Saturday, January 12, 2013

Genetically Engineered "Lifestock Improvement"

The discussion below looks at two new technologies for genetic engineering. One is Talens and the other is Cas9.  

I wonder whether the FDA has to approve these technologies or the USDA? I wonder what the long-term consequences are going to be for human health if Talens and Cas9 animals end up in our food supply?
  From the article "Editing Our Genes, One Letter at a Time" by Matt Ridley Jan 12-13 Wall Street  Journal, p. C4.

[Excerpted] "In recent years, it has become possible to insert a DNA sequence into a specific location on a chromosome using 'zinc finger proteins' which recognize target sequences. But these will work only for certain sequences, and with low efficiency. More recently, a process known by the acronym Talens has proved more adaptable.

This week, Recombinetics of St Paul Minn, patented gene-editing technologies that employ Talens for livestock improvement...."

Majia here: The article goes on to say that scientists led by Feng Zhang of MIT are promising a cheaper gene editing technology than Talens but it is still in the development phase. 

[paraphrasing] It uses an enzyme known by the acronym Crispr. This enzyme is created by bacteria when fighting off viruses. The particular Crispr enzyme known as Cas9 has been found useful for "precise cleavage" of cutting of DNA and it can be used at more than one site at a time, increasing the speed of gene editing.

Majia here: Talens genetically modified animals may be cloned, as suggested in this excerpt from a research abstract 

[Excerpted] TALEN-modified Ossabaw swine fetal fibroblasts were effective nuclear donors for cloning, resulting in the creation of miniature swine containing mono- and biallelic mutations of the LDL receptor gene as models of familial hypercholesterolemia. TALENs thus appear to represent a highly facile platform for the modification of livestock genomes for both biomedical and agricultural applications. (source Efficient TALEN-mediated gene knockout in livestock by D. F. Carlson et al, in PNAS

Here is an accessible article about Talens in Nature

What are the risks from modification?  Here one site summarizes the generic risks form GM animals (see also here):

Is Genetically Modified Food Safe? Benefits and Risk of Food and Livestock Modification Jennifer Gonzalez • edited by: Leigh A. Zaykoski • updated: 6/30/2011

[excerpted] Risks with Modification
While there are many benefits to genetically modifying food, there are also risks involved. One of the main concerns that come with ingesting genetically modified foods is an increase in allergic reactions in individuals that have known food allergies. For example, if someone eats a piece of meat or produce that has been altered with materials from another type of food that the individual is allergic to, the person may have an allergic reaction to the food that they never had a problem eating in the past. This could have a serious and potentially life-threatening outcome for some with severe food allergies, especially to items such as peanuts if they unknowingly consume food that has been altered with that substance.
Other risks include:

  • A plant that has been modified to resist pests that normally plague that plant may end up becoming weak to other forms of pests.
  • Plants and animals that have been altered can have unforeseen genetic changes that may become harmful.
  • Modified organisms may breed with unmodified organisms, which can cause the original organism to become extinct.
While genetically modified food is generally considered safe, no real research has yet been conducted. Currently there is no real way to know if you are purchasing or eating modified foods as there is no requirement for labeling at this time.

Majia here: an abstract from a research article on Talens (also see here ):

Reprod Fertil Dev. 2012 Dec;25(1):318. doi: 10.1071/RDv25n1Ab340. Gene inactivation and nonmeiotic allele introgression in livestock species using talens. Fahrenkrug SC, Tan W, Lillico SG, Stverakova D, Proudfoot C, Williamson G, Long CR, Whitelaw BA, Carlson DF.


[Excerpted] TALEN-induced double-strand breaks can be used for gene inactivation via repair by non-homologous end joining (NHEJ) or to stimulate homologous recombination (HR). HR can be used to introduce custom genetic modifications or to introgress naturally occurring alleles. We found that over 65% of custom-designed TALENs displayed activity in pig and cattle fibroblasts, with a typical percentage of indel positive chromosomes ranging from 20 to 45%. Isolation of individual clones with mono- and biallelic modifications to targeted loci was extremely efficient (up to 84 and 24% of clones, respectively) and could be accomplished without the aid of selection. Co-transfection of TALENs with a homologous repair template enabled precise insertion of a novel restriction site in nearly 40% of treated cells, with surprising levels of homozygosity. To prove that gene-edited Ossabaw swine cells were suitable for the generation of animals by cloning, we pooled colonies harboring both monoallelic and biallelic TALEN-induced frame-shift mutations in the swine low-density lipoprotein receptor (LDLR) and used them as nuclear donors for chromatin transfer. Pregnancy was established in 7/9 transfers, and 6 pregnancies were carried to term, resulting in the live birth of 18 piglets. Pigs heterozygous and homozygous for TALEN-induced mutations are being investigated as models of familial hypercholesterolemia (FH). We have additionally targeted the same locus for HR using a specified inactivating mutation. Fibroblasts heterozygous and homozygous for a specific 4-bp insertion into LDLR were created by allele introgression and have been cloned by chromatin transfer, demonstrating that gene editing can be used to create precise, swine knock-ins in a single generation. Allele introgression is also critical to livestock genetics, where crossbreeding has been a staple of breeding programs. Although major effect alleles for enhancing productivity and animal welfare have been discovered, the introgression of low-frequency alleles by traditional breeding is slow and inaccurate, involving recombination across the entire genome. The development of gene editing technologies would provide the opportunity to accelerate the genetic improvement in a diversity of livestock breeds. Co-transfection of a TALEN pair with a template containing a specific, naturally occurring allele was effective at the non-meiotic introgression of quantitative traits into the genome of cells from naïve cattle breeds, now being used to create founders by cloning. We will also present progress towards gene conversion by direct injection of livestock embryos. Injection of TALEN mRNA into the cytoplasm of pig and cattle zygotes was capable of inducing gene knockout (KO) in up to 75% of embryos analysed, nearly half of which harbored biallelic modification. We will present alternative strategies for the incorporation of gene editing into livestock genetic improvement programs by either cloning or embryo treatment.

MAJIA HERE: Coming to your dinner plate? I worry that genetically engineered animals are going to end up in our food supply before we know whether or not they are safe.

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