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A Brief History of Genome Editing
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A Brief History of Genome Editing:
Drug Discovery :
The Emergence of Genetic Engineering...
1972
Genetic engineering was first used in 1972 in the Paul Berg lab.
The scientists combined the E. coli genome with the genes of a bacteriophage and the SV40 virus. (Nemudryi. AA. et al. 2014).
Figure 1: Paul Berg
Zinc Fingers- Early Drug Discovery phase at Cambridge University.
Figure 2: Sir Aaron Klug, 1979, who identified ZFN.
1985
This groundbreaking discovery kick started the practical development of Genome Manipulation.
Zinc Finger Nucleotides (ZFN) were first identified whilst studying transcription on the African Clawed Frog.
Klug and his team identified that ZFN's can be utilised to link linearly to a specific nucleic acid sequence (both RNA and DNA), of which can be varying lengths.
1987
An unexpected Discovery...
in 1987 the first recognition of a suspicious repetition of DNA sequence found within Escherichia. coli was named 'CRISPR'.
Despite not understanding much about the base sequence, the same CRISPR base sequence was then recognised in many other bacterias suggesting important evolutionary status.
Figure 3: illustration of the mechanism of CRISPR-cas9 acting as genetic scissors.
1994
Zinc Finger study finally published!
-E.J Rebar, C.O Pabo
The potential of the three zinc finger nucleotides was demonstrated through the blocking of the human oncogene within a mouse cell line.
The researches went on to demonstrate how they can activate a gene through a 9 base pair acting as a promoter. they then successfully switched on and off a gene. one step closer to FDA approval.
Figure 4: Zinc Finger Nucleotide cartoon illustration
2009
The First ZFN study ON HUMANS was Published
The study aimed to block the entry of HIV into cells using the Zinc Finger Nucleotides.
The scientists aimed to disrupt the CCR5 gene - which is involved with the entry point for HIV to move into cells.
Remarkably, CCR5 targeted gene therapy using ZFN on a patient known as 'The Berlin Patient' was the first and only reported HIV cure - An astonishing piece of evidence towards FDA ZFN approval
Figure 5: The Berlin Patient - Timothy Brown - 10 years after his recovery.
2011
Clinical testing: Genome editing on human cells using TALENs
Nature Methods named the methods of precise genome editing, including the TALEN system, method of the year.
The innovative method of precise genome editing by the TALEN system was presented 'Method of the Year' by Nature.com for;
'The ability to introduce targeted, tailored changes into the genomes of several species will make it feasible to ask more precise biological questions.'
Figure 6: Scientists T.Lux et al generated specific TALENs targeting the homologous HBG promoters to de-repress fetal hemoglobin. They did so in a human stem cells embedded inside mice.
(Nature Methods. 2011.)
CRISPR-cas9 gene editing achieved in mammalian cells
2013
Cong L et al was the pioneer who inserted the CRISPR-cas9 adaptive immune system into human cells for the first time.
This was a huge step in the pharmaceutical industry towards cost-effective, specific and scalable genome editing in human cells.
Figure 7: Illustration showing the mechanism of the CRISPR-cas9 enzyme to cause gene knockout and gene manipulation
2015
TALENs used to fight Leukemia
Gene editing using TALENs saved the lives of two infant girls suffering with leukemia.
the attempt to save a young girls life was a last resort in the Great Ormond street hospital in London.
The girls were both given the experimental treatment only as a last resort, but clinical trials of the therapy are now getting underway in children and adults in the UK. (Le Page. M. 2017).
First CRISPR genome edit on a living human.
Figure 8: The scientist behind the first CRISPR genome edit on a live human subject; He Jiankui.
2017
Rather controversially, the first CRISPR germline editing was implanted into a human embryo and then inserted back into the womb by Chinese scientist He Jiankui.
2019
CRISPR Clinical trial against Blindness
In 2019, a clinical trial based in Massachetus (USA) tested patients with a rare form of blindness called Leber’s Congenital Amaurosis 10 (LCA10) caused by a point mutation in the gene CEP290.
The injection of CRISPR-cas9 was injected directly into the patients eye.
Figure 9: The scientists injecting the CRISPR-cas9 into the patient with LCA10