by Andrey N. LUCHNIK, Dr. Sc. (Biol.), Russian Academy of Sciences, Koltsov Institute of Developmental Biology
Perhaps, one of the most demonical pests of our time is cancer. For there is no person on Earth who would not fear it. Scientists have long been expected to produce a miracle. They have been trying their best to meet these expectations. Hundreds of oncogenes have been discovered as well as factors influencing tumor growth and the reasons of tumor origins. But the more information we got, the less hope remained that we found universal remedy from this terrible disease.
THE SYNDROME OF THE UNHEALING WOUND
Toward the end of the 20th century the experts came to the conclusion that the one common cause of malignant growth of cells does not exist. Rather these are different diseases having in common only the term "cancer". However, during the course of our investigations we came to conclusion that the all types of tumors can be designated by one word, because the mechanism of their growth is absolutely identical. Moreover, this mechanism seems to be as simple as bike. And since we understand its mechanism, we can learn how to break it. Say, by putting spikes in its wheels...
The mechanism promoting the growth of a tumor can be described as "the syndrome of the unhealing wound". The thing is that there are two types of cell death. One- predictable, or programmed-it is termed "apoptosis". Due to this mechanism our body destroys every day a part of "worn-out" cells, promoting the growth of others and thus keeping things in proper order. For example, about seven tons (!) of blood cells are destroyed during the lifetime of a person and are replaced with new ones.
Another type of cell death is unplanned or spontaneous-it is termed "necrosis". This type of cell death is unpredictable. Say, you have cut your finger with a knife. A minute before it your body did not expect anything. But then, a mass of cells dies at the site of lesion, because of mechanical injury.
What makes the organism to decide that a wound has to be healed? The reason is the appearance of necrotic cells which signal about their sudden death. This triggers the complex process of wound healing, beginning with blood coagulation, and blood cell aggregation (thrombocytes, granulocytes and macro-phages). Many of these contain the very important "signal" molecules-cytokins, including growth factors. The latter stimulate the division of cells, filling up the wound. The wound healing proceeds until new cells fill in the lesion and form a scar. By that time the primary SOS signal ends and cell division ceases.
But if one cuts his finger once again, the process of healing starts again. And so on and forth ad infinity. This occurs not only on a skin, but also inside the body. If, for example, a surgeon removed the part of the stomach affected with ulcer and sewed up its walls, a scar, or cicatrix, will be formed there-the organism fills the lesion with new cells. That means that lesions, or wounds, are healed in any part of the body and the evolution took care for this mechanism to be flawless and invulnerable. Because otherwise not only humans, but animals who suffer injuries more often, would have become extinct a long time ago.
Let us come back to the cancer cells. Bypassing the question of what produces a tumor (the causes are many and they deserve special consideration), let us ask-what makes a tumor grow? The causes of that are following.
By the end of the 20th century scientists came to the conclusion that all the malignant cells, irrespective of the type of tumor, share the one common feature-increased fragility of chromosomes. That means that in every cell division some 5 - 15 percent of cancer
Articles in this rubric reflect the opinion of the author. - Ed.
Cell dying of necrosis sends out many signals to its "neighbors".
cells undergo necrosis due to accidental chromosome breakage. Being aware of that the organism triggers the mechanism of healing of the wound and ... stimulates the division of the tumor cells. Tumor is being bored through with new blood vessels so that the oxygen and nutrients were supplied constantly to enable cells to divide. And every next division again produces 5 - 15 percent of the necrotic cells. The sudden death of the latter gives a new signal to the wound healing which stimulates cell multiplication again. This is like dragon in the Russian tale-you cut off its head and the two appear in its place. The same is with cells in a tumor: dead cells stimulate the growth of two, three, four others-they "shout" of their demise and "order" others to divide. And the process continues endlessly, or rather until the tumor and the metastases become too big for the organism to cope with them and so eventually it dies.
METAPHASE (MITOTIC) DEATH
Why do the necrotic cells appear in a tumor? It is known that they appear only in the process of mitosis (division with duplication of chromosomes).
Let us remember that every chromosome has a centromere-narrowing looking like "waist". In the course of mitosis two identical chromosomes (chromatids) move away towards the poles of the cell (centrioles), they are pulled off with special threads holding the centromere (waist), after that a partition is formed between the poles. Then the new cells separate from each other, each of them possess the identical set of chromosomes. But if any chromosome breaks in a dividing cell, the fragment of it devoid of waist can accidentally get into one of the daughter cells where that piece of the chromosome is already present. This "fragment" contains as many as several hundred genes! As a result there is overabundance of them in one cell and a deficit in another-a genetic imbalance usually leads to necrotic destruction of both cells. This type of death is called metaphase, or mitotic. Incidentally, this is the way by which cells (except lymphoid ones) perish after exposure to X-rays or treatment with chemical mutagenes, which break chromosomes.
DUBBING OF INFORMATION
A question arises: why all cancer cells possess an enhanced fragility of chromosomes unlike the non-cancer ones? What is the mechanism of this fragility, and why it is inherited in cancer cells?
According to our experiments, every chromosome of man, animal or plant contains not only one DNA double helix (discovered in 1953 by F. Crick and J. Watson and awarded by Nobel prize in 1962) but the two absolutely identical twin spirals (double helices), this means that all of the data within them are dubbed at a higher level.
What is the need to double information? Imagine: when two strands of a double helix are broken in one loop, a "twin-loop" or the "second original" (depicted as solid continuous line) comes to the assistance. Rapid contact is ensured by the attachment of these identical loops to one spot at the chromosome axis-DNA double-strand break is rapidly liquidated, and so does not cause the chromosome breakage.
Scheme depicting the growth of the clone of malignant cells. Black circles- cells dying from spontaneous lethal breaks of chromosomes.
Thanks to the second copy of DNA the reliability of the genetic apparatus is increased by about billion times. Why not two times? Every human cell contains about 1.5 m DNA, which means 75 cm of identical double helix. If some thousand DNA double strand breaks arise in the DNA, the probability of their coincidence at two homologous double helices is practically zero, because the spiral is very long, i.e. contains billions of nucleotides. That is why the reliability is increased not by two, but by billions of times. Thus the cells need no third copy of DNA since it almost does not change the security situation in any way.
It is known that every day dozens of DNA double strand breaks occur in our cells spontaneously, or due to harmful factors from food, atmosphere or due to natural radiation backgrounds. Had there been no second copy, or second original, our cells would die necrotically due to chromosome breaking leading to frequent appearance of malignant cells, then the man could hardly be viable.
Sections of DNA without copies often occur in cancer cells. And if within this unitary loop occurs a DNA double strand break (duplex break) it cannot be repaired: DNA breaks at this spot and the chromosome also breaks. As a matter of fact, this fragility is of no concern until the stage of division: then the pieces of chromosome, devoid of centromeres get into the wrong places, cause disbalance of the genetic material and the necrotic death of daughter cells. This triggers the mechanism of wound healing.
It should be pointed out that the stretches of DNA without copies are quite common in malignant cells. And this is often revealed in several chromosomes at once, and in rare cases even in the whole genome like in some leucoses where the rate of spontaneous chromosome breaks is higher than the average - in such cases the disease takes a more aggressive form. But not always: if more than 50 percent of cells in each generation die from chromosome rupture, such tumor cannot grow, but "consumes" itself and dies off. And the opposite is also true: when DNA double strand breaks are rare, a tumor will not grow because of the lack of wound-healing signals.
That means that in order to do away with cancer it is necessary to either reduce the number of necrotic cells, or increase this number considerably. The growth of tumor will stop in both cases.
Incidentally, this provides the basis for the currently accepted treatment methods, such as irradiation or chemotherapy. Millions and trillions of malignant cells die after the administration of successfully chosen mutagenic chemicals. The tumor and metastases shrink in size and the hope arises that they disappear completely. But with all of the advantages of the above methods they have a serious flaw. The thing is that while killing rather effectively the malignant cells, the above means, being mutagens, and also being very toxic, damage healthy cells. For example, local X-ray irradiation in a dose many times greater than the lethal causes brittleness of blood and lymphatic vessels damages neighbouring organs and tissues. Chemotherapy can damage the immune, endocrine and other systems. At the fourth stage of a cancer the patient often perishes not from the illness, but from the consequences of its treatment.
Today, however, alternative and safer therapies appear. They are directly connected with the described model of tumor growth. And so far we see the two approaches.
The first-treatment with pseudomutagenes. This class of chemical substances was discovered in 1980s by my father, professor of genetics N. Luchnik. Unlike traditional mutagenes, they do not break DNA either in healthy or in cancer cells, they break up chromosomes in whose DNA a second copy is partially absent. In other words, without affecting the healthy ones, pseudomutagenes wipe out the cells with fragile chromosomes-those promoting tumor growth.
Some time ago my father described the system of identification and testing of such agents (one of them-fluorouracil-has already been used in oncology for a long time for treatment of certain kinds of cancer). But it was only recently, ten years after my father's death, that this work was published by his pupils. It is hopeful that this method will help to achieve successful treatment, doing no harm to the patient, unlike currently used mutagenes.
There is also another approach that we are now trying to apply. It consists in
Drawing of a bineme chromosome (a) and its changes in a malignant cell (b). Solid line represents DNA double helix. The points of attachment of DNA to the chromosome axis or skeleton are shown as bipartite plates. Second DNA strand (duplex) serves as a matrix for the repair of DNA double strand breaks. At the single DNA-duplex section (b) DNA double strand breaks are not healed and lead to chromosome breaks visible under the microscope.
"switching" cell death from the necrotic to the apoptosic mode (programmed death). In this case the organism itself decides which cell is to be destroyed. After that it harmlessly dismantles it and the remaining proteins, fats, carbohydrates and nucleic acids are used as "building bricks" for normal vital functions. Eventually the replacement of the mechanism of wound healing for the apoptosis should lead to the disappearance of a malignant tumor.
Three years ago the scientists of our Institute, working together with colleagues from other centers of the Russian Academy of Sciences, discovered very effective natural source of remedy - it is generated by a marine organism. Our experiments established that these organisms produce a specific secretion. It translates the death of cells from the necrotic to the apoptotic mode and thus heals tumors and wounds of marine organisms upon which it parasitizes. The slices we watched under the microscope showed that such tumors were "dismantled" stage by stage under the effect of this secretion. And it is interesting that rumors are affected not directly, but through the changes of signals from the central nervous system of a sick animal.
Testing this preparation on volunteers, we obtained very encouraging results. Its approbation even at the fourth stage of cancer and even after the traditional therapy often caused changes for the better, even complete tumor disappearance.
But still and all, there is no room for excessive optimism - i.e. that a panacea from cancer has already been found. First, not enough statistics has yet been accumulated. Second, the preparation was tried on volunteers often at the terminal stage of the disease which is more difficult to cure. We have been working in conjunction with their doctors in order to obtain maximum data and avoid unexpected interaction of the preparation with other medicines. That is why one should remember: if the system of apoptosis, triggered by our preparation, comes into collision with chemotherapy, used by the doctor in charge, this can seriously complicate the whole picture.
It should also be added that biological resources of the organism whose secretions we use, without damaging its colonies, are very limited. That means that now it is necessary to establish the primary structure of oligopeptides, and mucopolysacchurides contained in the secretions in order to try to synthesize them by means of genetic engineering at pharmaceutical plants and get sufficient amounts of the medicine which could save many lives.
At the last. After the very first successful results of application of our preparation on cancer patients we have been given more food for thinking about the detailed mechanisms of recovery. It turns out that cancer has much in common with systemic disorders that depend on the state of the central nervous system. One of the risk factors related to the arising of malignancies are nervous depressions or permanent stresses. So it is not by accident that the preparation proved to contain some very active neuropeptides, which eliminate stresses and depression.
Encouraging results have been obtained with treatment of scattered sclerosis, psoriasis, chorea, neurodermitis, exzemas, benign tumors, lung emphysema, varicosis, vascular dystonia, autoimmune disorders, rheumatism and certain cardio-vascular pathologies, etc.
Studies of the effect of the aforesaid peptides upon systemic disorders should give us a better understanding of the mechanisms of their origin and, probably, broaden the list of disorders, which directly depend on the status of the subcortical structures of the central nervous system.
Illustrations supplied by the author