From The Swiss Federal Institute of Technology in Zürich [ETH Zürich] [Eidgenössische Technische Hochschule Zürich] (CH): “Making CRISPR hype more of a reality”

From The Swiss Federal Institute of Technology in Zürich [ETH Zürich] [Eidgenössische Technische Hochschule Zürich] (CH)

7.6.22
Dr. Eric Aird

This year we celebrate 10 years of genome editing with CRISPR.

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Scientific American/ Credit: Getty Images

The system is often referred to as molecular scissors, and this designation is quite accurate for its first applications. These short 10 years were marked by stunningly swift development and a great promise to cure thousands of genetic diseases with relative ease – with a single treatment dose that specifically corrects disease-​causing DNA mutations in the body’s cells. Sickle cell anemia and muscular dystrophy are two such diseases. And indeed, a decade later, we are now delivering on that promise in the form of many therapies currently being tested in human clinical trials.

Parallel to the development of the first such therapies, scientists have further evolved genome editing technologies. Recently developed molecular CRISPR tools have little in common with molecular scissors and are poised to make medical applications even safer.

Let’s take a brief look back: “first generation” CRISPR genetic scissors dock at specific sites in the genome and cut the DNA molecule. The cell generates short, arbitrary mutations at the break site to, for example, disrupt gene function. However, unintended genetic alterations to the cell are possible, and the scope of diseases treatable with this methodology are relatively small. An ill-​intended cut in the genome might manifest itself as a trigger for cancer decades later. Additionally, these scissors cause DNA damage, and such damage is inherently toxic and potentially lethal for cells. Stem cells, a primary target for clinical uses of CRISPR, react particularly sensitively to DNA damage.

A broad application of this first generation of CRISPR in humans is therefore not entirely risk-​free. This is also a major reason why scientists have developed molecular tools to generate genomic modifications without using scissors.

In the past few years, researchers across the globe have developed a host of such “next generation” CRISPR technologies. A more appropriate analogy for these innovative systems would that be of a molecular taxi. Such platforms can be used to shuttle, for example, specialized proteins to specific destinations in the genome. These proteins can directly change the DNA code without the same deleterious consequences caused by scissors.

Reduced toxicity

Not only does this approach reduce toxicity for cells, but it also vastly expands the range of treatable genetic diseases. Instead of simply cutting a gene to render it non-​functional, these CRISPR genome editors1 can be used to correct individual genetic mutations to restore gene function. It is estimated that more than 100,000 DNA mutations in our genome cause disease, a vast majority of which could be treated with such new technologies.

Next generation genome editing systems are expected to be used in human trials for the first time later this year. An American biotech company recently received approval to begin human trials to cure sickle cell disease and beta-​thalassemia.2 Treatments for high cholesterol and a form of blindness are also on the verge of moving into humans as well, not to mention the plethora of projects to treat a range of genetic disorders that are currently being tested in animals and could one day benefit humans. In all cases, these diseases can be cured by reverting the mutated genetic code back to the “normal” sequence, reversions which were not possible with the traditional CRISPR scissor-​based approach.

One-​time therapy

CRISPR-​based technologies have an enormous upside. Today, patients suffering from hemophilia need multiple infusions per week. A CRISPR treatment, on the other hand, would ideally take place once, and the cells modified with CRISPR would persist for the rest of the patient’s life.

This also means, however, that once the treatment has been started, it can no longer be discontinued. But would you choose a treatment where you can never stop taking the drug? This question arises with CRISPR-​based therapies.

Safety concerns about unintended editing have mostly, but not entirely, been alleviated with next generation CRISPR molecular taxis. It must be stressed that the first generation treatments currently being clinically tested have underwent extensive studies to determine and limit detrimental effects. Nevertheless, the safety of CRISPR-​based systems must be kept in mind. It is important that the long-​term safety profiles of CRISPR technologies are established, and therefore I expect the first CRISPR-​treated patients will be monitored for life.

A cure for previously incurable diseases

Given all the safety considerations, one must also consider the therapeutic alternatives. Take progeria for example, a genetic disease in which children rapidly age and medication only exists to marginally extend lifespan. A next generation CRISPR technology currently under development has the potential to revolutionize progeria therapy: it doubled the lifespan in mouse models. For a fatal disease like progeria, for which there is no or inadequate therapy, many patients are likely to opt for a CRISPR treatment, even if there is some residual risk of potentially negative outcomes in the long term.

The speed at which CRISPR technologies have advanced over the past decade has been tremendous. Regulatory agencies, which are required to assess the safety of these technologies, have sometimes failed to keep up with this pace. Urgently needed guidelines for the approval of the new technologies are not yet mature. This must change. There is a great need for action on the part of the regulatory authorities.

The first decade of CRISPR has brought immense potential, rapid technological development, and the first patients treated. As we look to the next 10 years, both first and next generation CRISPR systems are poised to deliver on its potential and provide life-​long cures to patients of both rare and more common genetic disorders.

See the full article here .

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ETH Zurich campus

The Swiss Federal Institute of Technology in Zürich [ETH Zürich] [Eidgenössische Technische Hochschule Zürich] (CH) is a public research university in the city of Zürich, Switzerland. Founded by the Swiss Federal Government in 1854 with the stated mission to educate engineers and scientists, the school focuses exclusively on science, technology, engineering and mathematics. Like its sister institution The Swiss Federal Institute of Technology in Lausanne [EPFL-École Polytechnique Fédérale de Lausanne](CH) , it is part of The Swiss Federal Institutes of Technology Domain (ETH Domain)) , part of the The Swiss Federal Department of Economic Affairs, Education and Research [EAER][Eidgenössisches Departement für Wirtschaft, Bildung und Forschung] [Département fédéral de l’économie, de la formation et de la recherche] (CH).

The university is an attractive destination for international students thanks to low tuition fees of 809 CHF per semester, PhD and graduate salaries that are amongst the world’s highest, and a world-class reputation in academia and industry. There are currently 22,200 students from over 120 countries, of which 4,180 are pursuing doctoral degrees. In the 2021 edition of the QS World University Rankings ETH Zürich is ranked 6th in the world and 8th by the Times Higher Education World Rankings 2020. In the 2020 QS World University Rankings by subject it is ranked 4th in the world for engineering and technology (2nd in Europe) and 1st for earth & marine science.

As of November 2019, 21 Nobel laureates, 2 Fields Medalists, 2 Pritzker Prize winners, and 1 Turing Award winner have been affiliated with the Institute, including Albert Einstein. Other notable alumni include John von Neumann and Santiago Calatrava. It is a founding member of the IDEA League and the International Alliance of Research Universities (IARU) and a member of the CESAER network.

ETH Zürich was founded on 7 February 1854 by the Swiss Confederation and began giving its first lectures on 16 October 1855 as a polytechnic institute (eidgenössische polytechnische schule) at various sites throughout the city of Zurich. It was initially composed of six faculties: architecture, civil engineering, mechanical engineering, chemistry, forestry, and an integrated department for the fields of mathematics, natural sciences, literature, and social and political sciences.

It is locally still known as Polytechnikum, or simply as Poly, derived from the original name eidgenössische polytechnische schule, which translates to “federal polytechnic school”.

ETH Zürich is a federal institute (i.e., under direct administration by the Swiss government), whereas The University of Zürich [Universität Zürich ] (CH) is a cantonal institution. The decision for a new federal university was heavily disputed at the time; the liberals pressed for a “federal university”, while the conservative forces wanted all universities to remain under cantonal control, worried that the liberals would gain more political power than they already had. In the beginning, both universities were co-located in the buildings of the University of Zürich.

From 1905 to 1908, under the presidency of Jérôme Franel, the course program of ETH Zürich was restructured to that of a real university and ETH Zürich was granted the right to award doctorates. In 1909 the first doctorates were awarded. In 1911, it was given its current name, Eidgenössische Technische Hochschule. In 1924, another reorganization structured the university in 12 departments. However, it now has 16 departments.

ETH Zürich, EPFL (Swiss Federal Institute of Technology in Lausanne) [École polytechnique fédérale de Lausanne](CH), and four associated research institutes form The Domain of the Swiss Federal Institutes of Technology (ETH Domain) [ETH-Bereich; Domaine des Écoles polytechniques fédérales] (CH) with the aim of collaborating on scientific projects.

Reputation and ranking

ETH Zürich is ranked among the top universities in the world. Typically, popular rankings place the institution as the best university in continental Europe and ETH Zürich is consistently ranked among the top 1-5 universities in Europe, and among the top 3-10 best universities of the world.

Historically, ETH Zürich has achieved its reputation particularly in the fields of chemistry, mathematics and physics. There are 32 Nobel laureates who are associated with ETH Zürich, the most recent of whom is Richard F. Heck, awarded the Nobel Prize in chemistry in 2010. Albert Einstein is perhaps its most famous alumnus.

In 2018, the QS World University Rankings placed ETH Zürich at 7th overall in the world. In 2015, ETH Zürich was ranked 5th in the world in Engineering, Science and Technology, just behind the Massachusetts Institute of Technology, Stanford University and University of Cambridge (UK). In 2015, ETH Zürich also ranked 6th in the world in Natural Sciences, and in 2016 ranked 1st in the world for Earth & Marine Sciences for the second consecutive year.

In 2016, Times Higher Education World University Rankings ranked ETH Zürich 9th overall in the world and 8th in the world in the field of Engineering & Technology, just behind the Massachusetts Institute of Technology, Stanford University, California Institute of Technology, Princeton University, University of Cambridge(UK), Imperial College London(UK) and University of Oxford(UK) .

In a comparison of Swiss universities by swissUP Ranking and in rankings published by CHE comparing the universities of German-speaking countries, ETH Zürich traditionally is ranked first in natural sciences, computer science and engineering sciences.

In the survey CHE Excellence Ranking on the quality of Western European graduate school programs in the fields of biology, chemistry, physics and mathematics, ETH Zürich was assessed as one of the three institutions to have excellent programs in all the considered fields, the other two being Imperial College London (UK) and the University of Cambridge (UK), respectively.