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10. Cancer Study - Part I: A Nuclear Genetic Disease or A Mitochondrial Metabolic Disease?

Updated: Jun 9, 2023

Dr. Thomas Seyfried has a Ph.D. in Genetics and Biochemistry and he is a Professor of Biology in Boston College. Dr. Seyfried has over 200 peer-reviewed publications and he is the author of the book, Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer (Wiley, 1st ed., 2012). He has been challenging the commonly accepted theory of cancer, which is the genetic theory for many years till now. In his talk - 'Cancer as a Metabolic Disease: Implications for Novel Therapies' , he explained how he came up with this theory. There are a lot of controversies out there challenging his theory. Let's try to apply the scientific method to his talk to verify what he said.



To refresh our memory first: the scientific method is a problem-solving approach at the core of biology and other sciences. It has five basic steps, plus one feedback step:

  1. Make an observation.

  2. Ask a question.

  3. Form a hypothesis, or testable explanation.

  4. Make a prediction based on the hypothesis.

  5. Test the prediction.

  6. Iterate: use the results to make new hypotheses or predictions.

Below is his explanation:

1. He made an observation: there is a ongoing cancer crisis in the US as well as the whole world. In the US alone, from 2013 to 2020, the new cancer cases per year increases by 8.1%, and the deaths per day increases by 4.3%. In 2020, the number of new cases is 1.8 million, and the deaths/day is 1662. This is a very depressing and concerning information that we have made little if any major progress in reducing cancer death over this period.



2. He asked a question: what is largely responsible for the failure to prevent or manage cancer?

3. He formed a hypothesis: In his view, the failure has to do with the view of how we understand cancer. Is it a nuclear genetic disease or a mitochondrial metabolic disease? Currently commonly accepted theory is that cancer is a genetic disease. Both mutations in genes that inhibit or stimulate cell division contribute to cancer. When normal cells suffer a series of random mutations, no one assures how many, the normal growth control cell eventually enters into a malignant cell. This malignant cell will then grow out of control and possibly spread throughout the body. He believes the metabolic theory can better explain the origin of cancer than the genetic theory. He listed multiple previously published papers that challenged the somatic mutation theory.



4. His prediction based on the hypothesis: it is the mitochondrial damage to oxidative phosphorylation that ultimately leads to the mutations in the nucleus. And the mutations in the nucleus are downstream epipharise as downstream epiphenomena of the damage to the mitochondria.

5. Test of his prediction: They have done a lot of experiments to support the mitochondrial metabolic origin theory. The cartoon shown below summaries the vast number of experiments they have performed. Fig 1. The normal cells in green contain a normal integrated nuclear genome, and they also have normal mitochondria in the cytoplasm. They can regulate their physiology normally both energetically and genetically. And they beget normal cells. Fig 2. The tumor cells in red beget other tumor cells. Tumor cells have many gene mutations in the nucleus, but they also have defects in the cytoplasm, in the mitochondria lacking cristae or having other abnormalities. Now is it the mutations in the nucleus that causes the cancer or is it the defects in the mitochondrion of the cytoplasm that causes the cancer? These questions were addressed clearly by nuclear and mitochondrial transfer experiments. Fig 3. The nucleus of the tumor cell is placed in the cytoplasm of a normal cell. What was found is that there were normal cells produced, sometimes normal tissues, and sometimes a mouse or a frog cloned from the nucleus of a tumor cell. But these organisms showed no cancer. Fig 4. On the other hand, the nucleus of the normal cell was placed in the cytoplasm of the tumor cell. Rather than forming normal cells, they continue to produce either dead cells or tumor cells. These results are the exact opposite of the results predicted by the somatic mutation theory of cancer. If which should have said that the origin resides in the nucleus: Fig 3 should have formed tumors. And Fig 4 should not have formed tumors. Case 5. Also when normal mitochondria are transplanted to cancer cells, you get no tumors. The development of the tumor can be suppressed. These five viewed together provide the strongest evidence to date that cancer cannot be from a somatic mutation in the nucleus. Together with the other literatures mentioned before, the disease cannot be a genetic disease.



6. Iterate: use the results to make new hypotheses or predictions. - To be continued



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