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.