The Total War on Cancer: Starving the Beast ?

The Total War on Cancer: Starving the Beast ?

The story of modern cancer research begins, somewhat improbably, with the sea urchin. In the first decade of the 20th century, the German biologist Theodor Boveri discovered that if he fertilized sea-urchin eggs with two sperm rather than one, some of the cells would end up with the wrong number of chromosomes and fail to develop properly. It was the era before modern genetics, but Boveri was aware that cancer cells, like the deformed sea urchin cells, had abnormal chromosomes; whatever caused cancer, he surmised, had something to do with chromosomes.Today Boveri is celebrated for discovering the origins of cancer, but another German scientist, Otto Warburg, was studying sea-urchin eggs around the same time as Boveri. His research, too, was hailed as a major breakthrough in our understanding of cancer.

Discovery of the Warburg Effect

Unlike Boveri, Warburg wasn’t interested in the chromosomes of sea-urchin eggs. Rather, Warburg was focused on energy, specifically on how the eggs fueled their growth. By the time Warburg turned his attention from sea-urchin cells to the cells of a rat tumor, in 1923, he knew that sea-urchin eggs increased their oxygen consumption significantly as they grew, so he expected to see a similar need for extra oxygen in the rat tumor. Instead, the cancer cells fueled their growth by swallowing up enormous amounts of glucose (blood sugar) and breaking it down without oxygen. The result made no sense. Oxygen-fueled reactions are a much more efficient way of turning food into energy, and there was plenty of oxygen available for the cancer cells to use. But when Warburg tested additional tumors, including ones from humans, he saw the same effect every time. The cancer cells were ravenous for glucose.

Born in 1883 into the illustrious Warburg family, Otto Warburg was raised to be a science prodigy. His father, Emil, was one of Germany’s leading physicists, and many of the world’s greatest physicists and chemists, including Albert Einstein and Max Planck, were friends of the family. (When Warburg enlisted in the military during World War I, Einstein sent him a letter urging him to come home for the sake of science.) Those men had explained the mysteries of the universe with a handful of fundamental laws, and the young Warburg came to believe he could bring that same elegant simplicity and clarity to the workings of life. Long before his death, Warburg was considered perhaps the greatest biochemist of the 20th century, a man whose research was vital to our understanding not only of cancer but also of respiration and photosynthesis. In 1931 he won the Nobel Prize for his work on respiration, and he was considered for the award on two other occasions — each time for a different discovery. Records indicate that he would have won in 1944, had the Nazis not forbidden the acceptance of the Nobel by German citizens.

That Warburg was able to live in Germany and continue his research throughout World War II, despite having Jewish ancestry and most likely being gay, tells us how obsessed the Nazi leadership was with their „Total War“ on cancer. Hitler and Joseph Goebbels took the time to discuss new advances in cancer research in the hours leading up to the Nazi invasion of the Soviet Union. The key to success in Warburg's mind was to turn a tumor’s dependence upon a steady flow of nutrients against it. This might eventually prove to be its fatal weakness.

Otto_Heinrich_Warburg_%28cropped%29.jpg

Otto Warburg (1931)


A Potential Cure

Galega officinalis (French lilac) a plant used in folk medicine for several centuries was the source for the first of the so called biguanide class of antidiabetic drugs. Metformin was first described in the scientific literature in 1922, by Emil Werner and James Bell, as a product in the synthesis of N,N-dimethylguanidine. In 1929, the German researcher Slotta and Tschesche published their article „Die Blutzuckersenkende Wirkung der Biguanides/ The sugar-lowering action of biguanide (in rabbits)”. These early research results caught the attention of Warburg, who saw Metformin as a potential "Glucophage" (glucose eater) and most important as a tool to starve cancer tumors, or at least prevent the glucose overconsumption by (potential) tumor cells slowing their growth.

The challenge Warburg faced then is the same one that metabolism researchers face today. Cancer is an incredibly persistent foe. Blocking one metabolic pathway has been shown to slow down and even stop tumor growth in some cases, but unfortunately tumors tend to find another way. If glucose gets blocked, they tumors switch to glutamine etc. Still, while Warburg's approach didn't offer the magic bullet against cancer he found a promising treatment and added another weapon to the medical arsenal.

Notes and Sources

This is basically just a modified version of the New York Time article below.

Sam Applemayan (2016): "Old Idea, Revived: Starve Cancer to Death"

The POD in on itself would probably not have changed much on its own but in my opinion is worth at least a short throwaway timeline.

Werner E, Bell J. The preparation of methylguanidine, and of ββ-dimethylguanidine by the interaction of dicyanodiamide, and methylammonium and dimethylammonium chlorides respectively. J Chem Soc, Transactions. 1921;121:1790–5

See Chemical Abstracts, v.23, 42772 (1929) K. H. Slotta, R. Tschesche. Uber Biguanide. II. Die Blutzuckersenkende Wirkung der Biguanides. Berichte der Deutschen Chemischen Gesellschaft B: Abhandlungen
 

As far as I understand it is vaguely related. Both drugs are used to “starve” the tumor. But the stuff Warburg discovers here is fairly harmless and is used to avoid the growth of cancer cells rather than destroy already advanced tumors.
 
How the Swiss Saved Our Balls (Literally)

Many American are rather fond of claiming that they “saved someones balls”. However if one person has or had any right to do so it was the Swiss professor William Silberschmidt. The least likely person ever actually doing so.

Silberschmidts was born 17. Januar 1869 in La Chaux-de-Fonds, where his father, a German immigrant had founded the first local clock factory. Silberschmidt graduated 1887 the Matura at the Pruntrut Gymansium. He studied medicine at the Universities of Bern and Munich. In 1892 he finished his Staatsexamen and finished his dissertation under Ernst Tavel. What followed was a short visit to the Pasteur Institute in Paris, followed by becoming an assistent to professor Oskar Wyss, at the Center for Hygiene of the Zürich university.

The day that would change everything was a lecture by Alfred Werner who for the first time explained the structural nature of cisplatin. It was first synthesized by Michel Peyrone in 1845, and henceforth became known as Peyrone's chloride/salt.


Cisplatin_and_transplatin.gif

As can be seen in the picture above. Both molecule have the same components, only their structural orientation is different.

Now this was certainly an interesting achievement but what made this discovery intriguing to Silberschmidt was another discovery made by his other fellow Swiss researcher Karl Wilhelm von Nägeli, the oligodynamic effect. A word composed of the Greek oligos "few", and dynamis "force". It is the biocidal effect of metals, especially heavy metals. Ever since microorganism have been identified as the source of disease interest in antimicrobial substances had grown.

Silberschmidt was curious if there was a potential difference in the destructive potential of trans and cis complex. With the permission of Wyss he began to study the effects of metal complex on E.coli. His intuition turned out right. Cis-[PtCl4(NH3)2] didn't kill or inhibit the bacterial cell growth but the cell division was arrested. The bacteria were growing as filaments up to 300 times their normal length. In transplatin, the trans stereoisomer of cisplatin, trans-[PtCl2(NH3)2] did not exhibit th same effect.

However the odd, unexpected elongation effect became know the center of his research. He began a series of animal experiments treating infected rats with cisplatin most of them less than encouraging. Since it was somewhat known that cancer was caused by some type of rogue cells, although the exact details were still debated, he also tested cisplatin on cancerous rats with remarkable, almost miraculous success.

The devil lays in the detail unfortunately. While cisplatin is still among the most powerful anti-cancer agents even today, it has some rather unpleasant side effects. Horrific nausea, potential hearing loss, etc. Nevertheless suddenly there was hope, especially for your balls. (1)

Notes and Sources

(1) Cisplatin is most effective against testicular cancer.It was was approved for use in testicular and ovarian cancers by the U.S. Food and Drug Administration on 19 December 1978 and is used to this day.

What I find especially nice is how this POD flows so naturally, it could almost have been OTL. And for anybody wondering, this little story is only loosely connected to the first. I just didn't want to open another thread for a mini timeline on cancer. Just for comparision

wikipedia: Silberschmidt, cisplatin etc.

Nägeli, Karl Wilhelm (1893), "Über oligodynamische Erscheinungen in lebenden Zellen", Neue Denkschriften der allgemeinen Schweizerischen Gesellschaft für die gesamte Naturwissenschaft, XXXIII

Alfred Werner: Beitrag zur Konstitution anorganischer Verbindungen. In: Zeitschrift für anorganische Chemie. 3, 1893, S. 267–330
 
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