The gene theory of cancer is challenged by a growing number of inconsistencies (23-27). Chief among these are the findings from nuclear-cytoplasm transfer experiments. Thomas Seyfried recently reviewed massive evidence showing that nuclei obtained from cancer cells—which presumably contain cancer-driver mutations—cannot drive carcinogenesis when placed in the cytoplasm from normal cells (28). On the other hand, tumors could develop after the placement of a normal nucleus into a tumor cytoplasm. Moreover, replacement of tumor mitochondria with normal mitochondria suppressed growth and metastasis of breast-cancer cells, whereas the opposite was the case when tumor mitochondria replaced normal mitochondria (28).
Figures 1 and 2 illustrate the findings from two of these experiments, while Figure 3 summarizes the findings from a broad range of nuclear-cytoplasm transfer experiments. It is clear that the findings from these experiments are more consistent with the mitochondrial metabolic theory (MMT) than with the somatic mutation theory (SMT), indicating that it is the defects in mitochondria of the cytoplasm rather than defects in the genome of nucleus that underlie the origin of cancer.
Figure 1A depicts the H&E staining of a mouse embryo (embryonic day, E-7.5) derived from a cell containing the nucleus from a medulloblastoma tumor. Figure 1B shows the boxed area in A (at a higher magnification), showing the three germ layers; ecto-placental cone (pla); embryonic endoderm (end); embryonic mesoderm (mes); embryonic ectoderm (ect).
The cytoplasm will contain normal mitochondria. The results show that a nucleus derived from a brain tumor can direct normal embryonic development when implanted into normal cytoplasm. Although the medulloblastoma-derived embryos aborted, none exhibited uncontrolled proliferation resembling tumorigenesis (29). These findings are inconsistent with the SMT.
Figure 2 shows an E-9.5 mouse embryo cloned from a melanoma-derived R545-1 embryonic stem cell. The embryo expressed neural tube closure, a beating heart, and normal limb-bud development consistent with regulated cell growth. The result shows that the nucleus of a malignant melanoma can direct early mouse development when placed into normal cytoplasm containing normal mitochondria. However, irreversible genetic alterations, from the melanoma donor genome, disrupted complete development similar to the situations found in the medulloblastoma experiments (Figure 1), and in Lucke frogs that were cloned from nuclei of renal tumors (30). These findings are also inconsistent with the SMT.
In Figure 3 below, normal cells are shown in green with nuclear and mitochondrial morphology indicative of normal gene expression and respiration, respectively. Tumor cells are shown in red with abnormal nuclear and mitochondrial morphology indicative of genomic instability and abnormal respiration, respectively.
From Seyfried: “1) Normal cells beget normal cells. 2) Tumor cells beget tumor cells. 3) Transfer of a tumor cell nucleus into a normal cytoplasm begets normal cells, despite the presence of the tumor-associated genomic abnormalities. 4) Transfer of a normal cell nucleus into a tumor cell cytoplasm begets dead cells or tumor cells, but not normal cells. The results suggest that nuclear genomic defects alone cannot account for the origin of tumors, and that normal mitochondria can suppress tumorigenesis.” (28)
Considered collectively, the findings from the nuclear-cytoplasmic transfer experiments provide compelling evidence showing that nuclear somatic mutations alone cannot account for the origin of tumors, and that normal cytoplasm containing mitochondria can suppress tumorigenicity. It is interesting that the findings from the nuclear-cytoplasmic transfer experiments are generally consistent across a broad range of tumor types, animal species, and experimental techniques (28). Importantly, most of the studies were not done to test the somatic mutation theory of cancer but rather to determine the importance of nuclear mutations in directing development. Consequently, data interpretation was largely unbiased.
Several distinguished leaders in the fields of genetics and developmental biology conducted nuclear-cytoplasmic transfer experiments (H. Harris, B. Mintz, R. Sager, J. Morgan, R. Jaenisch) that further supports the validity of the findings. This point is extremely important in light of the recent reproducibility crisis in the field of cancer biology and medicine, where the findings from a broad range of experiments cannot be reproduced (32-34). Although numerous inconsistencies have been documented that undermine the credibility of the SMT (27,35), none of these are as powerful as those presented from the nuclear-cytoplasmic transfer experiments.
Thomas N. Seyfried is professor of biology at Boston College. He received a doctorate in genetics and biochemistry from the University of Illinois—Urbana-Champaign in 1976. He did his undergraduate work at the University of New England, where he recently received the distinguished Alumni Achievement Award. He also holds a master’s degree in genetics from Illinois State University. Seyfried served with distinction in the United States Army’s 1st Cavalry Division during the Vietnam War and received numerous medals and commendations.
He was a postdoctoral fellow in the Department of Neurology at the Yale University School of Medicine and then served on the faculty as an assistant professor in neurology. Seyfried previously served as chair of the Scientific Advisory Committee for the National Tay-Sachs and Allied Diseases Association. He recently received a Lifetime Achievement Award from the Academy of Complementary and Integrative Medicine and the Uncompromising Science Award from the American College of Nutrition for his work on cancer.
He presently serves on several editorial boards, including those for Nutrition & Metabolism, Neurochemical Research, the Journal of Lipid Research, and ASN Neuro. Seyfried has over 180 peer-reviewed publications and is author of the book “Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer” (Wiley Press).
Note: these references include those previously published in “Is Cancer a Genetic or Metabolic Disease? Part 1” and “Part 2.”
All links accessed Jan. 25, 2019.