Can epigenetics make the link between experience and heredity?

There is a lot of hope being held out for the field of epi­ge­net­ics. Could it be the sci­ence that will estab­lish the link between the social and the bio­log­i­cal, behav­iour and hered­i­ty? While epi­ge­net­ics is an excit­ing dis­ci­pline, we must remain vigilant.

Epi­ge­net­ics is in vogue at the moment, but the word is not new. In 1942, Con­rad Wadding­ton sug­gest­ed using it to describe the sci­ence that estab­lish­es the rela­tion­ship between geno­type and phe­no­type – that is, between the sequence of genes and the way they are expressed in the organ­ism. For the British sci­en­tist and philoso­pher, he con­sid­ered it to be a con­cept that main­ly con­cern­ing embry­on­ic devel­op­ment. His future work opened up the field.

Epi­ge­net­ics is now defined as the trans­mis­sion of sta­ble, her­i­ta­ble traits that do not involve changes in the DNA sequence. It cov­ers all sys­tems of gene expres­sion reg­u­la­tion. Two mol­e­c­u­lar mech­a­nisms of epi­ge­net­ics under­lie the process: mark­ers; chem­i­cal mod­i­fi­ca­tions of DNA that mark genes as active or inac­tive; and the organ­i­sa­tion of the genome, that is, the way the DNA strand wraps around itself to allow the machin­ery that reads the sequence to access it – or not. 

To under­stand the phe­nom­e­non, we can study two mice from the same lin­eage: one is brown, the oth­er is yel­low. This dif­fer­ence is not due to a sequence dif­fer­ence with­in a gene, but to the methy­la­tion of a gene. When the agouti gene is not methy­lat­ed or only slight­ly methy­lat­ed in melanocytes (skin cells), it is expressed and the mice are yel­low. If the agouti gene is methy­lat­ed, it is “switched off” by the mol­e­c­u­lar machin­ery, and it will not be expressed so the mice will be brown. More impor­tant­ly, when we add folic acid to the diet of ges­tat­ing mice, the pro­por­tion of yel­low mice in the lit­ters is reduced. As such, we now know that folic acid is essen­tial for the syn­the­sis of a methy­la­tion donor mol­e­cule. Epi­ge­net­ics is there­fore influ­enced by meta­bol­ic path­ways and can respond to exter­nal sig­nals, such as a par­tic­u­lar change in diet.

Metab­o­lism also influ­ences the genome organ­i­sa­tion via his­tones. These are DNA-asso­ci­at­ed pro­teins that organ­ise DNA strand wind­ing. They com­pact the DNA mol­e­cule 10,000 times and allow it to be con­fined in the cell nucle­us. They also reg­u­late the expres­sion of the genome: com­pact­ed regions can­not be read and the genes con­cerned are con­sid­ered to be deac­ti­vat­ed. To bind to DNA, which is neg­a­tive­ly charged, his­tones are pos­i­tive­ly charged. A chem­i­cal mod­i­fi­ca­tion – known as acety­la­tion – changes their over­all charge and reduces their affin­i­ty for DNA. A mol­e­cule pro­duced by the break­down of sug­ars and lipids is required for this reac­tion, there­by pro­vid­ing anoth­er mol­e­c­u­lar link between metab­o­lism and gene expression.

Is it sim­ply enough then to change one’s diet to change the expres­sion pro­file of one’s genome? No, for most peo­ple the effects of such changes on gene reg­u­la­tion are minor. That said, the embryo is par­tic­u­lar­ly sen­si­tive to epi­ge­net­ic changes and a meta­bol­ic sig­nal can sig­nif­i­cant­ly affect development.

Exper­i­ments on ges­tat­ing mice show that envi­ron­men­tal fac­tors, such as stress, expo­sure to tox­ic com­pounds or diet, can have an impact on the epi­ge­net­ic mark­ers of the off­spring. Is this also the case in humans? It is not pos­si­ble to lock peo­ple up to con­trol their envi­ron­ment, but we can get around this by study­ing the impact of a major stress on a pop­u­la­tion. When researchers at the Uni­ver­si­ty of Lei­den stud­ied peo­ple who had lived through the great famine of 1944 in the Nether­lands, they iden­ti­fied a par­tic­u­lar type of methy­la­tion in their chil­dren. Some thought this was evi­dence of human epi­ge­net­ic inher­i­tance. How­ev­er, this obser­va­tion is not proof of a causal link and the demon­stra­tion of a mech­a­nism for trans­gen­er­a­tional trans­fer of marks is still lack­ing in humans. Indeed, epi­ge­net­ic marks are repro­grammed dur­ing gamete mat­u­ra­tion. They there­fore do not appear to be trans­mis­si­ble to future generations.

Anoth­er idea that is mis­tak­en­ly con­sid­ered proven is the link between biol­o­gy and behav­iour. In this field, researchers often study iden­ti­cal twins. These are two indi­vid­u­als with iden­ti­cal or near­ly iden­ti­cal genomes, for whom dif­fer­ences over time are often attrib­uted to the influ­ence of envi­ron­ment, lifestyle and expe­ri­ence in the broad sense. A per­fect mod­el for epi­ge­net­ics? No. It is dif­fi­cult to dis­tin­guish bio­log­i­cal facts from behav­iour. For exam­ple, if a child suf­fered abuse as a child and his or her descen­dants are also vic­tims. Is there a mol­e­c­u­lar or cul­tur­al mech­a­nism that needs to be addressed here? Dis­ci­plines at the bound­ary between social sci­ence and biol­o­gy are tack­ling these ques­tions, but some­times they draw hasty conclusions.

Final­ly, the fact that the field is becom­ing pop­u­lar can be explained by the reversible nature of epi­ge­net­ic marks. While it is at present dif­fi­cult to mod­i­fy the genome using gene ther­a­pies, the idea that treat­ments, called “epidrugs”, can mod­i­fy a patho­log­i­cal phe­no­type by act­ing on epi­ge­net­ic marks is attrac­tive. This is par­tic­u­lar­ly the case for can­cer, where the com­bi­na­tion of genet­ic and epi­ge­net­ic changes alters the iden­ti­ty of the cell and under­pins tumour behaviour.

Phar­ma­ceu­ti­cal com­pa­nies are devel­op­ing inhibitors to mod­i­fy epi­ge­net­ic marks. But, it is dif­fi­cult to tar­get the marks respon­si­ble for patho­log­i­cal phe­nom­e­na with­out alter­ing healthy marks. Patho­log­i­cal or not, they have the same chem­i­cal nature. Researchers are devel­op­ing mol­e­c­u­lar biol­o­gy tech­niques to try and resolve this issue, but clin­i­cal proof is still lacking.

All this research shows just how active the field of epi­ge­net­ic research is. It also points to a shift in think­ing in biol­o­gy, in which plas­tic­i­ty replaces the idea of deter­min­ism. We can thus look for­ward to change with opti­mism, and explore how edu­ca­tion and mod­i­fi­ca­tions in behav­iour can have a pos­i­tive impact on the future of individuals.