Engineering a permanent solution to genetic diseases

Engineering a permanent solution to genetic diseases
Basil Hubbard. Credit: Faculty of Medicine & Dentistry, University of Alberta

In his mind, Basil Hubbard can already picture a new world of therapeutic treatments for millions of patients just over the horizon. It's a future in which diseases like muscular dystrophy, cystic fibrosis and many others are treated permanently through the science of genome engineering. Thanks to his latest work, Hubbard is bringing that future closer to reality.

Hubbard's research, published in the journal Nature Methods, demonstrates a advancing the field of genome engineering. The method significantly improves the ability of scientists to target specific faulty genes, and then "edit" them, replacing the damaged genetic code with healthy DNA.

"There is a trend in the to develop therapeutics in a more rational fashion, rather than just relying on traditional chemical screens," says Hubbard, an assistant professor of pharmacology in the University of Alberta's Faculty of Medicine & Dentistry. "We're moving towards a very logical type of treatment for genetic diseases, where we can actually say, 'Your disease is caused by a mutation in gene X, and we're going to correct this mutation to treat it'.

"In theory, genome engineering will eventually allow us to permanently cure by editing the specific faulty gene(s)."

Genome engineering involves the targeted, specific modification of an organism's genetic information. Much like how a computer programmer edits computer code, scientists could one day replace a person's broken or unhealthy genes with healthy ones through the use of sequence-specific DNA binding proteins attached to DNA-editing tools. The field has made large strides over the last two decades and may one day revolutionize medical care.

One of the obstacles still to be addressed in the field before it can see widespread use in humans is how to ensure the proteins only affect the specific target genes in need of repair. With current technologies, the proteins bind to and edit the correct genes the vast majority of the time, but more improvements are needed to ensure off-target genes aren't modified—a result that could potentially cause serious health problems itself.

Through his research, undertaken as a post-doctoral fellow in the lab of David R. Liu at Harvard University, Hubbard has developed a way to reduce the off-target DNA binding of a class of gene editing proteins known as transcription activator-like effector nucleases (TALENs). The new method allows researchers to rapidly evolve the proteins autonomously to make them more specific and targeted over time.

"This technology allows you to systematically say, 'I want to target this DNA sequence, and I don't want to target these others,' and it basically evolves a protein to do just that," says Hubbard. "Using this system, we can produce gene editing tools that are 100 times more specific for their target sequence".

Currently much of the research in the field of genome engineering is focused on treating monogenic diseases—diseases that involve a single gene—as they're much easier for researchers to successfully target. Examples include diseases such as hemophilia, sickle cell anemia, and .

While the field is still in its relative infancy, Hubbard says human clinical trials involving sequence-specific DNA-editing agents are already underway. If successful, he expects the first clinical applications could be seen in the next decade. He hopes his current work will play a role in helping genome engineering reach its full potential and plans to continue his research in the quickly expanding field.

"Whereas traditional pharmaceutical drugs have a transient effect, could possibly provide a permanent cure for a lot of different diseases," says Hubbard. "We still have to overcome many hurdles but I think this technology definitely has the potential to be transformative in medicine."


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CRISPR-based genome editing technologies poised to revolutionize medicine and industry

More information: Continuous directed evolution of DNA-binding proteins to improve TALEN specificity, DOI: 10.1038/nmeth.3515
Journal information: Nature Methods

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Aug 10, 2015
I love this technology but have to wonder who decides whether a gene is beneficial or detrimental?
For example I read an article about a defective gene that slowed down a person's metabolism while he slept, leading to overweight. From the dawn of man up until maybe 200 years ago this would have been deemed a beneficial gene, that warded off starvation.

What about homosexuals? What if you could (fix?) them, And make them heterosexual?

Aug 10, 2015
"What about homosexuals? What if you could (fix?) them, And make them heterosexual?"

Homosexuality is not a broken state that needs fixing. Bigotry on the other hand . . .

Aug 10, 2015
I love this technology but have to wonder who decides whether a gene is beneficial or detrimental?


My guess is, unless your health care provider or the government is granted legal authority over your medical decisions, the individual person with those genes will decide. The doctors will provide information, e.g. this mutation in your gene is causing your cystic fibrosis, and then the patient would decide to have the gene edited or not. Each treatment would require FDA approval so if the FDA approved a gene therapy that could make homosexuals straight (or vice versa), then patients would have more options if they wanted. Although a complex personality trait like homosexuality is not likely to be affected by editing single genes, and probably could only work if done very early in development. Once the brain is wired a certain way probably not a simple matter of changing a gene to change the brain. But you raise the age old philosophical question...

Aug 10, 2015
Who cares about that...this stuff can get rid of diseases maybe improve human strength, memory, intelligence. America needs that - China has already instituted selective breeding programs, and all the americans being born are basically monkeys. I saw a chart that said that intelligence in north america has declined over 10% over the past 50 years, while it has been steady or increased other parts in the world. This technology, could it reverse that trend?

I wonder if it could be used as a weapon too?

Aug 10, 2015
The skies the limit.
IQ is a physical trait so it can be edited.
The greatest weapon in the universe is intelligence.
Once we know what all the genes do and how they are related (I repeat) the skies the limit.
And in time we will know.

Aug 10, 2015
Speaking of IQ, see if you can figure out why I put the question mark after (fix?), Tektrix

"What about homosexuals? What if you could (fix?) them, And make them heterosexual?"

Tektrix
Homosexuality is not a broken state that needs fixing. Bigotry on the other hand . . .


Aug 11, 2015
What else could we change? Physical traits like attractiveness? I wonder how long before human tests begin.

EWH
Aug 15, 2015
Changing genes in adults is billions of times more difficult than doing it in gametes or embryos, so embryo engineering will happen first. Also, it doesn't work to edit those genes in adults which control early development. Parents will be the ones making the decisions, and legal regulations won't have much effect - this technology is too small-scale and stealthy to be regulated easily.

According to physics professor Stephen Hsu, using compressed sensing techniques the knowledge needed to predict massively polygenetic traits such as intelligence will require about 300,000 full human genome sequences together with physical measurements, biographies and mental tests. CRISPR may never be reliable enough to change hundreds or thousands of genes as would be needed for large intelligence gains, but a combination of pre-implantation embryo selection and a few dozen edits could yield a standard deviation or two, which is big.

Aug 15, 2015
NEVER? Big word, and I am sure better methods than crisper will be developed.
Quote "billions of times more difficult"
Does that bean it can't ever be done?
Granted embryos editing is easer but the editing of a fully developed human being WILL happen.

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