Breakthrough gene editing reported that removes deadly embryonic mutations; biotech licks its chops as stakes are incalculable for ensuing blockbusters.

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The News:

Scientists have modified human embryos to remove genetic mutations that cause heart failure in otherwise healthy young people in a landmark demonstration of the controversial procedure, The Guardian reports.

It is the first time that human embryos have had their genomes edited outside China, where researchers have performed a handful of small studies to determine whether the approach could prevent inherited diseases from being passed on from one generation to the next.

While none of the research so far has created babies from modified embryos, a move that would be illegal in many countries, the work represents a milestone in scientists’ efforts to master the technique and brings the prospect of human clinical trials one step closer.

The work, reported by Ian Sample at the Guardian, focused on an inherited form of heart disease, but scientists believe the same approach could work for other conditions caused by single gene mutations, such as cystic fibrosis and certain kinds of breast cancer.

“This embryo gene correction method, if proven safe, can potentially be used to prevent transmission of genetic disease to future generations,” said Paula Amato, a fertility specialist involved in the US-Korean study at Oregon Health & Science University, Portland.

First discovered in bacteria, CRISPR (clustered regularly interspaced short palindromic repeats) is a genome-editing tool that can target specific genes in any organism based on RNA–DNA base pairing and then precisely cut the gene through the activities of the enzyme known as CRISPR-associated protein 9 or Cas9.

The scientists used CRISPR-Cas9 to fix mutations in embryos made with the sperm of a man who inherited a heart condition known as hypertrophic cardiomyopathy, or HCM. The disease, which leads to a thickening of the heart’s muscular wall, affects one in 500 people and is a common cause of sudden cardiac arrest in young people.

Humans have two copies of every gene, but some diseases are caused by a mutation in only one of the copies. For the study, the scientists recruited a man who carried a single mutant copy of a gene called MYBPC3 which causes HCM.

When the scientists made embryos with the man’s sperm and healthy eggs from donors, they found that, as expected, about half of the embryos carried the mutant gene. If the affected embryos were implanted into women and carried to term, the resulting children would inherit the heart condition.

Writing in the journal Nature, the researchers describe how gene editing dramatically reduced the number of embryos that carried the dangerous mutation. When performed early enough, at the same time as fertilization, 42 out of 58 embryos, or 72%, were found to be free of the disease-causing mutation.

“They’ve got remarkably good results, it’s a big advance.” said Richard Hynes, a geneticist at MIT who this year co-chaired a major report on human genome editing for the US National Academy of Sciences (NAS). “This brings it closer to clinic, but there’s still a lot of work to do.”

“A genetic alteration that enhanced one trait could have unexpected negative consequences on other traits, and this would be an inherited feature for the next generation,” Rossant, co-author of the NAS report on gene editing, said. “The NAS report came out strongly against any form of gene editing designed to simply enhance human potential.”

Steve’s Take:

Seems like only yesterday that CAR-T technology was the breakthrough of the century, applied to cancer treatment. It’s based on T-cells that are isolated from an individual patient and then genetically modified. The genetic “reprogramming” enables the immune cells to recognize and fight cancerous tissue once they are reintroduced into the patient. The approach holds vast promise due to its high specificity and low danger of inciting immune-reaction against the re-implanted cells.

Then just a couple of days ago, a group of scientists, led by Shoukhrat Mitalipov at the Oregon Health & Science University, report the successful use of a gene editing technology to correct a disease-causing mutation in viable human embryos. The focus of this study is a single mutation in the gene MYBPC3, according to Scientific America.

This error is “dominant”–a child that inherits just one copy of the mutant gene is at high risk for a serious disease called hypertrophic cardiomyopathy, which can cause sudden cardiac death. Since each person has two gene copies and receives one randomly from each parent, a child with an affected father or mother has a 50% chance of inheriting the disease.

Since details of this study were leaked last week in the MIT Technology Review, there have been renewed calls to carefully consider the ethics of making heritable gene edits to embryos, eggs, and sperm. Concerns range from off-target effects and the inability of future generations to consent to genetic editing to the potential for Gattaca-style “designer babies.”

There is an additional reason, seldom discussed, that this study and CRISPR research will not usher in a “brave new world” of eugenics: the genetics of most traits is too complex. For example, height is a simple trait that is easily measured and strongly determined by genetic factors. However, unlike in the case of hypertrophic cardiomyopathy, there is not a single gene determining height, but hundreds.

High on the list of buzz kills, a recent study revealed that using CRISPR to edit just two genes can lead to disastrous chromosomal rearrangements. These fundamental stumbling blocks prohibit engineering more complex traits such as IQ, lifespan, and athletic ability.

If engineering human embryos with CRISPR has no clear application, why is it being pursued? At minimum, scientists conducting this research should confront its ethical dilemmas and offer sufficient justification for studies that may draw widespread opposition and fear, Scientific America says. Such controversial uses of CRISPR may jeopardize the success of its less burdened applications. For example, CRISPR makes it easy to edit the genomes of many organisms that serve as new disease models.

Additionally, ongoing work to apply CRISPR to adult cells may generate new treatments for diseases such as cancer and diabetes  without the ethical concerns of embryo modification.

Bottom Line:

It was only a matter of time before CRISPR moved beyond academia, and in 2015 a number of companies invested in CRISPR technology. First it was pharma goliath Novartis AG, which signed two separate deals with gene-editing start-ups Intellia Therapeutics Inc. and Caribou Biosciences Inc. It plans to use CRISPR for engineering immune cells and blood stem cells, and as a research tool for drug discovery.

Just weeks after Novartis’s deals, AstraZeneca PLC sealed four deals with the Wellcome Trust Sanger Institute, the Innovative Genomics Initiative, the Broad Institute and Whitehead Institute in Massachusetts, and Thermo Fisher Scientific. Complementing the company’s in-house CRISPR program, the technology will identify and validate new targets in preclinical models across a range of disease areas.

Then immunotherapy firm Juno Therapeutics shook hands with gene-editing start-up Editas Medicine to create anticancer immune cell therapies; Vertex Pharmaceuticals and CRISPR Therapeutics, another start-up, signed an agreement that could be valued at $2.6 billion; while Regeneron Pharmaceuticals formed a patent license agreement with ERS Genomics, which holds the rights to the foundational CRISPR intellectual property from Emmanuelle Charpentier, one of the CRISPR pioneers.

Everyone in biotech is chasing a share of the CRISPR prize, and Germany’s Merck Group KGaA will likely become the next company to acquire intellectual property rights, adding to the horde it began building in 2012. Labiotech.eu reports that Merck’s CRISPR patent, which the European Patent Office (EPO) has just signaled its intent to grant, will cover the use of the technology in “a genomic integration method for eukaryotic cells,” according to the statement.

As Richard Hynes, Professor of Cancer Research at MIT, told The New York Times, “We’ve always said in the past gene editing shouldn’t be done, mostly because it couldn’t be done safely. That’s still true, but now it looks like it’s going to be done safely soon…[It’s] a big breakthrough.”

Merck KGaA may lead the charge on the other side of the Atlantic. Filed in May of this year, Merck’s patent application describes what it calls “proxy-CRISPR,” which improves the efficiency, flexibility, and specificity of the original technique by giving access to previously inaccessible cell locations.

Steve's Take: Companies are fighting for the financial plunder from #CRISPR Click To Tweet

The pharma says explicitly that the method “can be used to replace a disease-associated mutation with a beneficial or functional sequence,” limiting its CRISPR patent to therapies and disease models while ruling out the introduction of vanity genes, says Labiotech.eu.

The CRISPR space isn’t only confined to pharma either, as American conglomerate DuPont also formed alliances with Lithuania’s Vilnius University and Caribou Biosciences, with a specific interest in plant breeding and agricultural applications.

I’ll keep you posted as the companies fight for a seat at the table when the financial plunder from CRISPR is bestowed upon the successful players. And of course I’ll provide my ideas for the likely winners that could bolster your investment portfolio.