We rely on the complete genetic information of both parents in order to develop normally. This sentence may sound self-evident – but it isn't. In fact, its proof was a scientific sensation. Davor Solter and Azim Surani provided this proof in 1984 when they simultaneously and independently published their discovery of the phenomenon of genomic imprinting. Unlike ants, bees or lizards, mammals cannot develop natural offspring from unfertilized eggs. This is because, in mammals, certain genes among the two copies – one provided by each parent to the fertilized egg cell from which an embryo later develops – are selectively silenced. In addition to their genetic information, these gene copies carry molecular markers that determine whether only the maternal or only the paternal copy is active. The genetic material from an egg and a sperm is thus functionally different. A complete set of chromosomes from both germ cells is therefore essential for the development of a viable organism. The discovery of genomic imprinting opened up the research field of epigenetics as a new field of molecular biology. This discovery is of considerable importance to human medicine: It explains a number of developmental disorders and contributes to our understanding of the origins and development of cancer and neurological diseases.

The genes that carry our genetic information are packed together in the chromosomes of the cell nucleus. There exist a total of 22 different autosomes as well as the two heterosomes X and Y, the combination of which determines the sex. Each germ cell contains a single set of 23 haploid chromosomes. By contrast, a fertilized germ cell (zygote), from which an embryo with all its somatic cells develops, is diploid. It contains two sets of chromosomes, one of which originating from the egg cell and the other from the sperm cell. In nature, however, it is principally possible for a new organism to develop even without a male contribution. In such cases, the egg cell forms the diploid chromosome set on its own. This form of reproduction – known as parthenogenesis – occurs in many plants and can oftentimes also be found in some animal species, from aphids to turkeys. The question of why parthenogenesis is not feasible in mammals has long been a central problem in developmental biology, and it is the starting point for the research work of the two prizewinners. Both employed a new technique of transplanting cell nuclei, which Davor Solter and his postdoctoral student James McGrath had decisively developed further in the early 1980s . Their technique made it possible to aspirate the nuclei of a cell through a micropipette without destroying the cell by rupturing the membrane, and subsequently introduce another nucleus into the cell by capitalizing on the ability of a virus to facilitate cell fusion.

The Invention of Cell Nuclei Transplantation...
Solter applied this technique to the pronuclei of mice that are present in the egg immediately after fertilization– i.e. when an egg and a sperm have fused to form a single-cell embryo (zygote). By removing one of the two pronuclei and replacing it with a pronucleus from another strain of mice, Solter constructed three different groups of single-cell mouse embryos. In the first, both sets of chromosomes were of female origin, in the second both of male origin, while the control group contained one female and one male pronucleus . Based on prior knowledge, embryos from all three groups were expected to develop into viable mice under these circumstances. Indeed, at the time, the assumption was that an egg cell with a diploid set of chromosomes should suffice for embryonic development to occur. In addition, the zygotes used in the experiment were the result of a normal fertilization event, meaning they could not have lacked any potentially essential developmental contribution from the sperm cell in addition to its nucleus. Moreover, the transplanted second nucleus came from a different strain of mice, avoiding the duplication of chromosomal information with its inherent problem of uncovering "hidden" genetic defects. To the surprise of Solter, and Surani, who had adopted a near identical experimental approach at the same time, neither the embryos equipped with a double female nor those with a double male chromosome set were capable of normal development. Without exception, these embryos all perished. Only the embryos from the control group developed into viable mice. From this unexpected result, Solter and Surani concluded that in mammals, the maternal chromosomes provide functions that the paternal chromosomes lack – and vice versa. Since some genes are obviously only transmitted by the mother and some only by the father in an active, readable form, both parental chromosome sets have to be transmitted in their entirety for a child to develop. Azim Surani coined the term genomic imprinting to describe the phenomenon of uniparental predetermination.

... Opened the Door to a New Research Field.
With their discovery , , this year's prizewinners shook the foundations of classical genetics. According to Mendel's laws on inheritance, parents each pass on a functionally equivalent set of their genes to their offspring. While these parental copies sometimes appear as different alleles, both are typically active. Our body cells therefore use both copies as blueprints for producing RNA molecules and proteins. Both gene copies can influence a child's physical characteristics (phenotype), even if some appear dominant (meaning they override the other allele) while others are recessive (i.e. subordinate to the other allele). If one copy is mutated or damaged, the other usually compensates. However, in the case of imprinted genes, only one copy determines the phenotype – the other is permanently silenced from the outset of development. This means that if the active copy is mutated or damaged, there is no backup. The silencing of one parental gene does not occur because its DNA sequence differs from that of the active gene; in fact, their sequence is identical, but one copy is tagged or not with tiny molecular flags that prevent its expression. This silencing therefore happens not for genetic but for epigenetic reasons. With their discovery of genomic imprinting, Davor Solter and Azim Surani opened up a previously inaccessible path for scientific enquiry. They unlocked a new door in the old edifice of genetics, through which thousands of researchers have since passed to cultivate the vast and fertile field of modern epigenetics.

The Sign Language on Imprinted Genes...
Traditionally, epigenesis is a term coined by William Harvey in the 17th century to counter the then-emerging theory of preformation, which many scientists subscribed to after claiming to have observed tiny, fully-formed organisms using the earliest microscopes. They concluded that humans were already preformed as miniature beings in either the egg or sperm (the cell theory would not emerge until 200 years later) and simply needed to mature to full size during embryogenesis. Harvey opposed this idea with the view that an organism could only develop step by step. The more scientific understanding advanced, the more absurd the once influential preformation theory appeared. However, when genetics emerged in the early 20th century and demonstrated that an organism's phenotype is encoded in its genotype, many embryologists feared a resurgence of preformationist thinking. In response, they began using the adjective “epigenetic" to describe all those aspects of development that are not determined by genes. This is the root of the public misconception that epigenetic simply means non-genetic. Even British researcher Conrad Waddington, often considered the father of epigenetics, did not change this misunderstanding – despite being the first to use the noun epigenetics in 1942 to define a new field of science that was intended to describe all the mechanisms by which genes guide our development. Only one year later, Oswald Avery made the groundbreaking discovery that the deoxyribonucleic acid DNA, long considered chemically dull, is the carrier of genetic information. And another decade later, its structure was unraveled by Watson and Crick, thanks to the foundational work of the British chemist and crystallographer Rosalind Franklin. And another decade would pass before the genetic code was fully deciphered. Only then was the foundation laid to define epigenetics as the study of all molecular processes that significantly influence gene expression without altering the DNA sequence itself, as it is understood in today's foundations of molecular biology. However, it was the discovery of genomic imprinting that finally enabled this definition to be placed on a solid and experimentally supported basis.

...Solves an Evolutionary Conflict Not Without Risk.
The idea that methyl groups attached to specific DNA sites might play an important role in gene expression during embryonic development was first proposed in 1975 by two research groups – although at the time, they provided no empirical evidence. In the years that followed, several experiments did suggest the significance of methylation, but its central role in regulating gene expression only became apparent through detailed analysis of the mechanisms behind genomic imprinting. Shortly after the discovery of imprinting, it became evident that the decision as to which parental gene copy is active and which is silenced in imprinted genes is primarily determined by DNA methylation patterns. Such patterns can mark either the active or the inactive allele. A second major class of epigenetic marks, the modification of histones (around which DNA is wrapped), plays only a minor role in genomic imprinting. In mammals, methyl groups are exclusively attached to one of the four DNA building blocks: cytosine. Seven years after Solter and Surani's breakthrough, the first two imprinted genes were identified in 1991. Coincidentally, they turned out to be a ligand-receptor pair: the growth factor IGF2 and its receptor IGF2R. IGF2 promotes growth and is only active on the paternally inherited chromosome, while IGF2R inhibits growth and is only active on the maternally inherited chromosome. This observation favored the hypothesis that genomic imprinting was an evolutionary step essential for the emergence of higher mammals with internal fertilization and development in the uterus. Since the mother and the fetus growing compete for limited resources in the mother´s body, it is in the mother's interest to prevent the child from growing excessively – whether at her own expense or at the expense of future offspring. This contrasts with the evolutionary interest of fathers, who benefit if their newly conceived child grows as large as possible, regardless of the cost to increase the chances of survival after birth. Genomic imprinting provides a solution to this evolutionary conflict: growth-promoting impulses are delivered exclusively by the father, while growth-restricting signals come exclusively from the mother. However, the resolution of this inevitable conflict in this way carries the small but consequential risk of severe developmental disorders. For instance, active growth factor genes may accidentally be transmitted in a double-active form, as is the case with Beckwith-Wiedemann syndrome. Infants affected by this condition are born with excessive birth weight, often grow asymmetrically, and have enlarged tongues and internal organs; tumors are also common. Alternatively, the only active copy of a gene may fail completely, as in Prader-Willi syndrome. In affected infants, the diencephalon does not function properly. They are typically short in stature, intellectually disabled and become obese as toddlers due to insatiable appetite.

Regulating the Balance Between Health and Disease
In fact, the effects of many imprinted genes align well with the hypothesis that they play a balancing role in the evolutionary conflict between the competing interests of mother, father and child. However, not all imprinting phenomena can be explained by this theory. Thus, we still do not fully understand why the phenomenon of genomic imprinting exists. What we do know is that imprinting has medical relevance far beyond embryonic development, especially since around one percent of our genes are genomically imprinted. These genes are not evenly distributed across the genome; rather they are typically clustered around specific sites called imprinting control regions (ICRs). Many of these genes are involved in signaling pathways and metabolic processes that continue to influence health or disease in adulthood. For example, the loss of genomic imprinting of the IGF2 gene – meaning its unintended expression from both the paternal and maternal allele – has been linked to the development of colon cancer, glioblastomas and childhood kidney tumors (Wilms tumors). Conversely, excessive methylation (hypermethylation) of ICRs appears to contribute to the transformation of benign into malignant tumors in certain types of cancer. Imprinted genes are also particularly important for the development and function of the brain. Interestingly, imprinting patterns differ across brain regions, and differentiated neurological imprinting helps regulate social behavior. Disruptions in imprinting are likely involved in the development of both autism and epilepsy.

Can Experiences Be Inherited Epigenetically?
The discovery of genomic imprinting opened the door to the field of epigenetics – but epigenetics encompasses much more than just imprinting. Epigenetic DNA methylation and histone modifications are essential markers for cell differentiation, supplementing its genetically encoded transcriptional regulators. A liver cell, for example, reads different parts of the genetic information to make its essential proteins than does a muscle cell. Every cell type must develop up a kind of memory of what it is and which gene expression pattern defines its identity. In humans, these methylation patterns are mostly but not entirely erased twice during life. The first time occurs just before the embryo, which has just been created from two germ cells, implants in the uterus. At this stage, the germ cell program must be rewritten into a somatic cell program, which follows a different epigenetic pattern. The second time happens about two weeks later, when the somatic cells of the developing embryo begin to form the precursors of its first egg or sperm cells. These must then reacquire the germ line program. The imprinted genes survive the first wave of demethylation intact, resulting in one allele (either maternal or paternal) being active and the other being silenced in somatic cells. These imprints remain in the somatic cells of each person for life. However, during the second wave of demethylation – the reprogramming from somatic to germ cells – the imprinting marks are also erased and reestablished according to sex. This ensures that males can transmit only paternal imprints and females can transmit only maternal ones. The question of whether experiences – whether psychological, such as trauma, or biological, such as malnutrition – can change a parent's methylation patterns before conception in a way that alters the child's epigenome remains controversial. Scientists generally view the evidence for this theory in humans and other mammals as weak. Nevertheless, it remains a popular notion.