Preserved in the archives of the California Institute of Technology is a photograph of legendary physicist Richard Feynman's slate taken in 1988, the year he died of cancer. In one corner he had written: “What I cannot create, I cannot understand”. Many years later, a select group of researchers applied that maxim to biology: humans will only understand their nature when they are able to create their own genome from scratch. Achieving this continues to be one of the greatest challenges in science.
This Thursday a study is published that takes a decisive step towards that goal. Researchers from the University of Pennsylvania (United States) have created an artificial human chromosome that is capable of fitting into human cells, joining existing ones and passing from generation to generation.
Chromosomes are the large volumes in which our genome is grouped, a chaotic and repetitive sequence of 3,000 million chemical letters; and they are key in evolution, as they determine genetic inheritance and decide the sex of babies. Inside each of our cells there are 23 pairs of chromosomes that in turn contain smaller units, genes, responsible for producing all the proteins we need to be alive. Being able to write entire chromosomes or part of them opens the door to creating microbes, animals and human cells with new properties.
Anyone who consults the newspaper library in search of artificial human chromosomes will read that this was already achieved in 1997. A team from the United States introduced reduced versions of a human chromosome into human cells. It was a scientific triumph, but therapeutic applications were frozen, since, for unknown reasons, the small artificial chromosomes began to multiply uncontrollably until generating completely aberrant and probably carcinogenic genomes.
The human artificial chromosome presented this Thursday solves this problem. The researchers have created the artificial chromosome inside yeast cells, a very versatile microbe whose genome had already been almost completely rewritten in previous studies. They have focused on reproducing the centromere, the central part that is decisive for a chromosome to divide correctly and pass to the next generation. Once the artificial chromosome was assembled, a technique was used to fuse the yeast cell with a human cell. For the first time, the artificial chromosome has joined the rest of the chromosomes without causing aberrant multiplications, has remained stable and has been passed from mothers to daughters with high efficiency. The discovery is published in the journal Science, a reference for the best world science. Also participating in the discovery are scientists from the Craig Venter Institute, one of the pioneers who led the Human Genome Project, the first effort to read our entire genetic code, in the 1990s.
“It is an enormous achievement,” says Jef Boeke, a biochemist at New York University and one of the promoters of the Writing the Human Genome Project, whose goal is to achieve a completely synthetic human genome. “The difference between the chromosomes of 1997 and the current ones is like that between a Ford model T [uno de los primeros automóviles fabricados en serie en 1908] and a Tesla,” summarizes Boeke, who has not participated in the study. In 2016, his team listed the most promising applications of artificial chromosomes, such as creating human cells resistant to viruses or cancer, by multiplying gene copies. p53which acts as a tumor suppressor.
Those responsible for the work highlight that these new artificial chromosomes allow genomic editing to be carried out at a higher level. CRISPR and quality editing allow specific changes to be made to the genetic sequence, the equivalent of correcting a few typos in a paragraph. Viruses can also be used as transport vectors, but their capacity is also limited. This new system would allow genes or even groups of genes to be rewritten; which means changing entire chapters.
The artificial chromosome presented this Thursday has just 750,000 letters of DNA. The smallest of the human chromosomes, 21, whose triplication produces Down syndrome, has 46 million. Furthermore, only 182,000 letters of the artificial chromosome are of human origin (from chromosome 4); the rest are bacteria. It is these last sequences that provide stability and prevent aberrations, explains Ben Black, lead author of the work. “This system seems much more efficient than the previous ones. We think that it will not be difficult to increase the size of the artificial chromosomes to include larger sequences, which opens up many biotechnological applications,” he details. One possibility is to introduce suicide genes into tumor cells, he adds.
“It is a very important job,” highlights George Church, a researcher at Harvard University and another of the leaders of the project to write the first human genome. “Just as in computing we need computers with more and more memory, there is a great need to expand our storage capacity in genetic engineering,” he adds. This new technique allows the generation of “larger therapeutic loads” and the creation of organs for transplants with large sections of their genome previously designed.
Marc Güell, a bioengineer at the Pompeu Fabra University in Barcelona, believes that this technology could also improve and expand the possibilities of cell therapy, for example in treatments that genetically modify the patient's blood cells to treat cancer, the already famous CAR- T. “Another application would be to use these chromosomes to produce molecules of pharmaceutical interest, for example antibodies, with greater efficiency than currently,” he details.
Before you can write a genome you have to learn to read it. Although this project of more than a decade was concluded in 2003, the truth is that the complete genome of a specific person could not be read until two years ago. Karen Miga, a researcher at the University of California, Santa Cruz, is one of the scientists who led that work. One of the key points of the new human artificial chromosome is that “it is a genetic sequence that is transmitted safely from generation to generation, expressing its possible therapeutic value,” she highlights. “In humans, one could consider applying this new technology to pediatric genetic disorders in which large amounts of genomic DNA must be modified. Disorders of the hematopoietic system, including thalassemias, hemophilias, and anemias, are potentially suitable for correction with gene therapy vectors. Additionally, Duchenne muscular dystrophy, polycystic kidney disease, lysosomal storage disorders such as Hurler's disease, and cystic fibrosis are disorders that fall into this category,” she adds.
Francisco Antequera, an expert in synthetic biology at the University of Salamanca, appreciates the new work, although he warns that it is only a first step. “Human DNA fragments are still very small. But it is true that this method could serve to build increasingly larger chromosomes. I believe that in the future it will be possible to obtain entire chromosomes, but that will represent a new challenge, since handling such gigantic molecules in the laboratory is very, very difficult,” he explains. Beyond creating our own genetic code is the challenge of being able to manipulate it without producing nightmares.
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