Tag Archives: CRISPR/Cas9 system

Lifesaving moths and nanomagnets

Rice University bioengineers use a magnetic field to activate nanoparticle-attached baculoviruses in a tissue. The viruses, which normally infect alfalfa looper moths, are modified to deliver gene-editing DNA code only to cells that are targeted with magnetic field-induced local transduction. Courtesy of the Laboratory of Biomolecular Engineering and Nanomedicine

Kudos to whomever put that diagram together! That’s a lot of well conveyed information.

Now for the details about how this technology might save lives. From a November 13, 2018 news item on Nanowerk,

A new technology that relies on a moth-infecting virus and nanomagnets could be used to edit defective genes that give rise to diseases like sickle cell, muscular dystrophy and cystic fibrosis.

Rice University bioengineer Gang Bao has combined magnetic nanoparticles with a viral container drawn from a particular species of moth to deliver CRISPR/Cas9 payloads that modify genes in a specific tissue or organ with spatial control.

A November 12, 2018 Rice University news release (also on EurekAlert published on November 13, 2018), which originated the news item, provides detail,

Because magnetic fields are simple to manipulate and, unlike light, pass easily through tissue, Bao and his colleagues want to use them to control the expression of viral payloads in target tissues by activating the virus that is otherwise inactivated in blood.

The research appears in Nature Biomedical Engineering. In nature, CRISPR/Cas9 bolsters microbes’ immune systems by recording the DNA of invaders. That gives microbes the ability to recognize and attack returning invaders, but scientists have been racing to adapt CRISPR/Cas9 to repair mutations that cause genetic diseases and to manipulate DNA in laboratory experiments.

CRISPR/Cas9 has the potential to halt hereditary disease – if scientists can get the genome-editing machinery to the right cells inside the body. But roadblocks remain, especially in delivering the gene-editing payloads with high efficiency.

Bao said it will be necessary to edit cells in the body to treat many diseases. “But efficiently delivering genome-editing machinery into target tissue in the body with spatial control remains a major challenge,” Bao said. “Even if you inject the viral vector locally, it can leak to other tissues and organs, and that could be dangerous.”

The delivery vehicle developed by Bao’s group is based on a virus that infects Autographa californica, aka the alfalfa looper, a moth native to North America. The cylindrical baculovirus vector (BV), the payload-carrying part of the virus, is considered large at up to 60 nanometers in diameter and 200-300 nanometers in length. That’s big enough to transport more than 38,000 base pairs of DNA, which is enough to supply multiple gene-editing units to a target cell, Bao said.

He said the inspiration to combine BV and magnetic nanoparticles came from discussions with Rice postdoctoral researcher and co-lead author Haibao Zhu, who learned about the virus during a postdoctoral stint in Singapore but knew nothing about magnetic nanoparticles until he joined the Bao lab. The Rice team had previous experience using iron oxide nanoparticles and an applied magnetic field to open blood vessel walls just enough to let large-molecule drugs pass through.

“We really didn’t know if this would work for gene editing or not, but we thought, ‘worth a shot,'” Bao said.

The researchers use the magnetic nanoparticles to activate BV and deliver gene-editing payloads only where they’re needed. To do this, they take advantage of an immune-system protein called C3 that normally inactivates baculoviruses.

“If we combine BV with magnetic nanoparticles, we can overcome this deactivation by applying the magnetic field,” Bao said. “The beauty is that when we deliver it, gene editing occurs only at the tissue, or the part of the tissue, where we apply the magnetic field.”

Application of the magnetic field allows BV transduction, the payload-delivery process that introduces gene-editing cargo into the target cell. The payload is also DNA, which encodes both a reporter gene and the CRISPR/Cas9 system.

In tests, the BV was loaded with green fluorescent proteins or firefly luciferase. Cells with the protein glowed brightly under a microscope, and experiments showed the magnets were highly effective at targeted delivery of BV cargoes in both cell cultures and lab animals.

Bao noted his and other labs are working on the delivery of CRISPR/Cas9 with adeno-associated viruses (AAV), but he said BV’s capacity for therapeutic cargo is roughly eight times larger. “However, it is necessary to make BV transduction into target cells more efficient,” he said.

Here’s a link to and a citation for the paper,

Spatial control of in vivo CRISPR–Cas9 genome editing via nanomagnets by Haibao Zhu, Linlin Zhang, Sheng Tong, Ciaran M. Lee, Harshavardhan Deshmukh, & Gang Bao. Nature Biomedical Engineering (2018) DOI: https://doi.org/10.1038/s41551-018-0318-7 Published: 12 November 2018

This paper is behind a paywall.

Montreal Neuro creates a new paradigm for technology transfer?

It’s one heck of a Christmas present. Canadian businessmen Larry Tannenbaum and his wife Judy have given the Montreal Neurological Institute (Montreal Neuro), which is affiliated with McGill University, a $20M donation. From a Dec. 16, 2016 McGill University news release,

The Prime Minister of Canada, Justin Trudeau, was present today at the Montreal Neurological Institute and Hospital (MNI) for the announcement of an important donation of $20 million by the Larry and Judy Tanenbaum family. This transformative gift will help to establish the Tanenbaum Open Science Institute, a bold initiative that will facilitate the sharing of neuroscience findings worldwide to accelerate the discovery of leading edge therapeutics to treat patients suffering from neurological diseases.

‟Today, we take an important step forward in opening up new horizons in neuroscience research and discovery,” said Mr. Larry Tanenbaum. ‟Our digital world provides for unprecedented opportunities to leverage advances in technology to the benefit of science.  That is what we are celebrating here today: the transformation of research, the removal of barriers, the breaking of silos and, most of all, the courage of researchers to put patients and progress ahead of all other considerations.”

Neuroscience has reached a new frontier, and advances in technology now allow scientists to better understand the brain and all its complexities in ways that were previously deemed impossible. The sharing of research findings amongst scientists is critical, not only due to the sheer scale of data involved, but also because diseases of the brain and the nervous system are amongst the most compelling unmet medical needs of our time.

Neurological diseases, mental illnesses, addictions, and brain and spinal cord injuries directly impact 1 in 3 Canadians, representing approximately 11 million people across the country.

“As internationally-recognized leaders in the field of brain research, we are uniquely placed to deliver on this ambitious initiative and reinforce our reputation as an institution that drives innovation, discovery and advanced patient care,” said Dr. Guy Rouleau, Director of the Montreal Neurological Institute and Hospital and Chair of McGill University’s Department of Neurology and Neurosurgery. “Part of the Tanenbaum family’s donation will be used to incentivize other Canadian researchers and institutions to adopt an Open Science model, thus strengthening the network of like-minded institutes working in this field.”

What they don’t mention in the news release is that they will not be pursuing any patents (for five years according to one of the people in the video but I can’t find text to substantiate that time limit*; there are no time limits noted elsewhere) on their work. For this detail and others, you have to listen to the video they’ve created,

The CBC (Canadian Broadcasting Corporation) news online Dec. 16, 2016 posting (with files from Sarah Leavitt and Justin Hayward) adds a few personal details about Tannenbaum,

“Our goal is simple: to accelerate brain research and discovery to relieve suffering,” said Tanenbaum.

Tanenbaum, a Canadian businessman and chairman of Maple Leaf Sports and Entertainment, said many of his loved ones suffered from neurological disorders.

“I lost my mother to Alzheimer’s, my father to a stroke, three dear friends to brain cancer, and a brilliant friend and scientist to clinical depression,” said Tanenbaum.

He hopes the institute will serve as the template for science research across the world, a thought that Trudeau echoed.

“This vision around open science, recognizing the role that Canada can and should play, the leadership that Canadians can have in this initiative is truly, truly exciting,” said Trudeau.

The Neurological Institute says the pharmaceutical industry is supportive of the open science concept because it will provide crucial base research that can later be used to develop drugs to fight an array of neurological conditions.

Jack Stilgoe in a Dec. 16, 2016 posting on the Guardian blogs explains what this donation could mean (Note: Links have been removed),

With the help of Tanenbaum’s gift of 20 million Canadian dollars (£12million) the ‘Neuro’, the Montreal Neurological Institute and Hospital, is setting up an experiment in experimentation, an Open Science Initiative with the express purpose of finding out the best way to realise the potential of scientific research.

Governments in science-rich countries are increasingly concerned that they do not appear to reaping the economic returns they feel they deserve from investments in scientific research. Their favoured response has been to try to bridge what they see as a ‘valley of death’ between basic scientific research and industrial applications. This has meant more funding for ‘translational research’ and the flowering of technology transfer offices within universities.

… There are some success stories, particularly in the life sciences. Patents from the work of Richard Axel at Columbia University at one point brought the university almost $100 million per year. The University of Florida received more than $150 million for inventing Gatorade in the 1960s. The stakes are high in the current battle between Berkely and MIT/Harvard over who owns the rights to the CRISPR/Cas9 system that has revolutionised genetic engineering and could be worth billions.

Policymakers imagine a world in which universities pay for themselves just as a pharmaceutical research lab does. However, for critics of technology transfer, such stories blind us to the reality of university’s entrepreneurial abilities.

For most universities, evidence of their money-making prowess is, to put it charitably, mixed. A recent Bloomberg report shows how quickly university patent incomes plunge once we look beyond the megastars. In 2014, just 15 US universities earned 70% of all patent royalties. British science policy researchers Paul Nightingale and Alex Coad conclude that ‘Roughly 9/10 US universities lose money on their technology transfer offices… MIT makes more money from selling T-shirts than it does from licensing’. A report from the Brookings institute concluded that the model of technology transfer ‘is unprofitable for most universities and sometimes even risks alienating the private sector’. In the UK, the situation is even worse. Businesses who have dealings with universities report that their technology transfer offices are often unrealistic in negotiations. In many cases, academics are, like a small child who refuses to let others play with a brand new football, unable to make the most of their gifts. And areas of science outside the life sciences are harder to patent than medicines, sports drinks and genetic engineering techniques. Trying too hard to force science towards the market may be, to use the phrase of science policy professor Keith Pavitt, like pushing a piece of string.

Science policy is slowly waking up to the realisation that the value of science may lie in people and places rather than papers and patents. It’s an idea that the Neuro, with the help of Tanenbaum’s gift, is going to test. By sharing data and giving away intellectual property, the initiative aims to attract new private partners to the institute and build Montreal as a hub for knowledge and innovation. The hypothesis is that this will be more lucrative than hoarding patents.

This experiment is not wishful thinking. It will be scientifically measured. It is the job of Richard Gold, a McGill University law professor, to see whether it works. He told me that his first task is ‘to figure out what to counts… There’s going to be a gap between what we would like to measure and what we can measure’. However, he sees an open-mindedness among his colleagues that is unusual. Some are evangelists for open science; some are sceptics. But they share a curiosity about new approaches and a recognition of a problem in neuroscience: ‘We haven’t come up with a new drug for Parkinson’s in 30 years. We don’t even understand the biological basis for many of these diseases. So whatever we’re doing at the moment doesn’t work’. …

Montreal Neuro made news on the ‘open science’ front in January 2016 when it formally announced its research would be freely available and that researchers would not be pursuing patents (see my January 22, 2016 posting).

I recommend reading Stilgoe’s posting in its entirety and for those who don’t know or have forgotten, Prime Minister’s Trudeau’s family has some experience with mental illness. His mother has been very open about her travails. This makes his presence at the announcement perhaps a bit more meaningful than the usual political presence at a major funding announcement.

*The five-year time limit is confirmed in a Feb. 17, 2017 McGill University news release about their presentations at the AAAS (American Association for the Advancement of Science) 2017 annual meeting) on EurekAlert,

umpstarting Neurological Research through Open Science – MNI & McGill University

Friday, February 17, 2017, 1:30-2:30 PM/ Room 208

Neurological research is advancing too slowly according to Dr. Guy Rouleau, director of the Montreal Neurological Institute (MNI) of McGill University. To speed up discovery, MNI has become the first ever Open Science academic institution in the world. In a five-year experiment, MNI is opening its books and making itself transparent to an international group of social scientists, policymakers, industrial partners, and members of civil society. They hope, by doing so, to accelerate research and the discovery of new treatments for patients with neurological diseases, and to encourage other leading institutions around the world to consider a similar model. A team led by McGill Faculty of Law’s Professor Richard Gold will monitor and evaluate how well the MNI Open Science experiment works and provide the scientific and policy worlds with insight into 21st century university-industry partnerships. At this workshop, Rouleau and Gold will discuss the benefits and challenges of this open-science initiative.