The plot thickens -- you are what you eat in more ways than one

Your genome on lettuce
Banish the thought that you've got complete control over expression of your own genes.  It turns out that what you eat is also a player.  A paper in the April issue of BioEssays, "Beyond nutrients: Food-derived microRNAs provide cross-kingdom regulation" (Jiang, Sang and Hong), reports that not only do we derive nutrients from food, but that food-derived micro RNAs can affect expression of our genes.  Yet another instance of inter-species cooperation.

Micro RNAs are a relatively recently discovered component of the genome that modulate gene expression.  They silence protein-coding genes by binding to transcribed mRNA and preventing its translation.  As Jiang et al. report, more than 15,000 miRNA loci have been found in 140 species, and are annotated in the miRBase database.  These are miRNAs found inside cells, but recently micro RNAs have been found in blood serum and plasma, urine, saliva and other body fluids.  While RNA is known to be easily degraded and rather fleeting, it seems that these circulating RNAs are highly stable, and resistant to the usual destructive elements; RNAses, and high or low pH or temperature.  And, say Jiang et al., these miRNAs seem to be highly correlated with disease, such as cancers and diabetes, and with tissue injury, which suggests they could be of use as biomarkers.

But, the paper only notes this in passing, primarily focusing on these miRNAs as signaling factors.

Despite numerous reports of the detection of secreted miRNAs, the exact mechanisms of how these miRNAs are transported and act as signaling molecules are not clear. They have been implicated in stem cell function, hematopoiesis, and immune regulation. Recently, several lines of evidence have suggested that miRNAs are selectively packaged into microvesicle (MV) compartments to function efficiently in mammalian cells. MVs are membrane-covered vesicles and can be released by various kinds of cells.

It may be that being packaged in MVs is what gives these miRNAs their stability, as they are sequestered from RNAses and so on.  And, the packaging process seems to be selective, as only specific types of miRNAs have been found packaged in this way.

Jiang et al. write that "cross-kingdom regulation through miRNA/double-stranded RNA (dsRNA) has been observed in many organisms and engineered systems."  And, it often alters gene expression in the host organism.  Examples include planaria or other parasitic nematodes, which can take exogenous double stranded RNA into their cells, as do insects when fed plants.

For example, when cotton bollworm larvae are fed on plant material expressing dsRNA targeting CYP6AE14, whose gene product helps the insect to counteract the deleterious cotton metabolite gossypol, the transcript level of this gene is decreased and causes larval growth retardation.

It has recently been demonstrated (and we have to take Jiang et al.'s word for it, because the paper by Zhang et al. is in Chinese, unreadable by us) that "mature single-stranded plant miRNAs are present in the serum and tissues of mammals that use plants such as rice as their food sources."  They verified that these are plant RNAs, and that they survived passage through the mouse gastrointestinal tract intact.

Moreover, the authors identified the low-density lipoprotein receptor adapter protein 1 (LDLRAP1) as a target for MIR168a, a plant miRNA that was present at a relatively high level in human sera. The presence of exogenous pre-MIR168a or mature MIR168a miRNA can significantly reduce LDLRAP1 protein level in culture. Furthermore, feeding mice with rice that produces MIR168a reduced the amount of LDLRAP1 protein in liver, which in turn resulted in an elevation of the LDL level in mouse plasma. Both the decrease of LDLRAP1 and the increase of LDL in plasma, however, could be blocked by the addition of an anti-MIR168a antisense oligonucleotide. These elegantly executed experiments not only confirm the role of circulating miRNAs in intercellular communication, but also suggest that miRNAs can transport and function in a cross-kingdom manner.

How miRNAs would survive digestion and be absorbed is a question but without simple answers.  The first issue has to do with how they survive digestion and absorption across the gut.  A second is why we haven't evolved means to detect and degrade them; after all, our immune system is very able to recognize foreign stuff.  Jiang et al. describe the possible conditions under which plant miRNAs can survive this passage, and we won't replicate it here.  Suffice it to say that they note that plant miRNAs are packaged differently from mammalian miRNAs, and that mammalian intestinal epithelial cells 'somehow' ingest plant miRNAs.  They wonder if there's a receptor or some such on the mammalian cell surface that might recognize plant miRNAs and pave the way.  After being taken up by intestinal cells, these miRNAs then are passed to downstream cells, such as the liver, where they are involved in gene regulation.

There's a lot of hand waving going on here, but if true, this is a thought-provoking example of the synergy between organisms.  As this field matures, you can be sure that potential medical uses won't escape pharmaceutical companies.  

Regular readers may notice that in describing these newly discovered miRNAs, we've invoked a number of principles that we think are at the core of life, and that we've recently enumerated on MT -- sequestration, modularity, cooperation, signaling, chance, adaptability.  It's always gratifying when these principles apply in circumstances that were not known at the time we compiled them. 


Whose genome is it, anyway?
But what about evolution?  If we interact with genes (miRNA are coded from the originating species' DNA) from other species, and in at least many cases we depend on that, then perhaps the view of genomes as all contained within a species' cells is misleading.  Perhaps 'our' genome includes that of E. Coli that we need in our gut, or in each location 'our' genome includes miRNAs from foods we depend on for survival.

Normally, one would expect us to lose genetic mechanisms if they are replaced by something else.  If we depend on exogenous genetic information, then mutations in our own genes that do the same thing would have no selective disadvantage and would disappear.  In that sense, the species' genome becomes joined at the proverbial hip to each other.

Far-fetched?  Well, long ago mitochondria and chloroplasts entered cells and evolved from parasite to necessary cellular components.  miRNA and bacterial genomes and so on aren't so thoroughly incorporated (yet), though some viral genomes are.  So there is probably a gradient of intergenomic dependency among species.  This is an extension of predator-prey dependencies, but is similar in concept, just more localized in genes.

Once again, this discovery (if confirmed and shown to be more than trivial) will add to the causal complexity of human traits.

New findings in cancer research: Something old and something new

A story in the NY Times, a report from the annual meeting of the American Association for Cancer Research, suggests that cancer may be a different sort of disease than has been assumed.  It has been thought for several decades that cancer is a genetic disease, due to mutations that lead malfunctioning genes to cause a single cell to divide uncontrollably. The mutations cause the cell to divide rapidly, and at the same time, override the normal mechanisms that limit cell division.  One of the signature discoveries of the 1970s was that tumors in a person are usually clonal: they derive from a single 'transformed' cell.  That made cancer a 'genetic' disease at the cell level. 

Melanoma cells invading the brain

However, the story points out that recent discoveries have been complicating the picture with tangles of new detail. Cancer appears to be "even more willful and calculating than previously imagined", if you want to accept the usual hyperbole and anthropomorphizing. This story raises the possibility that there are additional mechanisms, including many kinds of RNA that are not the classical protein-coding parts of genes that textbooks (at least, out-of-date textbooks) describe as how the genome works (that is, not just due to misbehaving messenger RNA), as well as signals from the microbes that colonize our bodies.

Microbes comprise maybe 90% of the cells in our bodies, being integral to digestion, and other functions.  They need us and we need them, and this co-existence is maintained by communication between our cells and our resident microbes.  When this goes awry, our cells may be signaled to begin to divide; this aberrant signaling may be responsible for cancers of the digestive system -- the colon, stomach, and esophagus -- and perhaps other organs.

Another possibility is that segments of the non-coding DNA that makes up maybe 98% of our DNA may send aberrant signals that lead to uncontrollable cell division.  Pseudogenes, or remnants of gene duplication events long ago that on their own now have no function, or garbled function, may be one of the elements in non-coding DNA that incite uncontrollable cell division.

And finally, micro RNA may inhibit or alter the normal working of messenger RNA, disrupting normal cell signaling.  It has become apparent in recent years that micro RNA has a function in the regulation of much normal gene expression, but it seems that it could also be involved in the kinds of abnormal cellular functions that lead to cancer.  It's possible that pseudogenes interact with microRNAs to do this.

Well, these alternatives are clearly all possible, but unfortunately the story is the usual type of overkill and melodrama that we see every day in the media. Investigators making exaggerated claims of new discoveries, rather than simply reporting additional facts and mechanisms that are being found.  Contrary to the sense of the story, nothing in these new findings challenges the basic current idea about cancer, even as they make it clear that the usual approaches for finding genes 'for' cancer, such as genomewide association studies (GWAS), are generally not going to work. 

And indeed, there may be some mechanisms that cause cancer but do not alter DNA or create abnormal cells.  Instead, such mechanisms may simply induce genetically normal cells to respond to their environment in ways that are mistaken (relative to the survival of the organism).  These included some apparent context responses that should lead as a rule to many cells misbehaving in the same way -- polyclonal tumors, in which not all cells are derived from the same single misbehaving ancestral cell.  That was an older idea about cancer that hasn't had much credence for several decades.

Cancer is clearly a nasty problem for an organism, and one that involves evolution on the scale of one's individual lifetime, with some similarity to long-term evolution of species.  If cancer were to turn out to be polyclonal, it would make it more like infection, in which the body is occupied by descendants of many different infecting bacterial cells or viral particles.  Since the descendant cells of each founding cell will then undergo their own evolutionary history, attacking the tumor would become more difficult -- the tumor cells wouldn't share the same characteristics to the extent that a single clone of cells do.  The evolution will not be of a single tree of descent.

Viral cancers can be polyclonal if the virus independently transforms different cells in the individual, but this seems unusual.  Also, if only a small number of changes are required, and the person inherits one or more of them, and has many cells at risk of somatic mutations to generate the rest, there may be several independent tumors in the same person.  There are some examples of this.

But generally, the standard model of a mix of inherited variation that makes a cell less likely to respond normally, complemented by somatic mutations that finish the job of producing a single, badly programmed progenitor cell, seems basically safe.  Even if, as seems to be the case, we're finding new aspects of the genome and its behavior that are involved in the production of such a cell.