What is Gene-Editing?

Is gene editing human embryos a positive scientific breakthrough for human health?

Or misuse of a powerful research tool?

Over the next six months, we will outline the basic biology behind gene editing, followed by a description of the process in general and in human embryos, specifically. View the other posts in this series!

The Basics

The genetic information of humans, collectively termed the “human genome,” is contained within 22 chromosomes plus either 2 “X” chromosomes in girls, or 1 “X” chromosome and 1 “Y” chromosome in boys.

Human genome: All of the genetic information needed for the embryonic development and adult function of a human being.

Each chromosome is two long strings of four deoxyribonucleic acid (DNA) units (Adenosine, Cytosine, Guanosine, Thymidine; A, C, G, T) attached to each other in a sequence specific for that gene. The two long strings are held together by attractions between the units, i.e., A in one string is attracted to T in the opposite string. (this is explained nicely in this 45 second animation: https://youtu.be/8Gpsjk1HW2E from the Howard Hughes Medical Institute)

Chromosome:  a long string of genes attached end to end and then folded with proteins in a specific way.

Each species has its own number of chromosomes, e.g. the genome of the laboratory mouse is divided among 20 chromosomes, even though the total amount of DNA is the same in each mouse and human cell, approximately 5 picograms. An onion also has 20 chromosomes, but they are an order of magnitude larger than human or mouse, with approximately 50 picograms of DNA per cell. So the amount of genetic information does not correspond to the complexity of the organism.

Importantly, there are two copies of each chromosome present in all cells (total of 46), except for sperm, which have only one copy. This becomes an important fact for gene editing.

The specific sequence of A, C, G, T units is interpreted in two steps. First by assembling a copy of the gene sequence to serve as a template, and secondly by stringing amino acids together to generate the sequence specified by the template. The process is an engineering marvel that takes place billions of times every day in cells throughout the body. The gene’s code for a specific protein is the order of combinations of three of the four A, C, G, T units specific for each amino acid.

Gene: A specific sequence of A, C, G, T units that instruct the sequence of amino acids that comprise a specific protein. Humans have 20- to 25 thousand genes

Picture a train moving down a track. The two rails for the wheels are the two strands of DNA comprised of series of A, C, G, T units attached to each other and attracted to the opposite strand for stability. As the engine wheels pass by the units, the sequence for the emerging single stranded template is “read” in the car behind that contains a stockpile of A, C, G, U ribonucleic acid (RNA) units that are strung together in the same sequence as the gene. Behind the train car synthesizing the template is another car full of amino acids and the enzymes that string them together to create the protein specified by the gene. (for more depth on this “train track” analogy, you can read an entire article here)

For example, consider the gene that codes for a protein responsible for tissue rejection, beta 2 microglobulin, B2M. It is part of chromosome 15. The single stranded RNA template copy of the gene is 1675 units long and the protein it codes for contains 119 amino acids. The B2M protein begins with the string of eight amino acids linked together like beads: Methionine- serine- arginine- serine- valine- alanine- leucine- alanine… which corresponds to gene sequence ATG TCT CGC TCC GTG GCC TTA GCT… This example also illustrates that each amino acid can have more than one triplet code, e.g. the triplet codes for serine are both TCT and TCC. This provides an important buffer for the specified amino acid should a T- to C- mutation occur in one of the codes for serine. And it also illustrates why everyone’s DNA sequences are not identical.

Moreover, to illustrate the importance of faithful replication of each chromosome every time a cell multiplies, if one unit were lost in the middle of the above sequence for B2M, e.g. a C, a “frame shift” would occur, and the sequence would become ATG TCT CGC TCG TGG CCT TAG… This sequence would code for methionine- serine- arginine- serine- tryptophan- proline- followed by the “stop” triplet, TAG. Hence, no B2M protein would be synthesized as a result of a deletion of a single C.

The accuracy of the cellular machinery to “translate” gene sequences into the amino acid sequences for functioning protein molecules is both extraordinary and essential for normal cell functions.

Protein translation: The process of stringing together amino acids according to the sequence of A, C, G, T units in the gene

Not only is translating the code into specific proteins essential to normal cell function, creating accurate and complete copies of all 46 chromosomes each and every time a cell multiplies is also essential to normal body functions.

Because each amino acid is specified by a triplet sequence, if even one A or C or G or T is accidentally eliminated during replication of the chromosome, it would result in a “frame shift” in the triplet codes, as described in the B2M example (also described in this brief video).

Gene edit: A modification of a specific sequence of A, C, G, T units that instruct the sequence of amino acids that comprise a specific protein. The edit may or may not alter the amino acid sequence and the protein.

This possibility is thought to be the reason for the second copy of each chromosome — as insurance that at least one copy of each gene will be available for the cell to use for essential processes. This is not the case for the X and Y chromosomes in males, which is why the disease hemophilia occurs in men. The genes that code for the proteins responsible for blood to clot following an injury are on the X chromosome. There is no back-up in men for mutations in X-chromosome genes, so such mutations result in loss of key blood clotting factors, hence hemophilia.

But there are extensive “gene repair” systems in every cell to correct mutations as they occur (Learn more). Most mutations are probably due to the complexity of the enzyme systems themselves, others result from the relentless bombardment from gamma rays experienced by everything on earth. Every change in a gene sequence can be termed “gene editing,” whether or not it is repaired.