Preprint Review Version 3 Preserved in Portico This version is not peer-reviewed

Biochemistry, Not Oncogenes, may Demystify and Defeat Cancer

Version 1 : Received: 19 April 2021 / Approved: 22 April 2021 / Online: 22 April 2021 (09:37:10 CEST)
Version 2 : Received: 4 July 2021 / Approved: 6 July 2021 / Online: 6 July 2021 (11:32:47 CEST)
Version 3 : Received: 27 December 2021 / Approved: 28 December 2021 / Online: 28 December 2021 (10:53:54 CET)

A peer-reviewed article of this Preprint also exists.

Kulsh, J. Biochemistry—Not Oncogenes—May Demystify and Defeat Cancer. Oncology and Therapy 2023, doi:10.1007/s40487-023-00221-y. Kulsh, J. Biochemistry—Not Oncogenes—May Demystify and Defeat Cancer. Oncology and Therapy 2023, doi:10.1007/s40487-023-00221-y.


The presence of mutated genes strongly correlates with the incidence of cancer. Decades of research, however, has not yielded any specific causative gene or set of genes for the vast majority of cancers. The Cancer Genome Atlas program was supposed to provide clarity but it only gave much more data without any accompanying insight into how the disease begins and progresses. It may be time to notice that epidemiological studies consistently show that the environment, not genes, has the principal role in causing cancer. Since carcinogenic chemicals in our food, drink, air and water are the primary culprits, we need to look at the biochemistry of cancer, with a focus on enzymes which invariably facilitate transformations in a cell. In particular, attention should be paid to the rate-limiting enzyme in DNA synthesis, ribonucleotide reductase (RnR) whose activity is tightly linked to tumor growth. Besides circumstantial evidence that cancer is induced at this enzyme’s vulnerable free-radical-containing active-site by various carcinogens, its role in initiating retinoblastoma and HPV-related cervical cancers is well documented. Blocking the activity of malignant RnR is a certain way to arrest cancer.


carcinogenesis; cancer treatment; cervical cancer; DNA synthesis; free-radical; retinoblastoma; ribonucleotide reductase; somatic mutation theory (SMT)


Medicine and Pharmacology, Oncology and Oncogenics

Comments (1)

Comment 1
Received: 28 December 2021
Commenter: Jay Kulsh
Commenter's Conflict of Interests: Author
Comment: This is 2nd and probably the last revision of the article:
- The first section now has the word “Introduction” in its title, with a small extra paragraph – and a new section “Conclusions” has been added at the end.
- “2.3.1 The Cancer Genome Atlas (TCGA) program” section has been shifted down, but at a higher level, so it is now numbered 2.5.
- A sub-sub-section “4.1.1 Re-evaluating chemical structure of a compound for carcinogenicity” has been added.
- “5. Disabling ribonucleotide reductase will defeat cancer” section has been expanded with a specific example.
- A figure has been added in section 4.
- About twenty references have been added, because of above expansions, and to buttress the assertions in the article.
- English has been checked/corrected by a professional company.
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Comment 2
Received: 25 January 2022
Commenter: Mark Lintern
The commenter has declared there is no conflict of interests.
Comment: Hi Jay,

I loved your article and agree that cancer is not driven by DNA mutations. Ribonucleotide Reductase appears to be a prime target due to it being the rate-limiting enzyme for DNA synthesis, and because the trigger for tumour growth appears to be located within the cytosol.

You provide four factors capable of supporting an RnR-based model of carcinogenesis triggering upregulation of RnR. Chemicals, Asbestos and radiation, HPV-related cervical cancers, Retinoblastoma. This hypothesis seems entirely plausible and RnR upregulation is clearly involved. But I wonder, and I know you've dismissed the metabolic theory, is RnR upregulated because of the Warburg effect? Is a switch to glycolysis (or suppressed mitochondrial function) the reason for RnR upregulation? And is explaining the Warburg effect (hallmark 7) the key to identifying the underlying cause?

I know the metabolic theory fails to offer an explanation for the Warburg effect, highlighting that the energy system itself isn't responsible, although this energy system is still operating in an abnormal manner and this does need to be explained. Would you be claiming that RnR stimulation via carcinogens causes the Warburg effect?

Interestingly, there are some specific micro-organisms that can instigate the Warburg effect, in fact, the Warburg effect is a result of trained immunity.

Therefore, could it be possible that RnR upregulation is a direct result of micro-organism infection that coincides with trained immunity and the switch to glycolysis that occurs? Which would explain both hallmark 7 and RnR upregulation.

You use asbestos as an example, however, there is another interpretation - asbestos and the chronic inflammation it causes leads to iron overload, which in turn feeds the pathogenicity of certain micro-organisms. Also, glycolysis will already be upregulated to instigate an inflammatory response caused by asbestos damage, which coincides again with micro-organism infection and the upregulation of RnR - providing RnR is a downstream event of glycolysis.

Just a thought.
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