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-Synthego (2021) History of Genetic Engineering and the Rise of Genome Editing Tools. Versión digital, disponible en: https://www.synthego.com/learn/genome-engineering-history

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In the present decade, the development therapies that have been theorized and studied for years are finally being approved for humans, as the discovery of CRISPR, possibly the greatest achievement in the history of genetics, takes hold on the world.

Breaking into the next decade, we see a scientist creating the world's first synthetic life form, which technically means a living organism that was entirely built rather than evolved or born. In this experiment, a 1.08-mega-base pair Mycoplasma mycoides JCVI-syn1.0 genome was created by Craig Venter and his team, and transplanted into a M. capricolum recipient cell to create the new M. mycoides cells controlled entirely by the synthetic chromosome.

This marks an important stage in the field of biology, as it proves that life can be created synthetically, which has a great number of applications in the world of genetics.

While ZFNs represented a revolutionary change in that they were able to manipulate the genome, their DNA binding domain is notoriously hard to design for efficient cutting at the site of interest. The design process, therefore, can take months and still yield unsatisfactory results with off-target effects.

In 2011, generation two of designer nucleases came in the form of transcription activator-like effector nucleases, or TALENs, which recognize a single nucleotide rather than a trinucleotide motif. Compared to ZFNs, TALENs benefit from ease of design. Effective TALENs can be designed and manufactured in a few days, and can be multiplexed on the order of hundreds at a time.

TALENs appear to have fewer constraints on genome site, and can be easily targeted across the genome. TALENs were also found to have less off-target effects than ZFNs, and are less cytotoxic for the host cell. While TALENs have clear advantages over ZFNs, they also exhibit a few disadvantageous properties. They are significantly larger than ZFNs, and therefore can be harder to deliver and express in vivo. Along these lines, while knocking out a gene with ZFNs and TALENs proves fairly straightforward, knocking in a gene with this technology is more complicated.

In 2012, Jennifer Doudna , Emmanuelle Charpentier, and their teams elucidated the biochemical mechanism of CRISPR technology. By making precise targeted cuts in DNA, CRISPR ushered in endless potential in areas of medicine, agriculture, biomaterials, etc.

CRISPR-Cas9 is a bacterial adaptive immune system in nature, whereby pieces of DNA from invading viruses are snipped off by a bacteria nuclease, CRISPR associated protein. The DNA fragment that is chopped off is saved as memory for fighting future infections. The CRISPR-Cas9 system can be engineered to edit eukaryotic DNA by designing guide RNA complementary to the target sequence.

The guide RNA has a 20 base pair protospacer motif with flanking homology to the cut site of interest. Cas9 binds to this protospacer motif in the guide RNA, which in turn binds to the site of interest. Cas9 then binds to a protospacer adjacent motif (PAM) in the genomic DNA, and catalyzes a DSB in the DNA at a position three base pairs upstream of the PAM. If a homology arm is provided with the CRISPR-Cas9 cassette, HDR will occur, otherwise the cell will employ NHEJ to create small indels at the cut site of interest.

What CRISPR technology is being used for varies from developing cancer treatments, to tackling obesity, to creating hornless cows - and so much more. Whether it's diagnostics, treatment, or something else, there are new discoveries every day coming to the forefront of this field.

Just as significant was Feng Zhang's work in demonstrating the utility of CRISPR outside of the world of bacteria- in genetic manipulation of eukaryotic cells. His lab aims to use CRISPR to understand the functions of the brain using optogenetics, in which light is used to control genetically modified neurons to develop therapies that will treat brain disorders.

Though CRISPR was seen as an incredibly revolutionary potential treatment for countless diseases, Kevin Esvelt took the idea to a whole new level when he realized the potential of CRISPR gene drives. Gene drives are genetic elements that "cheat evolution" by biasing their transmission to offsprings beyond Mendelian laws. CRISPR based gene drives have promising potential in eradication of malaria and other vector borne diseases, as well in saving endangered species.

Esvelt realizes the potential danger of a system like this; the implications within even a small ecosystem could be catastrophic, and it would take immense amounts of testing before something like this was ever released. That's why the current studies of gene drives take significant precautions.

Photo courtesy AquaBounty

The salmon produced by the company AquaBounty were the first to be sold for human consumption as a genetically engineered animal. This process was more than 25 years in the making, and approved because of the simple need to provide a solution to the world's overfishing crisis.

In 2015, CRISPR was used to edit human embryos by Junjiu Huang at the Sun Yat-Sen University in Guangzhou. Originally rejected by Western science journals because it did not follow ethical rules of science, this later made its way into publication in other ways. Because Huang had altered the germline cells that affect heredity, his experiment aiming to fix a gene error causing a blood disease was not considered ethical, and became a controversy almost instantly. This was three years before human trials for CRISPR were officially approved by any governing body.

In 2017, two CAR T-cell therapies were approved: one for acute lymphoblastic leukemia in children, and one for advanced lymphoma in adults. This is a huge step for CAR T therapy, which, if treatments prove as effective as expected, will likely replace chemotherapy as the primary form of cancer treatment, as CAR T is not toxic to the human body, and has demonstrated complete ablation of cancerous tumors in as little as 10 days.

In a joint initiative by two companies, Vertex Pharmaceuticals & CRISPR Therapeutics, an experimental treatment for the blood disorder beta-thalassemia has been approved to start clinical trials. If successful, this therapy could end cases of this disorder, and sickle cell anemia. It would pave the way for future CRISPR treatments, changing the way disease is treated for humans.

In October 2019, Andrew Anzalone, a postdoctoral fellow from Dr. David Liu's lab, along with his colleagues published a paper on the development and application of prime editing in Nature. This novel gene editing technique can perform targeted small insertions, deletions, and base swapping in a precise way, while limiting negative effects. What sets this tool apart from CRISPR is its ability to do targeted editing without making double stranded breaks.

2020: The Year of CRISPR:Nobel Prize, Success of Clinical Trials and More

Dr. Haydar Frangoul (left) and Victoria Gray (right). Image credit: Amanda Stults/Sarah Cannon/TriStar Centennial

In the summer of 2020, the results of the CRISPR clinical trials began to slowly trickle in. Victoria Gray was the first patient to undergo the sickle cell disease treatment and her promising results started making headlines. Less than six months later, at the ASH meeting that took place in December 2020, the data presented showed that a total of ten patients that had received the CTX001 therapy had made significant progress. Seven of these patients were being treated for beta-thalassemia and the remaining three for sickle cell anemia. All of these patients showed a great improvement in fetal hemoglobin levels in their blood, had relief from bouts of pain and no longer required blood transfusions.

CRISPR also made headlines in October 2020 when it was announced that Emmanuelle Charpentier and Jennifer Doudna finally won the Nobel prize in chemistry for the development of CRISPR.

We hope you enjoyed this history of genetic engineering timeline, but the journey of genome engineering is far from finished. With discoveries burgeoning across the globe, human health and disease, along with areas such as agriculture, energy, animal husbandry, and environmental science among others all stand to benefit enormously from these strides forward. As CRISPR becomes as easy a tool to implement as hammer to nail, the world as we know it is continually bettered by the efforts of scientists who drive genome engineering technology forward.

If you're interested in the history, you're probably also interested in what's going on now! If you're looking for updates, be sure to check out our huge list of the best CRISPR news sources. If you have ideas of your own to share, or a story you think our readers would love, be sure to reach out by email at connect@synthego.com, or let us know on our Twitter page!

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History of Genetic Engineering and the Rise of Genome Editing Tools

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Understanding the history surrounding the progress of genetic engineering is incredibly important to understanding the current state of the field. Some important events include the discovery of the double helix, recombinant DNA (rDNA), human cancer therapies, the invention of CRISPR, and more.

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Gomez-Marquez, J. (2013) "La revolución de la ingeniería genética". Nova Acta Cientifica Compostelana. 20. 13-21 pp.

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Universidad de Guadalajara
Centro Universitario del Sur
Licenciatura en Agrobiotecnología
5° Semestre

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Barboza Del Toro José Alejandro
Calixto González Pedro Alejandro
Herrera Ramírez Paola Guadalupe
Recibe: Dr. Laura Elena Iñiguez Muñoz

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Descubrimiento de las leyes básicas de la herencia.

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Aislamiento de la nucleína, componente de los cromosomas.

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Demostración de que el material genético es ADN empleando bacterias tipo neumococos

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Confirmación de que el ADN es la molécula portadora de la información genética empleando el virus bacteriófago T2

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Watson, Crick y Wilkins establecen la estructura de la doble hélice de ADN con el apoyo de las imágenes de difracción de rayos X de Rosalind Franklin

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Se aíslan las polimerasas y se sintetiza el primer DNA in vitro.

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Descifran el código genético

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Descubrimiento de las enzimas de restricción, enzimas capaz de cortar ADN no metilado.

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Descubrimiento y aislamiento de las enzimas de restricción tipo II, a partir de la bacteria Haemophilus influenzae Rd.

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Demostración de la utilidad de las enzimas de restricción para el mapeo genético.

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Síntesis de la primera molécula de ADN recombinante

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Introdujeron ADN recombinante en bacterias.

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Conferencia de Asilomar, donde establecen los riesgos de la ingeniería genética

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Primeras directrices del National Institutes of Health "NIH" sobre la investigación en ingeniería genética

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Desarrollo de la técnica de secuenciación del ADN

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Primer secuenciado de genoma en virus X174

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La empresa Genentech produce la primera proteína humana, la "somatostatina", en la bacteria E.coli.

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Descubren el mecanismo de transferencia de ADN entre la bacteria Agrobacterium y las plantas.

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Genentech produce insulina humana en E.coli

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El tribunal supremo de EE.UU. dictamina que se pueden patentar microorganismos manipulados genéticamente.

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Creación del primer animal transgénico en el laboratorio usando ratones.

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Invención de la técnica de la reacción en cada de la polimerasa PCR

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Desarrollo de la "huella genética" como técnica fundamental de la Biología Forense

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Autorización de la primera vacuna, contra la hepatitis B, para uso en humanos producida por ingeniería genética

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Primer ensayo de terapia génica con una niña burbuja

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Primer vegetal transgénico "tomate FlavSavr" aprobado para el consumo humano.

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Primer genoma de una célula " Hemophilus influenzae" secuenciado

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Clonación del primer mamífero "oveja Dolly" a partir de células diferenciadas adultas

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Publicación en Nature y Science del primer borrador completo de la secuencia del genoma humano

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Se aprueba la primera medicina ligada a un gen objetivo.

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Se aprueba internacionalmente los cultivos transgénicos como una forma de apoyo a productores de países en desarrollo y como una medida para resolver crisis alimenticias.

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Se producen las primeras células pluripotentes animales a partir de la tecnología iPSC

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Aprobación de la primera vacuna recombinante preventiva a cáncer.

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Se crea la primera forma de vida sintética (Mycoplasma mycoides JCVI-syn1.0)

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Descubrimiento de tecnología TALEN para edición genómica específica.

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2013 Jennifer Doudna & Emmanuelle Charpentier

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2013 Jennifer Doudna & Emmanuelle Charpentier

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Descubrimiento de la herramienta dual CRISPR/Cas 9.

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Un embrión humano es editado empleando CRISPR.

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Se aprueba la primera terapia CAR T contra el cáncer.

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2018 Vertex Pharmaceuticals & CRISPR Therapeutics

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2018 Vertex Pharmaceuticals & CRISPR Therapeutics

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Se aprueban las primeras pruebas con CRISPR para un tratamiento contra blood disorder beta-thalassemia en humanos.

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"Prime editing". Edición génica de una sola cadena (no necesita romper dobles hebras).

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Al día de hoy, se continúan diseñando, corriendo y aprobando más estudios y experimentos, por lo que la ingeniería genética se sigue desarrollando como área de conocimiento, un futuro lleno de posibilidades se encuentra abierto.