electrode work in thalmic, hypothalamic, cortical relations,
27:21
disturbing paradoxical sleep and other sleep rhythm patterns which Juve is so interested in and this is happening with all the viruses. In addition, we are finding if we use perfusion and early sacrifice, neuronal nuclear amytotic division by nucleate and trinucleate neurons,
27:44
fusion of neuron to neuron and neuron to glial cell as we now know these agents cause in vitro as well in tissue cultures and we have a whole gamut of exciting pathology going on in the normal animal years before disease, only beginning to ask the question
28:01
does this ever go on in man? Since it's associated with only what we would consider allowable personality disturbances and sleep disturbances and it requires perfusion studies to study, it is a difficult question to decide upon and one many of us are not anxious to have investigated that thoroughly.
28:21
Now, the Kuru patient who first produced chimpanzee disease took 21 months incubation. When that brain material was placed in other chimpanzees, it dropped to 11 months and 13 months. In fact, this has been done over many times and again, we get a drop in incubation
28:41
from the usual one and a half to two years to less than a year to 13 or 14 months on first passage. This immediate drop on second passage to a shorter incubation period has been done over again over 60 times. We know it occurs and with other species, the same one passage adoption, adaptation
29:03
looks like a selection process which we are not familiar with in virology. We are more used to a step-by-step slow adaptation to a new host. It doesn't proceed further on further passage. By the oral route, there was no infection
29:21
and this animal 12 years later is still well having had millions of lethal doses of the agent. By the use of skin liver, a spleen liver kidney, a visceral suspension without brain, we still got the disease and using peripheral non-intracerebral inoculation,
29:40
we got the disease very early in the work. I'm not going into all the passage studies. Next slide. This simply shows the first demonstration that we could shift from the chimpanzee to South American monkeys, new world monkeys with the sacrifice of a short incubation period of one year
30:00
and making our waiting time into two years again. This has not reduced on further passage. Next slide. The new world monkeys, a dozen species of them, owl, spider, squirrel are all now used in work with the human diseases and it has permitted the curtailment of work with the diminishing rare species of chimpanzee
30:23
which incidentally in our breeding colonies, we breed more rapidly than we use. We had 30 newborn chimpanzees last year and only use five or six. Eventually, we may be able to return them to Africa where they are being killed more frequently
30:40
and indiscriminately. The passage in chimpanzee is not continuing. We're using smaller animals and other hosts now that we can. Next slide, please. I'm not going into the experiments that that involved. This is a biopsy of a European patient with Creutz-Wallyakob disease to reemphasize the punched out spongiform change
31:03
in the cortex. Next slide. And to show you that we also found chimpanzee passage in 13 months of this disease possible and then in 12 and 14 months in another chimpanzee but almost three years and almost four years
31:22
when we went to capuchin monkeys and marmosets. In other words, these smaller monkeys require much more patience in the experimenter. Again, when we found we could go to small animals and finally cats, we ceased chimpanzee work but one line has been continued.
31:41
Next slide. Now, to depart, I'm going to not use the small remaining time to elaborate extensively on all the animal work that has been done and continues but to tell you a little about the worldwide form of Kuru.
32:00
One sixth of the cases are familial. These patients had the disease. They weren't autopsied but it's a clinically recognizable syndrome. So here are two aunts and mother of the Propositus plus his grandmother all dying of Creutz-Wallyakob disease. Next slide, please. Another family from Germany with three generations
32:21
of many proved autopsied cases from which the virus has been isolated. In fact, these genealogies, which are every bit as good for a dominant inheritance when they are looked at in a whole as for Huntington's Korea, for instance, number over 60 now in the number of families
32:40
we know with the disease. And from 11 of the first 17, we have had brain biopsy material on. We have already isolated the virus and the remaining six are not negative. They have not been inoculated long enough. Next slide. So here we have a disease which would undoubtedly be acceptable as a gene control to reto familial disease
33:01
where a degenerative pathology is virus determined and with no genetic control that we know of in the fully susceptible hosts. Here is a huge amyloid plaque staining PAS positive, metachromatic, agentophilic, the plaque that all of us have in our brains as we age.
33:24
Some people unfortunately have a great deal of it before 60 years of age and we call it Alzheimer's disease. This plaque is present in 20% of the Creutzfeld patients. It's present in 60% of the Kuru patients, even children.
33:42
But since it is not present in the remaining 40% of the Kuru patients, brothers, aunts, uncles, and parents of the other victims who have it, we are sure it's a host phenomenon that has nothing to do directly with pathogenesis. On the other hand, in Alzheimer's disease,
34:02
it and the tangles are what we most focus on and it is very remarkable that a fair number of Creutzfeld patients have the disease. Many lead to pathological disputes as whether they are Alzheimer's or Creutzfeld until we finally isolate the virus. Next slide.
34:20
Simply demonstrating the spherical symmetry with crossed nickel prisms of the amyloid which by EM is amyloid and by long chain and short chain analysis is amyloid. Next slide. To bring you up to date on what is just in press a world epidemiology and an American of Creutzfeld,
34:42
we now know that anywhere we look hard, we find 0.5 cases per million per annum death. This makes it a very rare cause of death indeed. But when one realizes that this means 200 deaths a year for the United States
35:00
and we have not had 10 deaths a year for rabies with a 50 state surveillance in the last 20 years, it's fully a 50 times more frequent than rabies, probably a hundred. This is a minimum. We are actually finding one per million per annum anywhere in large cities we look intensively.
35:21
The European studies now impress with Catalla and Paul Brown working on them in Paris for all of France, parts of Germany, most of Italy and Spain are showing 0.5 per million per annum on first survey for the last 10 years with one to two per million per annum in some foci and large intense foci in Hungary,
35:42
Slovakia, Palma in Italy and in Israel. Next slide. Creutzfeld is a worldwide disease. The countries of Africa where it's been found are few and far between. Survey has not been intensive. We don't know why we haven't been to Argentina.
36:02
The other countries in South America, everyone we visited, we found it and in high incidence. It far outranks rabies as a world cause of death from infectious brain disease by probably a factor of a hundred on all continents. Next slide.
36:21
The scrapie virus is probably also ubiquitous where sheep are kept, but most countries with it do not recognize it. We have and British workers have carried it for decades through mice and to our horror, after long incubation period of 73 months,
36:41
the cinnamolgus monkey developed a spongiform encephalopathy identical with Creutzfeldt-Jakob disease. After scrapie sheep brain inoculation, as did after almost three years, squirrel monkeys. On passage, the incubation period has dropped in the squirrel monkey,
37:01
but not in the cinnamolgus. Here, it has been passed back into sheep and goat with disease, proving that it is still the scrapie virus biologically, although we're since no Creutzfeldt-Jakob virus go this way. We are very worried, however, since European strains of scrapie
37:21
taken from the Compton Laboratories, once transmitted to monkeys, lose their ability to go back to sheep and goat. Conceivably, scrapie is the source of some of the human Creutzfeldt. Next slide. It incidentally can be found in the butcher shops throughout the world. There's a high selection for the butcher
37:41
of all scrapie-infected sheep and even laboratory-infected sheep throughout Europe have in past decades ended up in the butcher shop. Scrapie is a worldwide disease. The next slide. Now, in a rush travelogue, I promised you I will try to tell you where this story began.
38:00
It began not in this enormous second largest island in the world, but in one small highland area here in New Guinea. Next slide. The Kourou region is at 2,000 to 3,000 meters with human population scattered in the eastern highlands of a very mountainous area where all the grass-covered areas represent
38:22
the effects of millennia, more than centuries of human cultivation by slash-burn agriculture. Next slide. The villages are small, few humans see or saw in the Stone Age period when we first described Kourou
38:41
more than a few hundred individuals between their birth and their death in adult life. The population unit is under 100 in most places, up to 200 in some and never exceeding that. Next slide, please. This is a village in which we're returning. The area has rugged and the first year
39:01
of patrolling throughout the area required a moderate amount of mountaineering. Next slide. And bridge building. Next slide. But the next slide, I'd go through these rapidly, and the Mesolithic level culture of the population involved with Kourou
39:20
are people who quite significantly never washed in a lifetime, covering their body with the rendered grease from their pigs, which run wild and mate with the wild pigs, or of their relatives. Next slide. The Kunai fields are high grass, which a long carrier line is carrying our supplies through.
39:42
Next slide. And in that area, we would meet one of the 11 language groups which were defined during the Kourou Research Project since only two of them had had European contact at the beginning of our Kourou epidemiological work. This is an Anga Kua Kua group, which is just on the border.
40:02
Next slide. The villages contain groups of women who were slow to leave, as most women, on our arrival, preferred not to walk, but when tested, could walk, but with minimal ataxia. They told us through the one- and two-level
40:21
child translation we had into a language we could finally use that they were dying of Kourou, and they were invariably right. The disease rarely lasted more than a year and was characterized by midline cerebellar ataxia with preservation of cortical functions
40:40
and no sensory disturbance. Next slide. The patients at this stage are unable to focus their eyes or hold their neck properly, so she looks demented, but with grunting signals can evidence very good contact with reality and good intellect still. However, she is so ataxic
41:01
that she can no longer stand without support. Next slide. And in every village of 100 people, we found people dying with no exception. Next slide. We found over 300 death the first year, and in a given hundred-population village, three women using sticks to keep ambulating to their gardens to bring food back to their houses
41:22
were already evidence that they had Kourou. They agreed that they did have no foray woman required a stick to maintain her balance unless she had Kourou or some other injury. Next slide. The smallest patients were children of four or five years of age. Next slide. And the area we found was of enormous linguistic diversity.
41:45
The New Guinea people, the Melanesians, speak over 1,000 languages, not dialects like French, Spanish, and Italian, or German and Dutch, but real languages. At a dialectical language, it's much more diverse
42:02
than that. In the eastern highlands alone, there's this enormous level of languages in at least five language families. Next slide. As we worked out the boundaries of Kourou, next slide, we also gave names to most of the people, which as is always the case with indigenous populations, they are the fallacious names,
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usually an insult like the bastards over the hill used by their enemy neighbors. The people themselves have no names for themselves. So our fallacious names have stuck, and the new generation children don't know that we are the source of them. And this is the boundary of Kourou against the language groups that had it,
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showing that here culture and language have determined the boundary completely. And here, culture and language have had nothing to do with the boundary of the disease. Next slide. When we counted up cases at the end of a year, and this prevalence data can be read as yearly mortality, the disease usually lasts about a year. So this was 1.6% of the population dying per annum.
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This went on for 50 years previously, and has gone on through most of the first 10 years of surveillance, but there's been a change. Next slide, please. This simply, the Kourou area would be superimposed on here, and this is decreasing population density
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into high altitude mountain ranges and virgin bush with no people, showing that the people became less and less dense as we went in this direction. Next slide. But the running away from Kourou, which they consciously attributed their location in the virgin forests to,
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was with no success whatsoever, since maximum incidence with 3% dying per annum occurred in the least dense, most remote populations, bordering on populations here that had no disease at all. But there's no intermarriage or contact culturally between these groups, there's no ecological shift. Next slide.
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We began to accumulate patients, they were willing to come in, until we had from 40 to 100 at one time dying in the Okapa Hospital, which we built. Dr. Ziegus, next slide, a New Guinea government physician who discovered the disease and has worked on it with me since the beginning,
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is Vincent Ziegus here, myself, in an early day with a child patient at Okapa. Next slide. And we would have this boy himself knows he's dying of Kourou, but hadn't convinced us yet. His autopsy six months later certainly proved he was right. He is supporting the girl with the disease, and these two have the disease,
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and that young girl does too. Next slide. The moon fascias is a result of in unsuccessful attempts at cortisone therapy. Next slide. Next slide. It simply caught a patient during the movement. I should be showing you cinema, not still pictures. We don't have the apparatus. Next slide, please.
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And a severe strabismus, an extreme dysarthria, a final total neuromuscular incapacity with minimal loss of intellectual function characterized all patients. Children usually died in six months to nine months. Next slide. Fully a third of all the patients were children,
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and most of the patients were female, except among children where the male to female ratio became a little more reasonable. This 13 to one to 78 to one ratio of female to male in adult life was very difficult to imagine epidemiologically at first.
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Next slide. We eventually found that from genealogical studies that one of three wives, the people are polygamous, and this enormous death of women had reduced the sex ratio to three to one, raised it in favor of males in the southern villages
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for polygamous society with a total sex ratio of three to one. This made it closer to five to one for marriageable age males. Polygamy on top of it made it very hard for many young men. Every case with no exception of the 4,000 we have studied
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has had similar intense family history. Next slide. I'm not gonna dwell on the usual family history. At present, we know from the dating of these histories that this patient here was the contaminating source for the whole crowd, but this has taken years of epidemiological sleuthing. I'm not going into it.
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Next slide. And here is what's happened, an exotic disease that few of us have had a chance to see and now we tell you it is almost gone before you've gotten to see it. It has disappeared progressively and the male and female patients have left us with only a few deaths. This was plotted prematurely.
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The final number in 77 actually was under 20 for the total. Next slide. This year it will be under 20. Next slide. But the most dramatic thing is that these are taken at three year intervals, leaving out the intervening year in case of epidemiological end of year prejudice.
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It doesn't make much difference. It's a matter of Christmas, New Year, European physicians doing less patrolling at that time. It shows that the zero to nine year old patients rapidly decreased, decreased, and then disappeared from the world.
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The adolescent, early adolescent patients rapidly decreased, but later, five years later, then disappeared. Finally, the older adolescent patients decreased and then disappeared. And now the 20 to 25 year olds are gone. Every year the youngest patient is somewhat older. The law that no patient who was born
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since Kuru cannibalism stopped in his village has ever died of the disease holds. It tells us a great deal more than that first remark might immediately reveal. It tells us that the suspected transplacental transmission, milk factor transmission, vertical transmission
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from mother to child born during the disease or born before the mother is ill is not occurring. Were it occurring, this incredibly uniform and if I projected to 78, still more uniform with this mostly gone and that gone, disappearance would be unaccountable.
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Next slide. We do not have any such knowledge for the familial cases of Creutzfeldt-Jakob in Germany and the rest of the world. If one doubts our ability to assess age of these now disappeared types of patients, prepubertal children of both sexes, here is a group on dimercaprol
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and calcium versinate therapy when we were looking for a Wilson's disease like copper or molybdenum toxicity and failed to find it. We had many false alarms in the beginning and all of them died of Kuru. There are no such patients in the last 10 years in the world. Next slide. The Kuru epidemiology was done mostly
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by the Robert Browning technique of the Pied Piper of Hamlet with assistance of here who are all married polygamous men today. Next slide. They rapidly, a group of some 30 of them provided, next slide, provided us with translation of all 11 languages into the one language we learned. The young men who were leaving the area
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had to be initiated into adult life at which stage of life, all still prepubertal, they have totally left the women's society never in their life even as polygamous adults to enter the house of a woman in traditional culture. All copulation and procreation was a daylight affair
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in the gardens where the privacy was greater than that obtained in the most remote Swiss Valley. And the phenomenon of sleeping with a wife is unknown to Highland New Guineans until missionaries introduce this strange custom to them. And the phenomenon of crawling in darkness
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for copulation under a roof is a phenomenon unheard of and rather repelling to them a subject of jest, not to be taken seriously. Anointed with pig grease and never washed, this would be human grease in a cannibal ceremony. Next slide. But only for the smaller children and never the males.
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At this age, people have left the women's culture, only the women opened the Kuru victims' bodies and contaminated themselves and children with them. Next slide. They celebrated their initiation into manhood. Those three young men incidentally are all college graduates in the United States today. Next slide.
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They are, I'm not exaggerating. Next slide. But this is the age at which all warfare took place. Most New Guinea Eastern Highland groups left that for the adolescent sex segregated culture while the old men, as in most cultures, planned the wars but didn't take part in them.
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Next slide. And this age produced the sex segregation which did produce this enormous difference in sex predominance of the disease. Next slide. Girls at a early pubertal age were married with pig omentum on their head. Next slide. And usually the young wife of a polygamous older man,
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older widows, went to the adolescent boys as their first wife. Next slide. And all cooking was done over steam cooking with no vessels in pits of heated rock a meter and a half under this pile of several hundred pounds of pig meat and vegetables.
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It's an autoclave. Essentially a volcano-like heap of earth is heaped on top of it. And there's very little enteric disease since it comes right out of steam cooking. However, the temperature attained would have been insufficient to inactivate the Kuru virus and human tissue was similarly handled. Next slide. On the other hand, with men handling pig tissue,
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this would have been women for human tissue and the children around would have been infected. We believe the all infection was through mucous membranes and skin, not orally. It takes multimillion lethal doses to infect with scrapie orally, only a millionth as much through skin or mucous membranes
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and with Kuru and Kreinzfeld it doesn't take orally. It is not eating the dead even though Claude Levi-Strauss would have it totem-wise symbolically that way. Next slide. Simply showing the children's involvement with the Mumu pit of steam cooking. Next slide. And finally, the disappearance from the world
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of childhood Kuru. 10 years later, the disappearance from the world of adolescent Kuru. Now the disappearance of young adult Kuru and hopefully within 20 years, the disappearance from the world of Kuru. How we will get rid of Creutzfeldt-Jakob disease is another matter. We can tell you that only a few percent
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of the cases in the world, five or six percent, are attributable to the atrogenic cause. In Zurich, the use of stereotactic electrodes contaminated from a Kreutzfeldt patient has produced two deaths years later in young people who were cured of their epilepsy by the surgery only to die from Kreutzfeldt-Jakob disease.
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Our form of neocannibalism, brain use in brain surgery of duramater from older patients and the use of corneal transplants from victims of Kreutzfeldt-Jakob disease has in fact caused the disease. Most major American and European clinics,
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if thoroughly studied and if they have good enough records, can detect the case caused by their neurosurgery. We do have a series of several dozen atrogenic cases. The complex medical legal aspects of the issue and the humane aspects of the panic produced by epidemiological questioning of those in danger
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has restricted reporting of many of them. On the other hand, we do already have the published accounts of a half dozen. One of the easiest ways, of course, to our utter horror of finding the virus is visiting a neuropsychiatric clinic where it would accumulate. And we are just now aware of this hazard
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and changing the sterilization methods necessary to prevent the atrogenic spread since conventional sterilization with alcohol, ethylene oxide, sterilizers, Zephyrin, and many of these usual hospital antiseptics don't work.
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Hospitals that smell like hospitals should in two, 30 years ago with Clorox, Permanganate, and iodine around, which none of us as young physicians want to take home to our families any longer on our clothes, did inactivate the agents. Phenol did, but the modern, most of the modern antiseptics don't.
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There has been warning in all the world literature, especially to pathologists. Neurosurgeons have died of the disease. Pathologists and dentists have. We do not know and have no way of knowing whether the number that has died is a significant increase above what would be expected
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because of course they are closer to the medical profession and this rarely made difficult diagnosis is really, even now, missed in major academic neurological clinics, as we are discovering in the worldwide epidemiology. I leave you then with a failure to have told you about the plural,
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the phenomenon that the Kuru focus is not the only intense focus of neurological or other chronic disease in primitive populations, which we have pursued and are, we are pursuing others, amyotrophic lateral sclerosis foci of 1,000 to 2,000 fold the intensity of any other civilized part of the world
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in West New Guinea populations and key peninsula of Japan and Guamanian Micronesian populations. Obviously, if we ever find the answer to amyotrophic lateral sclerosis in these small enclaves, which can be visited in a week, where this has become the first cause of death
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in adult life, are the place to find it. I thank you.