December 07, 2015

George Church Aging Reversal Prediction and the costs and capabilities of genetic treatments are nearing levels for effective human treatments

The specific prediction made by George Church in regards to antiaging and aging reversal is

in the 5 to 10 year timeframe there would be at least one aging reversal drug in clinical trials. This may already be true.

What is George Church's opinion of potential antiaging drugs [Metformin and rapaymycin] as compared to the prospective effectness of genetic treatments ?

George said in an email ** Too early to say, but since there are dozens of implicated genes, (plus combinations) the genetic treatment route seems quite appealing.

George Church wanted me to emphasize that recent research shows that editing sperm stem cells could be the safest approach to genetically editing humans. Jinsong Li, a biologist at the Shanghai Institutes for Biological Sciences has managed to use CRISPR to edit a gene that causes eye cataracts in mice, creating healthy newborn animals with “100 percent” success. Scientists say working with eggs will be harder. Men produce millions of new sperm a day—clear proof of stem cells at work. But women’s bodies work differently. Women appear to be born with all the eggs they’ll ever have, and biologically, it seems unlikely there is such a thing as an egg stem cell in adults.

Yet other scientists are already developing a work-around. They predict it will eventually be possible to take a skin cell from a woman and use a technology called “reprogramming” to convert it into an artificial egg in the laboratory. And they could make sperm the same way.

That means IVF clinics in the future might take a skin punch from a customer and return either gene-edited eggs or sperm a few weeks later. “There is no reason to think it can’t be done,” says George Daley, a noted stem cell researcher at Harvard University’s medical school. From what he’s seen, he says, the prospect of installing custom DNA edits into lab-grown reproductive cells is “very real.”

Here is a copy of a recent ten page presentation by George Church

Compelling medical applications of germline therapies

1) Mitochondrial diseases
2) Families in which post-natal remedies are not optimal and both parents are fully afflicted (20% of marriages involve close relatives)
3) Treating and screening single germ cells is safer than treating millions of somatic cells, since each cell adds to the collective risk of cancer.
4) PGD-IVF is not acceptable for medical or personal reasons.
5) Complex diseases with single-target solutions, which work better when applied earlier.

Nuclease Specificity
100-fold: Theoretical and empirical searches Mali et al., Cong et al. (Church & Zhang labs) Science 3-Jan-2013
1000-fold: Paired nickases. Mali, et al, Ran et al (Church, Zhang labs). Nat Biotechnol. 1-Aug-2013. Cell 12-Sep-2013
less than 5,000-fold: Truncated guide RNAs. Fu, et al. (Joung lab). Nat Biotechnol. 26-Jan-2014
over 100-fold: RNA-guided FokI nucleases (Joung & Liu labs) Nat Biotechnol. 25-Apr-2014
over 25-fold: Cas9 charge Slaymaker (Zhang lab) Science 1-Dec-2015

Whole Genome Sequencing costs will soon be below $10 a genome from about $1000 today

Efficiency and specificity goals?

Off-target: 1% to 0.002% of cells
Spontaneous error rate = ~50% per cell division
Clonal cells, e.g. spermatogonial stem cells (SSC)
Increase efficiency from 5-50% to 100%. (and Specificity.)
Analysis: BLESS, Guide-Seq, Digenome-seq, HTGTS, IDLV, whole genome, targeted seq.

We are not limited by natural variants or complexity:

GH therapies for non-GH alleles
• Turner syndrome
• Chronic renal failure
• Prader–Willi syndrome
• Intrauterine growth retardation
• Idiopathic short stature
• AIDS Muscle wasting
Also, Not limited to gene therapies: genetic counseling, gene drives, xenotransplantation

Enhancement via somatic gene therapies

Somatic protocols can spread more rapidly than germline modifications, since only 1% of the population per year (that is births) are of the correct age for germline impact, while somatic therapy is applicable at any age.
Pathogen resistance CCR5, FUT2
Cognitive (ASD/AD) NGF, NEU1, GRIN2B, PDE4B

SOURCE - George Church email, presentation and interview

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