In an exciting discovery reported last year, a team of Chinese researchers found that some of the genetic material in our food might survive digestion and go on to regulate our genes and affect our physiology. This new mechanism for genetic interactions between very different species raises interesting evolutionary questions and will probably have implications for the study of health and nutrition, but it’s important to understand what the study was actually about, particularly since this will likely affect the debate around GMO foods.
When I started studying biology, we were taught the “central dogma” of molecular biology: DNA is translated into RNA which is translated into proteins which are the molecular machinery of life. I imagine this is what undergraduate students are still taught, even though we know it’s an immense oversimplification. Some bits of DNA encode short RNA molecules which never get translated into proteins. Instead, they interact with the other RNA molecules which do encode proteins; by interfering with this process, these micro-RNAs (miRNAs) can effectively lower the expression of a gene by blocking the translation of RNA into protein. Each miRNA targets only a specific set of genes, but altogether they are thought to regulate about 60% of our genes and play an important role in everything from development and the immune response to diseases like cancer.
Using modern high-throughput sequencing, the researchers looked at the different kinds of miRNA that could be found in blood samples. miRNAs are known to circulate in microvesicles, small membrane compartments released by many kinds of cells; packaging things in microvesicles is one way cells communicate over long distances. To their surprise, the team found more than 30 different kinds of miRNA from plants in the blood samples. In order to make sure that these miRNAs were from plants, the researchers took advantage of a difference in the chemical structure of plant and mammalian miRNAs. They treated the RNA with a chemical that would attach to mammalian miRNA (but not plant miRNA) and stop it from being sequenced. By comparing the sequencing results before and after this treatment, they were able to eliminate the mammalian miRNA and be sure that they had found genuine plant miRNA in human blood samples.
The miRNA may have survived digestion intact and entered the blood without having any further effect. To find out if this was the case, the team decided to focus on one of the most common miRNAs they had detected, MIR168a. Using a bioinformatic analysis, they predicted possible targets of MIR168a, including LDLRAP1, a gene which is active in our liver and is critical for removing LDL cholesterol from the blood. They then treated liver cell cultures with MIR168a and saw decreased activity of LDLRAP1. To test the entire chain from gut to liver, the researchers cultured intestinal cells with MIR168a; the cells took up the miRNA and released it in microvesicles. The researchers collected these microvesicles and mixed them into cultures of liver cells. The liver cells took up the microvesicles and had a drop in LDLRAP1 activity; the team had successfully shown the transmission chain from uptake in the gut to gene regulation in the liver.
Despite this, something was still missing from their tests: the digestive system, full of acids and enzymes to break down food. Although the miRNAs they had found are common in foods like rice, wheat and potato, it’s been thought that the digestion would quickly break down whatever had survived the head of cooking. The researchers were surprised to find that these miRNAs were still present in cooked vegetables; they were even stable in warm, highly acidic conditions designed to simulate our digestive tract. The best possible test would be to use a real digestive tract, so the researchers fed mice a diet of rice, which has higher levels of MIR168a than their normal food. Within six hours, the mice had high levels of MIR168a in their blood and liver along with with decreased expression of LDLRAP1; three days later, they also had higher levels of LDL cholesterol in their blood.
To determine how general these results were, the researchers looked at samples from calves, rats, horses and sheep; in every case, plant miRNAs were in the blood. They also found that mice were able to take up mammalian miRNA from their food, suggesting that this may be a widespread, general process. The authors described these miRNAs as “a novel nutrient component”; given that they may be regulating physiological processes in a wide range of animals, this seems like an appropriate description. The discovery of this kind of communication and regulation not just between different species but between different kingdoms of life is a pretty amazing finding which immediately provokes a host of questions. Is this process regulated? If so, how? Does it provide some kind of adaptive advantage to either the plant or animal? Has the uptake of plant miRNAs left a genetic imprint in different groups of animals? The fact that plants can directly regulate animal genes in this way also raises the tantalisizing possibility of some kind of co-evolution based around this interaction.
It’s also important to realize what this study isn’t about: it’s not about genes from our food getting into us. That would require foreign genetic material to get into the nucleus of a cell and integrate into our genome, which is very different from what was reported in this study. Since existing GMO crops haven’t been engineered with miRNA but rather by the introduction of novel genes, these results aren’t directly relevant to them. However, this study is a good reminder of how much we don’t know and highlights the necessity for properly testing and regulation of novel GMO crops and technologies as they continue to be developed. At the same time, it demonstrates the importance of continued research by exposing an entirely new class of interactions between plants and animals.
Zhang, L., Hou, D., Chen, X., Li, D., Zhu, L., Zhang, Y., Li, J., Bian, Z., Liang, X., Cai, X., Yin, Y., Wang, C., Zhang, T., Zhu, D., Zhang, D., Xu, J., Chen, Q., Ba, Y., Liu, J., Wang, Q., Chen, J., Wang, J., Wang, M., Zhang, Q., Zhang, J., Zen, K., & Zhang, C. (2011). Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA Cell Research, 22 (1), 107-126 DOI: 10.1038/cr.2011.158