[smart (OP)]

Yesterday I watched a disturbing news report on tv about how people with Down syndrome could become affected by Alzheimer later in their life. I felt really bad for people affected by this condition. It must be a living hell to have this disease. 

So, is there any ways we could eradicate this disease permanently from the human genome with genetic engineering technology like CRISPR?

How far are we from improving the human genome and preventing this disease from happening in the first place?

What do you think?

[RD]

Yesterday I watched a disturbing news report on tv about how people with Down syndrome could become affected by Alzheimer later in their life ...

Unusually few people with Down's syndrome make it to an age where Alzheimer's kicks-in :
their average life expectancy is about 55. Congenital heart-defects bring down their average.

An extra copy of chromosome 21 is not entirely negative, see ...
https://www.newscientist.com/article/dn2073-downs-syndrome-lifespan-doubles/

[smart (OP)]

An extra copy of chromosome 21 is not entirely negative, see ...
https://www.newscientist.com/article/dn2073-downs-syndrome-lifespan-doubles/

What does that mean?

Can you use CRISPR for editing the human genome by suppressing bad genes ?
 

[evan_au]

is there any ways we could eradicate (Down Syndrome) permanently from the human genome with genetic engineering technology like CRISPR?

I'm afraid not.

Down syndrome is is caused by a problem in development of the egg and sperm. It is not inherited from the parents.
So even if you eliminated it from one generation, it would reappear in the next generation.

Down Syndrome
Down Syndrome, or "Trisomy 21" is not related to "one bad gene", but an extra copy of a whole chromosome.

Chromosome 21 is the smallest human gene, and is estimated to have around 230 protein-coding genes and 300 genes that code for RNAs. With a third chromosome, some of these genes can be expressed 50% more than normal; but it's not clear which genes are causing the problems. Down syndrome is very variable in presentation, so the genes causing the problems may differ significantly between individuals.

It is this "small" number of genes that makes the third copy less lethal than a third copy of non-sex chromosomes (mammals have some established ways of dealing with extra copies of sex chromosomes).

See: https://en.wikipedia.org/wiki/Down_syndrome
https://en.wikipedia.org/wiki/Chromosome_21_(human)

CRISPR
While CRISPR is undoubtedly a huge advance over previous genetic engineering techniques, it is still only effective at making a single change in in 80-90% of isolated cells (with current techniques).

If you now try to make 500 coordinated changes in a single cell, your chance of success drops to around 0.85⁵⁰⁰, or around 5x10^-36.

Worse than that, these genes are not "faulty" - the 2 other copies of Chromosome 21 have near-identical copies of the same genes. With 85% success rate, the chance that you will wipe out all 3 copies of a particular gene is 0.85³ = 61%. Having zero active copies of a gene is far more lethal than having 3 active copies. Now multiply that by 500 genes, and the therapy would be fatal.

In reality, CRISPR is mostly suitable for single cells exposed in a dish (or perhaps exposed in the retina of the eye or the walls of blood vessels), rather than cells already assembled in an organ, a baby or an adult. It is just too hard to get the CRISPR to the cells you want (and not the cells you want untouched), and then separate the numerous failures from the successes. 

[RD]

An extra copy of chromosome 21 is not entirely negative, see ...
https://www.newscientist.com/article/dn2073-downs-syndrome-lifespan-doubles/

What does that mean?

If you read the NewScientist article you'd learn that people with Down's syndrome have a lower incidence of some cancers ...
http://scienceblog.cancerresearchuk.org/2010/06/14/discovering-how-down%E2%80%99s-syndrome-can-protect-against-cancer/

If you could edit-out their extra copy of Chromosome 21 after they were born, that would not correct their abnormal anatomy, (e.g. brain & heart ), but would remove their extra-protection from cancer.

[smart (OP)]

If you could edit-out their extra copy of Chromosome 21 after they were born, that would not correct their abnormal anatomy, (e.g. brain & heart ), but would remove their extra-protection from cancer.

I want to repress the duplication of Chromosome 21 through RNA/DNA editing with CRISPR.

[evan_au]

I want to repress the duplication of Chromosome 21

It occurs in the formation of both eggs and sperm.

But an extra chromosome in a sperm (even a small one like chromosome 21) slows down the sperm a little, so it is less likely to be first across the finish line.

In practice, it is seen that the majority of trisomy 21 cases inherit the extra chromosome from their mother.
The incidence of trisomy 21 increases with the age of the mother; the incidence of Down syndrome increases by a factor of 30 between ages 20 and 45.
So you could repress it by encouraging people to have their children earlier.

I want to repress the duplication of Chromosome 21 through RNA/DNA editing with CRISPR

The chromosome miscount occurs to imperfect separation of chromosomes during meiosis.

It is possible that the cohesin links which hold the chromosomes in place becomes less effective over the 16 to 50 years that eggs are "on hold". These egg cells (and their cohesin bonds) are formed before a girl is born.

It is not clear which genes you would tweak (or how) to produce longer-lasting cohesin.
See: https://en.wikipedia.org/wiki/Meiosis#Nondisjunction
https://en.wikipedia.org/wiki/Nondisjunction#Molecular_mechanisms

One of the mottos of medicine is "do no harm".
At the current state of the technology, CRISPR (or any form of genetic engineering) is banned for use on human germline, because the risks are far greater than the benefits.

CRISPR has a high risk of doing nothing at all, and an unacceptably high probability of actually harming cells due to "off-target effects".

You must not risk the lives of generations to modify germ-line cells, in order to fix something which somewhat rare (1%) and is not normally fatal (Down syndrome).

If the CRISPR reliability could be increased from (say) 80% to 99%, then it might be justified using it to correct a known single-nucleotide mutation which is known to be 100% fatal.

In general, things like genetic counselling before marriage is best for at-risk groups.

High-risk groups (eg for untreatable conditions on the Y chromosome) are probably best treated with Pre-Implantation Genetic Diagnosis to select an embryo without the lethal condition. This is much more reliable than CRISPR, at the current state of the technology.

See: https://en.wikipedia.org/wiki/Preimplantation_genetic_diagnosis