No random beneficial mutations but a huge number of genetic maladies - Genetic entropy

15,000 human genetic illnesses due to over half a million harmful mutations in human genome

https://www.scientificamerican.com/article/new-gene-editing-pencil-erases-disease-causing-errors/

Excerpt: "There are more than 50,000 known human genetic maladies that have, in most cases, few good treatments and no cure. Now researchers at the Broad Institute of Harvard and MIT have developed a new tool that would theoretically make it possible to correct the genetic errors behind about 15,000 of these illnesses—including sickle-cell disease, cystic fibrosis and several forms of congenital deafness and blindness.

Standard gene-editing tools, such as the well-known CRISPR–Cas9 system, function like scissors; they can cut an offending gene from a strand of DNA. This could be useful against diseases such as Huntington’s, which is caused by duplications of genetic material.

The new tool, called ABE (adenine base editors), is more like an editing pencil, according to lead researcher David Liu. It lets scientists precisely change individual pairs of bases—the “letters” that form the “sentences” of the vast human genome—and thus might help address diseases like sickle cell that can be treated with a single letter change. Liu emphasizes that one tool is not better than the other; rather they can be used to address different types of problems.

But before ABE can be tried in human patients, Liu says, doctors would need to determine when to intervene in the course of a genetic disease. They would also have to figure out how to best deliver the gene editor to the relevant cells—and to prove the approach is safe and effective enough to make a difference for the patient.

Genes are made up of DNA—two long, parallel strands of molecules called nucleotides that are linked by pairs of chemical bases. The base A (adenine) always pairs with T (thymine); and G (guanine) joins with C (cytosine). But when the genetic machinery makes mistakes and puts a pair in the wrong place, it sometimes leads to disease. The new tool targets genetic errors in which an A–T base pair should be a G–C.
 

Liu is a professor of chemistry at Harvard University and a vice chair of the faculty at the Broad Institute. Along with his students and postdoctoral researchers he had previously developed base editors that convert C–G base pairs into T–A pairs. (The order is important, so a G–C mistake is not the same as a C–G one.) Liu, who is also an investigator with the Howard Hughes Medical Institute, said Tuesday in a news conference that he and others have been working on additional tools, which could correct other types of “spelling mistakes” in DNA. This led them to ABE.

The new ABE technique uses an enzyme Liu and his colleagues developed. It rearranges the atoms in A so they form a base that resembles G in a DNA strand. The ABE system also nicks the mated DNA strand that contains the T. The cell’s repair mechanisms then turn on to fix the tear. In doing so, the cell replaces the T with a C, correcting the other half of the base pair. The net result is the troublesome A–T base pair is converted into a beneficial G–C pair.

Using ABE in a lab dish, Liu and his colleagues were able to precisely edit genes that cause a hereditary form of hemochromatosis—a disease that leads the body to store too much iron, causing pain, fatigue, weakness and, if untreated, liver and heart failure. They also used ABE to install a different genetic mutation that compensates for the DNA defect that causes sickle-cell disease.

The ABE gene-editing process is efficient, effectively editing the relevant spot in the genome an average of 53 percent of the time across 17 tested sites, Liu said. It caused undesired effects less than 0.1 percent of the time, he added. That success rate is comparable with what CRISPR can do when it is cutting genes.

Dirk Hockemeyer, an assistant professor at the University of California, Berkeley, who was not involved in the Broad research, said he is impressed in the work and the tool the team developed. But it is still a long way from helping patients. “In clinical applications the key question is always delivery, delivery, delivery: How do I get the editing agent to the position in the cell that I want to repair?” he says. But “if it cures a single disease, we should all be happy.”"

My comment: I just wrote an article about random beneficial mutations in human genome. Seems that they don't exist. You can read more about it here. However, there are over half a million harmful genetic mutations that have resulted in 15,000 genetic diseases. Human genome is rapidly degrading. Mutation rate is fast: 100-200 new germline mutations will be brought by every generation. This study revealed 1 million human genome sequence errors. However, genetically (DNA) all people are 99.9 % similar. The 0.1% difference is strongly related to hereditary diseases. Behind this scientific fact is the NHGRI (The National Human Genome Research Institute). Scientists try to repair 32,000 GC > AT mutations in human genome because any imaginary selection is not able to weed them out.

Evolution has no mechanism because there are no random beneficial mutations and genomes are degrading so rapidly. Don't get lost.