An enzyme may hold the key to understanding and beating cancer
The gene-centric view of cancer does not offer any insight into initiation and progression of the disease. Independent researcher Jay Kulsh claims that such understanding is possible by shifting focus to the enzyme ribonucleotide reductase (RnR) which controls the bottleneck step in DNA synthesis and is tightly linked with cancer growth. The free radical containing active site (heart) of RnR seems uniquely vulnerable to various carcinogenic agents. Furthermore, Kulsh puts forward the idea that gentle electrotherapy, which would selectively disable malignant RnR by quenching free radicals, is an effective and non-toxic universal cancer treatment.
In 1971, President Nixon signed the National Cancer Act into law. Today, 51 years after this declaration of ‘war on cancer’, survival rates have improved, thanks to early detection and intervention. Sadly, however, the global research community has not yet found effective treatments for the disease.
The genetic theory of cancer, and its inadequacies
The presence of mutated genes strongly correlates with cancer incidence. According to the prevailing genetic model, cancer is caused by the mutation of specific genes that are either present at birth (inherited) or acquired (somatic) through interaction with carcinogenic agents or due to old age.
The genetic basis of cancer received a boost in 1971 with the identification of the RB gene whose malfunction was directly associated with retinoblastoma (infant eye cancer).
However, independent US scientist Jay Kulsh points out that even today, despite intensive research over the last five decades, retinoblastoma remains the only cancer whose occurrence is directly related to a gene. This puts a big question mark on genetic causation of cancer. (Kulsh, below, provides an updated interpretation of the role of RB gene – involving a critical enzyme in DNA synthesis – in causing cancer).
To understand gene–cancer relationships, genes have been divided into two groups: those that prevent cancer (‘tumour suppressor genes’), and those that cause cancer when mutated (‘oncogenes’).
Note that the gene that causes retinoblastoma is in the first category. The cancer occurs in the gene’s functional absence. Five more similar genes were identified that may have an inborn error, but when missing or mutated they only increase the chance of developing cancer, not cause it. Hence such rare medical conditions are called ‘cancer susceptibility syndromes’. This phenomenon is also seen in 5−10% of breast cancer cases and some ovarian cancers, where certain mutated inherited genes increase susceptibility to the disease.
It is significant that more than 90% of all cancers are somatic in nature and are linked to oncogenes of the second category. In tumours, such mutated genes are found to be varied and complex at all levels, making any functional and causal interpretation very difficult. The cancer genome atlas (TCGA) was established in 2006 with the aim of untangling these intricacies of cancer genetics. However, the enormous amount of data did not yield a specific causative gene, or set of genes, for any cancer. Instead, observed genetic mutations remain diverse and random, leading Kulsh to wonder if oncogenes may not be the cause but the consequence of cancer: ‘As if after a battle, each soldier is wounded in its own way.’
Additionally, the gene-based theory of cancer fails to answer basic questions about the process of carcinogenesis. For example, it is still unclear how cancer-causing molecules would selectively target the genes involved in cell division, which constitute less than ten percent of the protein-coding genome (the complete set of genes).
Source of carcinogenesis found in cytoplasm, away from nucleus/genes
A 1987 study reported that when cells are reconstituted by fusing nucleus from cancerous cells with the cytoplast (the material outside the nucleus) of normal cells, the new cell was no longer malignant. In 1988, the same authors reported that in cells derived by fusion of cytoplasts from cancerous cells with nucleus of normal cells, tumours were seen in 97% of cells. This suggests that the source of cancer is not in the nucleus where genes reside.
Cancer origin in the biochemistry of cytoplasm
Since epidemiological studies consistently show that chemical carcinogens in the environment, not genes, play a principal role in causing cancer, Kulsh proposes that we should look at the biochemistry, rather than the genetics of cancer.
In biochemistry, enzymes are of paramount importance since they invariably mediate transformations in a cell. (Enzymes are specialised proteins that speed up vital biochemical reactions). The obvious candidate for a role in cancer is the enzyme ribonucleotide reductase (RnR) since its activity is tightly linked – much more than that of any other enzyme – to tumour growth.
RnR enzyme converts the building blocks of RNA into the building blocks of DNA (Figure 1). The enzyme, which resides in the cytoplasm and not in the nucleus, is also involved in DNA repair. It is the rate-limiting enzyme for DNA synthesis; without it no cell can replicate, and no cancer can grow. The enzyme consists of two dissimilar subunits: proteins RRM1 and RRM2. The smaller RRM2 contains a tyrosyl free radical which is stabilised by an adjacent oxo-bridged binuclear iron centre.
The free radical at the active site (heart) of RnR is essential for all its enzymatic action (Figure 2). The levels and activity of RnR are tightly regulated via multi-layered mechanisms that optimally regulate cell multiplication.
Cancer initiation at ribonucleotide reductase
RnR, critical for cell division, is known to impact cancer susceptibility. Kulsh goes a step further and proposes that the RRM2 subunit of this enzyme, containing the diferric-tyrosyl-radical active site, is the primary, and perhaps the only, target of all types of carcinogenic agents.
Kulsh argues that carcinogenic compounds and/or their metabolic products, due to their electrophilic and hydrophobic nature, are especially suited to access the electro-magnetically charged active site of RnR and, once there, would disturb the finely tuned rhythmic controls in place. (Reactive species generated by asbestos particles and radiations would follow a similar path). The accumulation of these irritant molecules may go on for years (‘latency period’) until persistent overstimulation leads to unrestrained cell proliferation or cancer.
In 1993, Kulsh got a chance to discuss these ideas with James Watson – of DNA double-helix fame. (Watson spent four decades exploring the genetic aspects of cancer as director of Cold Spring Harbor Laboratory, NY). In that ten-minute meeting, Watson could not be persuaded that biochemistry may have a role in cancer causation.
However, 23 years later, Kulsh was surprised and delighted to read this statement of Watson in the New York Times of May 12, 2016:
…locating the genes that cause cancer has been ‘remarkably unhelpful’… If he were going into cancer research today, he would study biochemistry rather than molecular biology.
Kulsh may have been ahead of his time.
In recent decades, elucidation of mechanisms of retinoblastoma and HPVs-related cervical cancers has revealed that the RRM2 protein of RnR has a central role to play in both, supporting Kulsh’s hypothesis. E7 gene of HPVs causes excess production of RRM2 by inactivating the retinoblastoma gene RB. (RRM2 has now become a molecular marker for the diagnosis and clinical outcomes of cervical cancer). Finally, free radicals are being recognised for their important role in cell signalling and a strong case has been made to view the RRM2 subunit as ‘oncoprotein’ – in addition to its being part of a critical enzyme.
Free radical of RnR: A potential cancer target
Whether or not cancer is initiated, in all cases, at the enzyme RnR, there is consensus among cancer researchers that if you can block the activity of RnR, you can stop cancer. Therefore, this enzyme is considered a classical target for cancer therapeutics. Chemotherapeutic drugs have been synthesised since 1970s aiming to inhibit the RnR enzyme. However, they are only partially successful, and produce toxic side-effects due to lack of selectivity.
In 1994, Kulsh proposed that the free radical that plays a central role in the RnR enzyme’s activity can be destroyed by free-floating electrons, easily available in the form of direct electric current. Gentle electrotherapy thus would disable RnR and arrest cancer growth. Since the active site of RnR is well-shielded in healthy cells, this treatment would selectively target malignant RnR.
Kulsh could find ten scientific papers published up until that point that studied the effect of electricity on cancer. All confirmed his hypothesis. About half of the experiments did not result in significant benefit because they used electricity at too high a voltage, which resulted in harmful electrochemistry, and left little or no electrons to quench free radicals. This also supported his proposition because to disable the RnR enzyme, pure electrotherapy (possible at low voltage) is desired. A 1985 Cancer Research study reported that, on passing gentle electric current for one hour daily, for five days, tumours of hamsters were reduced by as much as 98%.
On being contacted, the MD Anderson Cancer Center, Houston, and the National Cancer Institute of USA acknowledged the validity of this approach to treat cancer. In 1997, Kulsh published a paper about this novel cancer treatment.
Gentle Electrotherapy to Inhibit a Pivotal Enzyme (GEIPE)
Building on this discovery, Kulsh has developed the protocol gentle electrotherapy to inhibit a pivotal enzyme (GEIPE). He has built and optimised several GEIPE devices, which have been used to treat a few patients whose cancer no longer responded to conventional treatments or who are averse to those treatments.
In one case study, a Nigerian patient with a large malignant squamous cell carcinoma of the sinus cavity was successfully treated with a GEIPE device (Figure 3). The treatment was given for eight hours daily for a total of eight weeks leading to total remission of the disease. In a second case study, a 93-year-old man with a protruding carcinoma on the face was successfully treated at home with a GEIPE device with doses of four hours per day for 12 weeks. Kulsh reports that other patients benefited to various degrees from GEIPE therapy and, based on his observations, suggests that the non-invasive modality is well suited for patients whose tumours are on, or near, the surface.
For interior tumours, semi-invasive or invasive GEIPE modality, using one or both needle electrodes (with only the tip exposed and inserted in the tumour, rest insulated) must be employed.
This treatment is unsuitable for conventional clinical trials since at the conclusion of the successful studies there would be no patentable procedure to recoup the cost of the trials. However, as the word spreads, hospitals may start offering this treatment to patients for whom conventional cancer treatments have failed. There is no downside for patients since the treatment is non-toxic.
Since tumour cells in any cancer need to make DNA to grow, his therapy is applicable to all cancers. Kulsh says, ‘at a molecular level, cancer is a single disease.’ He concludes, ‘by targeting this enzyme, we may be nipping cancer in the bud, in a non-toxic manner.’
- Apple, S, (2016) An old idea, revived: starve cancer to death. New York Times, Sunday Magazine. www.nytimes.com/2016/05/15/magazine/warburg-effect-an-old-idea-revived-starvecancer-to-death.html [Accessed 20 June 2022]
- Su, YF, Wu, TF, Ko, JL, et al (2014) The expression of ribonucleotide reductase M2 in the carcinogenesis of uterine cervix and its relationship with clinicopathological characteristics and prognosis of cancer patients. PLoS ONE. 9(3):e91644. doi.org/10.1371/journal.pone.0091644
- Kulsh, J, (2014) Low-level electric current and cancer – a promising, but languishing non-toxic cancer therapy. Explore (New York, NY), 10(1), 53–4. doi.org/10.1016/j.explore.2013.10.004
- Shao, J, Liu, X, Zhu, L, Yen, Y, (2013) Targeting ribonucleotide reductase for cancer therapy. Expert Opin Ther Targets, 17:1423–37 doi.org/10.1517/14728222.2013.840293
- Kulsh, J, (1997) Targeting a key enzyme in cell growth: a novel therapy for cancer. Medical hypotheses, 49(4), 297–300. doi.org/10.1016/S0306-9877(97)90193-6
Jay Kulsh (Ajay Kulshreshtha) uses biochemistry, where enzymes play a pre-eminent role in various transformations, to understand cancer causation and devise protocols that selectively block critical biochemical pathways, to bring about cancer cessation.
Jay Kulsh During his graduate studies in the Department of Chemistry and Biochemistry at the University of California, Los Angeles, Jay Kulsh became interested in the potential role of the enzyme ribonucleotide reductase (RnR) in causing cancer. As an independent scientist, he has published multiple papers about a non-toxic cancer treatment which effectively blocks RnR.
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