Your mother *is* always with you

Mother and child, microchimeras

When you’re in utero, you’re protected from the outside world, connected to it only via the placenta, which is supposed to keep you and your mother separated. Separation is generally a good thing because you are foreign to your mother, and she is foreign to you. In spite of the generally good defenses, however, a little bit of you and a little bit of her cross the barrier. Scientists have recently found that when that happens, you often end up toting a bit of mom around for decades, maybe for life.

The presence of cells from someone else in another individual is called microchimerism. A chimera in mythology was a beast consisting of the parts of many animals, including lion, goat, and snake. In genetics, a chimera carries the genes of some other individual along with its own, perhaps even the genes of another species. In microchimerism, we carry a few cells from someone else around with us. Most women who have been pregnant have not only their own cells but some cells from their offspring, as well. I’m probably carrying around cells from each of my children.

Risks and benefits of sharing

Microchimerism can be useful but also carries risks. Researchers have identified maternal cells in the hearts of infants who died from infantile lupus and determined that the babies had died from heart block, partially from these maternal cells that had differentiated into excess heart muscle. On the other hand, in children with type 1 diabetes, maternal cells found in the pancreatic islets appear to be responding to damage and working to fix it.

The same good/bad outcomes exist for mothers who carry cells from their children. There has long been an association between past pregnancy and a reduced risk of breast cancer, but why has been unclear. Researchers studying microchimerism in women who had been pregnant found that those without breast cancer had fetal microchimerism at a rate three times that of women who with the cancer.

Microchimerism and autoimmunity

Autoimmune diseases develop when the body attacks itself, and several researchers have turned to microchimerism as one mechanism for this process. One fact that led them to investigate fetal microchimerism is the heavily female bias in autoimmune illness, suggesting a female-based event, like pregnancy. On the one hand, pregnancy appears to reduce the effects of rheumatoid arthritis, an autoimmune disorder affecting the joints and connective tissues. On the other hand, women who have been pregnant are more likely to develop an autoimmune disorder of the skin and organs called scleroderma (“hard skin”) that involves excess collagen deposition. There is also a suspected association between microchimerism and pre-eclampsia, a condition in pregnancy that can lead to dangerously high blood pressure and other complications that threaten the lives of mother and baby.

Human leukocyte antigen (HLA)

The autoimmune response may be based on a similarity between mother and child of HLA, immune-related proteins encoded on chromosome 6. This similarity may play a role in the immune imbalances that lead to autoimmune diseases; possibly because the HLAs of the mother and child are so similar, the body clicks out of balance with a possible HLA excess. If they were more different, the mother’s immune system might simply attack and destroy fetal HLAs, but with the strong similarity, fetal HLAs may be like an unexpected guest that behaves like one of the family.

Understanding the links between microchimerism and disease is the initial step in exploiting that knowledge for therapies or preventative approaches. Researchers have already used this information to predict the development of a complication in stem cell transplant called “graft-versus-host disease” (GVH). In stem cell transplants, female donors with previous pregnancies are more associated with development of GVH because they are microchimeric. Researchers have exploited this fact to try to predict whether or not there will be an early rejection of a transplant in kidney and pancreas organ transplants.

(Photo courtesy of Wikimedia Commons and photographer Ferdinand Reus).

How the genetic code became degenerate

Our genetic code consists of 64 different combinations of four RNA nucleotides—adenine, guanine, cytosine, and uracil. These four molecules can be arranged in groups of three in 64 different ways; the mathematical representation of this relationship is 4 x 4 x 4 to illustrate the number of possible combinations.

Shorthand for the language of proteins

This code is cellular shorthand for the language of proteins. A group of three nucleotides—called a codon—is a code word for an amino acid. A protein is, at its simplest level, a string of amino acids, which are its building blocks. So a string of codons provides the language that the cell can “read” to build a protein. When the code is copied from the DNA, the process is called transcription, and the resulting string of nucleotides is messenger RNA. This messenger takes the code from the nucleus to the cytoplasm in eukaryotes, where it is decoded in a process called translation. During translation, the code is “read,” and amino acids assembled in the sequence the code indicates.

The puzzling degeneracy of genetics

So given that there are 64 possible triplet combinations for these codons, you might think that there are 64 amino acids, one per codon. But that’s not the case. Instead, our code is “degenerate;” in some cases, more than one triplet of nucleotides provides a code word for an amino acid. Thus, these redundant codons are all synonyms for the same protein building block. For example, six different codons indicate the amino acid leucine: UUA, UUG, CUA, CUG, CUC, and CUU. When any one of these codons turns up in the message, the cellular protein-building machinery inserts a leucine into the growing amino acid chain.

This degeneracy of the genetic code has puzzled biologists since the code was cracked. Why would Nature produce redundancies like this? One suggestion is that Nature did not use a triplet code originally, but a doublet code. Francis Crick, of double-helix fame, posited that a two-letter code probably preceded the three-letter code. But he did not devise a theory to explain how Nature made the universal shift from two to three letters.

A two-letter code?

There are some intriguing bits of evidence for a two-letter code. One of the players in translation is transfer RNA (tRNA), a special sequence of nucleotides that carries triplet codes complementary to those in the messenger RNA. In addition to this complementary triplet, called an anticodon, each tRNA also carries a single amino acid that matches the codon it complements. Thus, when a codon for leucine—UUA for example—is “read” during translation, a tRNA with the anticodon AAU will donate the leucine it carries to the growing amino acid chain.

Aminoacyl tRNA synthetases are enzymes that link an amino acid with the appropriate tRNA anticodon.  Each type of tRNA has its specific synthetase, and some of these synthetases use only the first two nucleotide bases of the anticodon to decide which amino acid to attach. If you look at the code words for leucine, for example, you’ll see that all four begin with “CU.” The only difference among these four is the third position in the codon—A, U, G, or C. Thus, these synthetases need to rely only on the doublets to be correct.

Math and doublets

Scientists at Harvard believe that they have solved the evolutionary mystery of how the triplet form arose from the doublet. They suggest that the doublet code was actually read in groups of three doublets, but with only the first two “prefix” or last two “suffix” pairs actually being read. Using mathematical modeling, these researchers have shown that all but two amino acids can be coded for using two, four, or six doublet codons.

Too hot in the early Earth kitchen for some

The two exceptions are glutamine and asparagine, which at high temperatures break down into the amino acids glutamic acid and aspartic acid. The inability of glutamine and asparagine to retain structure in hot environments suggests that the in the early days of life on Earth when doublet codes were in use, the primordial soup must have been too hot for stable synthesis of heat-intolerant, triplet-coded amino acids like glutamine and asparagine.

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