by Ditsa Keren

Horizon Supports Scientists On The Path From Research To Therapy

Horizon Supports Scientists On The Path From Research To Therapy

Horizon Discovery drives the application of gene editing and gene modulation within the global life science market, supporting scientists on the path from research to therapy. In this fascinating interview, Horizon’s Global Head of Strategy and Corporate Development Brian Burke explains how Horizon’s portfolio of tools and services can help scientists gain a greater understanding of gene function, identify genetic disease drivers, deliver biotherapeutics, cellular and gene therapies for precision medicine and develop validated diagnostic workflows. 

Please describe the story behind the company: What sparked the idea, and how has it evolved so far?

I joined Horizon towards the end of 2012. I came from Millipore Sigma, as it is now known, or Sigma Aldrich back then. I was part of the team in the UK and Ireland that helped launch the first commercially available gene editing reagents, Zinc Finger Nucleases. 

When I joined Horizon, it struck me that while Sigma’s gene-editing reagents were highly efficient, Horizon focused much more on what the technology could achieve.  As a result, Horizon created what would have been the world’s largest collection of isogenic cell lines for cancer. This allowed researchers to ask questions about the effect of engineered changes between the parental and edited cell lines.  This was a powerful tool in areas such as synthetic lethality. 

In 2014 Horizon was listed on the London Stock Exchange. Since then, we’ve gone from 50 or 60 people to around 400 people and we continue to do more and more around the cell, using different gene editing or gene modulation technologies.  In 2017 Horizon acquired Dharmacon further extending the capabilities of the company towards gene modulation and gene editing reagent manufacturing.

One of the key tenets of Horizon’s approach to the market is to be agnostic to technology choice.  Horizon believes in using the best available technology for each customer.  In the Horizon portfolio, there is a range of different technologies. Horizon offers both small or short interfering RNA (siRNA) and short hairpin RNA (shRNA); We have different types of CRISPR technologies, and we’ve used other technologies in the past. Experience has shown us time and again that no one technology is universally perfect for everything. 

One of the rather interesting things about Horizon is that before becoming a gene-editing pioneer, we were a cancer research company. Cancer heritage has stayed with us throughout our journey and is highly valued by many of our biopharmaceutical customers. The relatively recent shift in screening techniques that were made possible using CRISPR systems, single-cell technologies, and the growth of sequencing power has changed how we and others have approached the cancer field. This has been incredibly powerful for us, both in developing our offerings and solving the challenges that our customers face.

The design and the outcome of the experiment is something that we have more insight into than perhaps other companies in this field.  We don’t see data as transactional and perhaps in that respect, we’re a bit old fashioned.  We want our customers to succeed! 

Here’s a quick introduction to Horizon’s CRISPR screening technology:

What is the difference between gene editing and gene modulation?

The older, more widely adopted technology was gene modulation. There are several different types, but essentially, gene modulation can be described as a dimmer switch for genes. It allows you to turn the light from being quite bright to dull and almost off or vice versa. In some cases, the light is off, even if there’s just a minor trace of that gene still active. By doing that, you can ask very powerful questions of cell models, you can make inferences about diseases and the methods by which these could be targeted by drugs. Modulation technology is very important and through the acquisition of Dharmacon, we gained a massive capability there. Dharmacon is one of the world’s major suppliers of that type of technology. 

By contrast, gene-editing technology, instead of being a dimmer switch, is more like an on and off switch. The advantage is that it removes any ambiguity because in biology you go from DNA to RNA to protein. Just because you turned something down with a dimmer switch, doesn’t necessarily mean it’s been eliminated. Sometimes, you only need a tiny amount of signal and you still have the protein in the system. At that point you’re comparing to some more systems because the protein is still there; versus when you gene-edit, you turn the gene off and the protein is gone. It’s a more reductionist and more elegant experiment. 

That said, there are advantages and disadvantages to both technologies. With gene editing, it can take three to four months to modify the cell line before you get to do the main experiment. That’s one of the drawbacks, and if you’re in an exploratory phase, or if you have a lot of different targets, that is a considerable amount of work. There are groups in the world who would do that, but the alternative would be to reach back to the gene modulation technology. It’s quicker to use. You can use it in a matter of hours or days, and you’re ready to start your experiment. That flexibility, even though you don’t get the full extent of gene knockout, gene knockdown is still very powerful and can be very appropriate. 

In some cases, for example, when studying essential genes, if you knock the gene out and completely turn it off, you’ll kill the cell. With gene modulation technology, you can reduce the presence of that gene to a level where the cell is still viable, proceed with the experimental question, and therefore attain success, whereas with CRISPR or a ZFN, the cell would not survive the edit. 

What are some typical use cases for Horizon?

In biology, one of the great challenges is the unknown unknowns.  It is hard to design a rational experiment around something you don’t yet know. It’s something that modern screening techniques and tools like CRISPR and RNAi are starting to overcome. 

One of the things that the technology has been used for was published in the Nature Communications Journal recently. The group looked at the Box Jellyfish, which has a very toxic venom that can be deadly if stung. An anti-venom was not able to be generated because one couldn’t get enough material to produce an antidote, as they do with snakes and spiders. A team from a university in Australia started studying this using CRISPR screening. They didn’t know what they were looking for, so they applied the toxins to the cells in one vessel; each cell had a different genetic change. They worked out which cells had better or worse survival rates, and they found that this was related to disruption of the cell membrane and additionally phospholipids and how they behave. There’s a new on-market drug for Diabetes that can be formulated as a treatment to minimize the effect of the Box Jellyfish venom. But it was only through the use of multiple CRISPR screens, where you’re embracing the unknown unknowns, that you could translate them back to a solution that matters. 

That’s the real power of the CRISPR screens. They are genome-wide, and because of the different techniques you can use, you’re able to distill down things that would otherwise take humans 100’s of years.

What are some of the challenges that scientists are struggling with these days, and how does Horizon help?

The complexity of what’s expected now from a peer-reviewed paper is quite incredible. When I did my Ph.D., if you did one technique and one or two experiments, there was a reasonable chance that the result would be meaningful and you could publish the paper. Nowadays, each paper has so many different techniques and so many different ways to look at a problem. In the same paper, you will see Microarray techniques, sequencing, PCR, protein expression, western blotting, all on the same paper.

Cultured cell lines remain one of the dark secrets of the life sciences.  The field is still overly reliant on cultured cell lines, typically derived from tumors that have evolved in different labs over the years to be a source of significant variability. It is really difficult to find biologically relevant cell lines that mimic human physiology. Other technologies are available, such as induced pluripotent cell lines. However, these are still not widely adopted and do not offer a perfect solution.  Horizon helps researchers develop panels of engineered cell lines to help them better understand how genotype drives biology, giving the end-user greater confidence in the data they’re generating.

Biopharmaceutical companies continue to conduct large amounts of screening to identify and understand potential drug targets.  Establishing mechanisms of action for the hits identified in these screens can be very time consuming due to the complexity of the genome. Horizon helps researchers in a number of different ways.  Our CRISPR screening allows for genome-wide and highly cost-effective experiments to investigate how different drug targets work. Our products and services in this area allow scientists to essentially run thousands of experiments in parallel in a single mixture. 

Following on from this type of work, Horizon can support scientists looking to further validate their work. Once upon a time, you had the choice of genome-wide screens or you had to individually pick and plate each individual reagent. To make this easier for scientists, Horizon has a Cherry-Pick system that allows people to build their experiment with as few as hundreds and as many as tens of thousands of different reagents, whether they’re CRISPR or RNAi type reagents. This saves time and money. 

How is Horizon involved in COVID-19 vaccine research?

Horizon was realistic about what it could and couldn’t do with regards to COVID-19. We didn’t try to become a diagnostics company or try to become infectious disease experts. 

What we did do was speak to people in the research community who were researching SARS CoV-2. We made them aware of the different ways we could configure sets of reagents that could accelerate any proof of concept or exploratory research that they are doing, often on the mechanics of how COVID was working, using our Cherry-Pick custom reagent libraries. 

At the same time, we spoke to many of the diagnostics developers about the different reagents that we could offer them in developing their diagnostic kits. We also offered favorable access to our CHO Source cell line for companies manufacturing antibodies for COVID. 

Companies that were going to develop any sort of COVID-19 specific therapy enjoyed much more attractive terms for accessing the platform so they can further their research towards GMP. 

We also donated a huge amount of Personal Protective Equipment to local hospitals, as well as plastic ware to some of the firms that were doing testing in the initial phases when supply chain challenges were acute. So even though we’re not in the front line of COVID research, we’ve definitely been supportive of the wider effort.

Which trends or technologies do you find to be particularly interesting these days around your field of work?

One of the key things is the move towards single-cell type studies. In our improved CRISPR screening, we are now able to do single-cell RNAseq, which means that instead of taking a view based on a single experimental reading such as cell death, we are instead able to achieve individual transcriptomes for each cell.  This means researchers can understand the broader changes in cellular gene expression for each individual gene targeted by CRISPR. 

Another thing that is beginning to emerge is the use of data, as artificial intelligence starts to come of age. The ability of computers to look at high-quality data sets and to identify trends and connections that human scientists would be unlikely to see is very powerful. It is likely to revolutionize how researchers work in the future.

How do you envision the future of your industry?

For me, there’s a topic that comes up again and again because it’s never been resolved. In biology, we aspire to deliver science the same way as researchers do in physics and chemistry, which are more mature fields. We want to be reductionists and we want to be very high tech; we’ll spend hundreds of thousands if not millions on expensive microscopes, sequencers, or other instruments that do amazing things. 

That’s all good until you look at the cells we’re using. In many cases, they are still the cells that were derived more than 20 or 30 years ago, where the biology is not as close to what you’d expect in a human, and where the cells themselves have changed over the years. It might come from a human embryonic kidney or liver originally, but many of these cells are now polypoidal, having adapted to years of cell culture. They have huge genetic rearrangements because of the way they have been handled over the years. This really limits how valid they are as models for human life.

I see this as one of the limitations of biology. As I mentioned earlier, other technologies such as induced pluripotent cell lines, have been emerging, but more work needs to be done. 

There is also a debate between the use of 2D and 3D cell culture. In the standard cell panel screening we do at Horizon, we routinely use 2D culture. But you can go even further to 3D cell culture, as well as multi-cell 3D culture.  At this point, samples start to behave more like organs because most organs are not 100% made up of identical cells; they have many different cells and many different functions. The interplay between those is important for understanding the wider biological implications. Between the methods we have for producing the cells, checking the quality of the cells, and the AI that we have to interrogate what’s going on, I think the value is there for the industry to start shifting towards more meaningful models which should hopefully give much better and more predictive results, especially in the area of human health.

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About Author
Ditsa Keren
Ditsa Keren

Ditsa Keren is a technology blogger and entrepreneur with a strong passion for biology, ecology and the environment. In recent years, Ditsa has been specializing in technical and scientific writing, covering topics like biotechnology, algae cultivation, nutrition, and women's health.

Ditsa Keren is a technology blogger and entrepreneur with a strong passion for biology, ecology and the environment. In recent years, Ditsa has been specializing in technical and scientific writing, covering topics like biotechnology, algae cultivation, nutrition, and women's health.