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How Nanopathology Was Born

At the beginning of the nineties a surgeon gave us a vena cava filter he had removed from a patient. He had done so because, for reasons he did not know but which he was curious about, that metal device had failed and had broken inside his patient's inferior vena cava.

Nowadays, in similar circumstances, nobody would cut open a subject to remove a broken filter. That particular surgery is quite challenging, and the advantage obtained, if any, is minimal indeed since that device, even if in conditions which are certainly not ideal and because of that being unable to work properly, does not cause inconveniences, at least in general. But, regardless of any consideration which does not belong to us, we got that filter along with the question 'Why did it break?'

The answer was quite easy: it had broken because it had slid caudally, and one of its six prongs had entered one of the renal veins, getting stuck there. The movement counterstream but in favour of gravity towards the iliac junction with a prong which, blocked as it was, could not follow the rest of the device, and the continuous, repeated deformations of the filter brought about by respiration and, especially, by Valsalva maneuvers had eventually caused the failure. Nothing particularly interesting: only the technical observation that the filter had been placed too cranially.

Advances in Nanopathology: From Vaccines to Food

Antonietta Morena Gatti and Stefano Montanari

Copyright © 2021 Jenny Stanford Publishing Pte. Ltd.

ISBN 978-981-4877-29-9 (Hardcover), 978-1-003-05622-5 (eBook) w w w. j e n ny sta nf o rd. co m

What was interesting and, indeed, baffling was something which had nothing to do with the original question, that is, what we found on the surface of the device and, more in particular, at the fracture point. Looking there through an electron microscope and with the aid of an instrument called energy-dispersive spectrometer (EDS), we found chemical elements which did not belong either to the filter or to the human body. Why they were there was a question we had no answer to, and somewhat sadly, it was something which did not interest the doctors we consulted.

Some months after, we faced the same problem but, in that circumstance, with a different brand of filter, made of a different metal alloy: AISI 316 L stainless steel in the former case, and Phynox, a cobalt-chromium-nickel-based alloy, in the latter. Also in that circumstance, we got the same qualitative result: chemical elements different from what we found in the first device but, again, definitely foreign both to the filter and the human body. Same question, same answer: we did not know where they could come from, and the problem, puzzling to us, did not seem to interest anybody. So, in both cases, our questions about the drugs those patients were taking because of their health conditions were greeted with some annoyance. Evidently, what can't find an immediate, credible enough or anyhow accepted explanation is removed from the brain and wondering about it is considered a waste of time.

We kept thinking that something foreign to the organism like those elements could somehow enter the blood circulation, and medicaments were the agent we suspected most, but without any evidence.

It was only at the end of 1997 that we found the answer.

After an unsuccessful tour through many hospitals, a patient had come to the University Hospital of Modena (Italy), lamenting a collection of troubles: fever for more than eight years, lachrymation from one eye, pain at the ipsilateral ear and, what was more important, liver and kidneys in a very poor condition, so that turning to a chronic hemodialysis treatment seemed inevitable.

A biopsy was taken of the liver and of the kidney, and the diagnosis issued by the histopathologist was ‘cryptogenic granulomatosis of both organs’. A granulomatosis is a particular inflammatory condition of a tissue. Cryptogenic is a learned word whose meaning is nothing more than ‘I do not understand why'.

The cases have already been described in a few publications, and it is not worth repeating a more accurate description than the one which can be found in our books Nanopathology: The Health Impact of Nanoparticles (Pan Stanford Publishing, now Jenny Stanford Publishing) and Case Studies in Nanotoxicology and Particle Toxicology (Elsevier Academic Press). We will limit ourselves to report that we analysed the biopsic samples of the liver and the kidney with an electron microscope equipped with an EDS and found micro- and nanoparticles made of ceramic embedded in the tissues. Those particles had behaved for what they were - foreign bodies - and, as such, had attracted macrophages which released cytokines, and an inflammatory reaction had started - hence the formation of granulomatous tissue which had caused the fever and the malfunction of the kidneys and the liver.

The origin of the ceramic particles was found in the two dental bridges the patient carried. They were badly made, and the subject, feeling uncomfortable with them, became a bruxer, thus wearing out the ceramic the prostheses were made of. To make matters worse, the dentist filed the prostheses. The small fragments had been ingested and, reasonably travelling through the circulatory system, had reached the two organs.

The solution to lachrymation and pain in the ear was easily found in replacing the two dental bridges with as many well-made ones, while fever and problems with the kidneys and the liver were palliated by administering a cortisone-based therapy, a therapeutic strategy which saved the patient from haemodialysis. It may be interesting to add that, as soon as the patient interrupted the anti-inflammatory treatment, the symptoms of the organs involved reappeared. The reason is easily explained: the micro- and nanofragments were not biodegradable, and were still there as an inflammation inducer.

Starting from the basis of that case, though with great difficulty, we started to investigate the biopsic samples of cryptogenic granulomatosis stored in hospital archives, and we noticed that in all cases, that is, when the pathology was not due to bacteria, parasites, etc., and its origin could not be found, the cause was the presence of non-degradable micro- and nanometric foreign bodies.

That successfully solved case gave us also the answer to our question about the puzzling chemical elements we had detected on the two vena cava filters we had investigated. For some reason, the subjects involved had ingested (or, as we later discovered, possibly inhaled) micro- and nanoparticles which were carried by the blood and some of them had deposited on the surface of the device they carried.

After a few very difficult years, we got a grant from the European Commission which allowed us to carry out our research (nanopathology) in a more efficient way. Then, after that first project was concluded, another European grant enabled us to get further, very important results. The project called DIPNA (FP6-NMP-STRP 032131) about nanotoxicology made us understand what the basic mechanisms of toxicity are of nanoparticles, be they engineered or accidentally produced.

What Is Nanopathology?

Nowadays it may sound unbelievable, but it was only at the end of the 19th century that the so-called miasmatic theory was abandoned by medicine. According to that universally accepted line of thinking supported, among others, by an authority as was Galen, infectious diseases, and not only those, were due to a sort of‘bad air’ or miasma, a Greek word (jufaopa) meaning pollution. The firm belief was that particularly during the night, the soil, urban ghettoes, rotting vegetation and foul water give off noxious organic matter, causing what then were called zymotic diseases, those we now call infectious. Of course, there was a huge number of‘demonstrations’ to back the assumption. An academic school of thought of the 1800s, somewhat extending the limits of the theory, even maintained that one could become obese just by smelling food.

That century-old theory, supported by all top ‘scientists', was finally replaced, but only after having defeated a very strong resistance, by germ theory: infectious diseases are caused by microorganisms. It was Gerolamo Fracastoro in the mid-16th century who first intuited the phenomenon, but it was only the works of Louis Pasteur and Robert Koch which provided the irrefutable evidence with research begun in the 1850s and finally accepted, not always willingly, in the 1880s. Just to get an idea of what the scientific approach used to be, the great Rudolf Virchow (died in 1902) ridiculed Pasteur and boasted that he had never brought his eye near a microscope. One of its strong points to demonstrate how wrong Pasteur was, was, 'If microbes were responsible for illnesses, ubiquitous as they are, we were all ill.’ An argument which shows an insufficient knowledge of how biology works but an argument which resurfaces again about the pathologies induced by particles.

There is no doubt: the discoveries of Pasteur and Koch gave a fundamental turning to medicine, allowing a much more correct and efficient approach to the understanding and diagnosis of many pathologies and, as a consequence, what is even more important, to the implementation of much more effective therapies.

But what they did and the impulse to research which they gave, though still lasting, is not enough. Pathologies are not only the infectious ones, and nowadays we witness the dramatic increase of diseases which once were rare when not unknown or non-existent at all. As a matter of fact, the so-called orphan diseases, pathologies about which we know very little and to which there are no therapies available, can be counted in several thousands. In addition, for a non-negligible number of known diseases the real cause is partially unknown, utterly ignored or, maybe and with even worse consequences, misunderstood. Unfortunately, not unlike what happened with the criticisms on miasmatic theory and many other medical beliefs, there are discoveries which, though supported by indisputable evidence, are not welcome. To this grudging reception many explanations can be put forward, from mental laziness to fear of the new, from presumption to vested interest.

We humans are an integral and inseparable part of the environment like all other animals, vegetables and any living being, and like them, we suffer the interference which we receive from what surrounds us. And dust is one interference along with heat and cold, radiations, electric and magnetic fields, humidity, noise, etc.

Human beings have always lived with dust. Volcanoes eruptions, the sand raised by the wind, rock erosion and occasional fires are all sources of natural dust. In all cases, that dust is harmful, since it can be inhaled as it floats in the atmosphere, or can be ingested when it falls on fruit, vegetables, cereals, etc., and our organism does not accept it willingly. But, for that matter, nature has a number of mechanisms to kill any creature which inhabits the planet in order to make place to new lives, and dust is one of her means. Nature has produced solid particles for billions of years, and, to that production, starting about half a million years ago, though with great geographic differences, man has started to add his own.

Every combustion generates dust, and when man discovered how to turn on the fire, a novel type of pollution appeared on the earth. Many centuries after, man learned how to use that fire, how to cook food, how to fabricate artifacts, so something unknown to nature was introduced into the environment: waste.

Nature does not have the concept of waste. What a living being discards is used as a rule by other beings for their lives. The simplest example of that is the carbon cycle, that is, the substance turnover by which carbon is exchanged among the biosphere, the soil, the water and the atmosphere of the earth. That can be easily illustrated by the physiology of the Viridiplantae, that is, the green plants which get most of their energy from sunlight through photosynthesis, using water and carbon dioxide. What that complicated chemical process discards is oxygen, a gas essential to the life of many animals, man included. But what those animals discard is carbon dioxide, thus restarting the cycle. Along with the nitrogen cycle and the water cycle, the carbon cycle comprises a sequence of natural events, incidentally not reproducible by man's technology, which are what makes our planet capable of sustaining life. In short, nature works in a circular way.

Man is the only being living in a linear way, which simply means living against nature’s rules. As by-products of many of our activities, we introduce into the planet something which nature does not recognise and has no means to utilise. If, at the beginning of our technical progress, our technological processes were very simple and we were, after all, rare animals, now the human population has grown to exceed seven billion and, what is more critical, our technology has become extremely sophisticated, in addition to being, unfortunately, too often out of control, at least as far as its final consequences is concerned.

As it has already been mentioned, all high-temperature operations produce particles and, as a rule of thumb, those particles are the smaller, which means the more capable of creeping into the body, the higher the temperature at which they are produced. If up to not many years ago it was technically difficult and expensive to reach high temperatures, nowadays the task has become not only easy but cheap, with all the positive consequences on the possibility to make newer and cheaper products and the negative ones on the environment. So, the environment is being invaded by a growing quantity of unnatural, smaller and smaller particles, and it is those particles which are mainly responsible for the long list of diseases we, back in the late nineties, called nanopathologies.

Like it or not, these illnesses are growing more and more common and, furthermore, pathologies once unknown or, even more often, sets of diseases which apparently have nothing to do with each other are beginning to become usual.

They will be discussed in more detail later in this book, but as an anticipation, it comes to some cardiovascular diseases, cancers, neuroendocrine diseases, behaviour abnormalities, miscarriages, foetal malformations, reproduction disorders, etc.

For many years, medicine has been using histological observations performed through optical microscopy. For reasons related to the wavelength of visible light, with this system it is in fact impossible to exceed 1500 magnifications. Much more recently, molecular biology has become part of medical research. With this approach, what happens at the molecular level is evaluated without, however, having a vision of it but only getting an analytical knowledge. A very wide dimensional gap (3 to 4 orders of magnitude) opens up between the two approaches, and in that dimensional range matter behaves in a different way from that of the atom or molecule and from what exists within the dimensions visible under an optical microscope. That is precisely the gap which is filled by the electron microscopy technique which we use and which we propose.

Appendix: Deep Vein Thrombosis and Caval Filtration

In a sense, it is thanks to our interest in caval filters, deep vein thrombosis and pulmonary thrombo-embolism that nanopathology was born.

Three broad categories of factors contribute to the formation of thrombi, that is, blood clots inside a vein or an artery: hypercoagulability, an impediment to the blood flow or an excessively turbulent flow and an endothelial injury. Though Rudolf Virchow, the already mentioned German scientist of the nineteenth century, never suggested those three factors as responsible for thrombosis but saw them as a consequence of that pathology, they are grouped together under the name of Virchow's Triad. We will see later in this book that there is a fourth origin of blood clots, and that is the presence of micro- and nanoparticles in the blood. In that case, a nanopathology.

The formation of thrombi is a rather common occurrence in the venous system, but the majority of people have the physiological ability to dissolve them very quickly thanks to four enzyme pathways whose function is to reduce thrombin (a serine protease) production and/or its activity. Plasmin is the major enzyme of the fibrinolytic system, and its function is that of dissolving already formed clots by degrading fibrin.

In a minority of people or under certain circumstances like, among many others, bone fractures, long-lasting immobility in bed, major surgery, pregnancy, overweight, cancer, tobacco smoking and the use of some contraceptive drugs, there is a risk of the formation of thrombi, particularly in the veins of the lower limbs and the pelvis. That pathology is called deep-vein thrombosis. In general, a venous thrombus starts forming at the inner wall of the vessel (tunica intima) and grows in the direction of the heart. In some circumstances, the vein is occluded by the growing thrombus, while in others the thrombus breaks off, is carried by the bloodstream, crosses the right heart and reaches the pulmonary circulation. The phenomenon is called pulmonary thrombo-embolism. Since the pulmonary vessels containing venous blood (inside the lungs, they are called arteries) grow smaller and smaller in diameter, while proceeding towards the alveoli, when the thrombus arrives where the lumen is smaller than its size and is wedged there, the vessel is inevitably occluded. If the thrombus is big enough to stop the flow in a large vessel, the condition is a life-threatening one.

Anticoagulant and fibrinolytic drugs working with various mechanisms are normally used in those circumstances to try and dissolve the thrombus. When there is a danger of recurrence of thrombo-embolism, the usual prescription is that of a chronic, often life-long, therapy generally based on drugs antagonising vitamin KI recycling, drugs initially used as pesticides against rats and mice which, ingesting them, died of internal bleeding.

The dosage of those drugs is not easy because the body’s reaction to them changes rather quickly even with the ingestion of some food and the dosage needs to be frequently adjusted. There are cases where those drugs are contraindicated, often due to the risk of haemorrhage, particularly in people living an active life and, therefore, with the possibility to incur a road accident or other traumas. Although used in a minority of cases, the safest means to prevent a thrombo-embolism, then, is implanting inside the inferior vena cava, at the level of the renal veins, a filter, for some years also available in removable versions.

The models are rather numerous, and their look is quite varied, but the most common is that of six thin metal stems joined at the top of a conical shape like the framework of a tepee. Each stem has a distal hook with which the device is secured at the vein's wall.

The clot which is carried by the bloodstream towards the right heart travels along the central axis of the vessel where the speed is higher, is captured by the apex of the filter where the prongs leave the narrowest passage, is lapped by the bloodstream and more or less quickly dissolves.

There are cases in which caval filtration is ineffective, since there is no actual thrombus focus, downstream of which a filter could be reasonably placed. Patients suffering from the so-called Trousseau's syndrome, that is, the formation of thrombi in case of cancer or endocarditis where no consistent and identifiable origin exists, will not gain any benefit from the filter. What is interesting for our discussion is the so-called migratory venous thrombosis, also a condition belonging to that syndrome and the subject of uncertain explanations. We will see later in this book how, at least in certain circumstances, it can be explained.

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