the BiRth of a systems Biology PoweRhouse

scientific creationism:

On February 13, 2014, Fluidigm Corp. completed its acquisition of Canadian biotechnology company DVS Sciences, Inc. in a cash and stock deal worth approximately $207.5 million.

the birth of a systems biology powerhouse

Photo: Left to right are Vladimir Baranov, Olga Ornatsky, Gajus Worthington, Dmitry Bandura and Scott Tanner.

It was a deal that had the biology fi eld buzzing, and for good reason. By acquiring DVS, a pioneering company in single-cell multi-dimensional proteomics, Fluidigm, the leading single-cell genomics company that created microfl uidicbased chips and instrumentation for biological research, established itself as the premier source for single-cell biology tools.

At the centre of this deal is DVS Science’s CyTOF™ Mass Cytometer, a technology that has been labeled a “game changer” within the industry. The CyTOF is unique in providing researchers with the ability to interrogate single cells for many surface and intracellular proteins at the same by combining the analytical capabilities of atomic mass spectrometry with the power of fl ow cytometry for cell analysis.

“We’ve been looking for a company like DVS Sciences for a long time. It has a technology that we became enamoured with going back a number of years, and for me personally, it had a breathtaking capability,” says Gajus Worthington, president, CEO and co-founder of Fluidigm Corp.

Coupled with the products already in Fluidigm’s arsenal, Worthington expects big things to come for the company going forward.

“What we’ve managed to do with this deal is create a real juggernaut in this new fi eld of single-cell biology; specifi cally I think it’s safe to say we’re now the powerhouse in single-cell analysis. Combined with our existing technologies, we have for the fi rst time the ability to offer a complete picture at the individual cell level. There’s no other combination of tools in the world like this, and I think we’re positioned well to drive another period of real revolution and growth within this market of single-cell analysis,” says Worthington. He explains this is crucial because more and more scientists see the understanding of individual cell behaviour as critical to their research.

On the fl ip side of the deal, DVS Sciences has delivered a sound exit strategy for its investors while at the same time maintaining its presence in Canada but as a new entity; Fluidigm Canada. It’s everything that the founders -- Vladimir Baranov, Olga Ornatsky, Dmitry Bandura and Scott Tanner -- could hope for when they started the company almost a decade ago.

“This merger is really great for us. It’s good for our employees, good for the company and good for the investors who stuck by us. The normal exit for investors is three to fi ve years, and so the timing for them was perfect. More importantly, it’s good for our technology and where we want to take it.”

This last point is the most important to Tanner.

“It was pretty clear we were doing well. We had a product on the market and a good reputation. We were cash fl ow positive and profi table. The next phase for us was obvious, to get even bigger and to work with someone who could help us expand our scope even further. This deal with Fluidigm does just that and put simply, we’re not giving anything up. We’re still engaged and we still have a dream and our dream happens to merge really well with the Fluidigm dream. Together, we will enable systems biology at the single-cell level: in terms of fulfi llment from a scientist’s and a founder’s perspective, this is a great step. It gives us even more impetus, support and a wider market segment to address,” says Tanner.

Both Worthington and Tanner agree that because they share many of the same customers and clientele, the deal was made all the more possible. In fact, this was a real critical point in Worthington reaching out to

“the next phase for us Was obvious, to get even bigger and to Work With someone Who could help us expand our scope even further. this deal With fluidigm does just that and put simply, We’re not giving anything up. We’re still engaged and We still have a dream and our dream happens to merge really Well With the fluidigm dream.” — scott tanner

DVS, and Tanner accepting the offer.

“Spending time to try and understand our customers -- not just what they’re doing with our equipment but more importantly where their science is headed – gives us visibility of where the fi eld is going and what we need to do in order to be enabling and relevant. It was during these discussions going back almost four years ago that I fi rst heard about the CyTOF technology. Some of our customers described its function to me and I realized right away that if it actually worked, it would be really important.”

To explain how CyTOF™ is the perfect complement to Fluidigm’s existing portfolio, one must fi rst understand the types of products Fluidigm offers. Before Fluidigm came along, it was almost impossible for systems biologists to study genomics at an individual cell level. Often they would have to combine many thousands of cells together into a “stew” to have enough genomic material to analyze and produce results.

“What we were able to do was reduce the reaction volumes by 1000x, and increase the amount of throughput and integration of complex steps so that scientists could do genetics at an individual cell level,” explains Worthington.

For Fluidigm it all began when co-founder Stephen Quake invented a microscopic valve while he was teaching at Caltech in 1998. Quake and Worthington, who had befriended each other in an undergraduate physics class at Stanford University years earlier, founded Fluidigm in 1999. As Worthington explains, Fluidigm was really the fi rst company to get microfl uidics right.

In the late 1990s, most microfl uidic experts came from the semiconductor industry and preferred substrates such as silicon, glass or plastic, but not Fluidigm. Quake’s invention created the chip out of fusing multiple layers of rubber. That substrate is unique within the bio-chip industry and is illustrative of how Fluidigm has pioneered its path to creating a variety of PCR-based solutions.

“There were other companies before us who did microfl uidics, but frankly they lacked the technology and the conceptual orientation for it to really work. You really did have to think about it like a semiconductor, and think of it as an integrated circuit.”

Much the way a transistor controls the fl ow of electrons in a computer chip, Fluidigm’s microfl uidic valve performs the same function for the life sciences industry in a microfl uidic chip made of rubber.

“It started with the TOPAZ® System, a product for protein crystallization that served a relatively small application in the industry. While it was good way to get started, it certainly wasn’t the home run.” The home run came later when Fluidigm began to understand how they could apply its technology to genomics.

“We did that when we developed the BioMark™ System for Genetic Analysis, a multiapplication hardware/software platform based on our Fluidigm Dynamic Array IFCs (integrated fl uidic circuits). The introduction of the BioMark™ system heralded a practical solution for ultra-sensitive detection by PCR. And while we were developing the BioMark™ system we realized that it allowed genomic application all the way to the level of the individual cell. And that turned out to be fundamentally and scientifi cally important. It turned out that the kinds of experiments that we enabled with BioMark fi rst and later with the C 1 TM Single-Cell Auto Prep System, a product we launched in the middle of 2012, were so important to fi elds like cancer, stem cell biology, immunology, infectious disease and neuroscience, that it created a brand new market and fi eld which is now called single cell genomics or single cell biology.”

Nature publishing group labeled Single Cell Sequencing as the technique of the year for 2013 and single-cell research is radically changing the views that biologists have about how disease, how our bodies, and of course, how all kinds of biological functions work. But understanding single-cell genomics is only part of the equation.

“It’s a basic thing in biology that DNA is the code of life and then what your cells do with the DNA is they make RNA, which in turn is a template that translates the genes into the proteins that are the machinery inside the cell. Proteins are actually what do everything, they’re what create all your metabolic functions, responses, cell signaling and they do the work. So, in order to really understand what’s going on you have to be able to measure both the messengers and you also need to be able to measure what the proteins are doing. Without the ability to measure what’s going on at the protein level, you only have half the picture. DNA analysis informs on the framework that enables the cell’s function, but does not evidence that the cell is actually performing that function. And that’s what ultimately led us to DVS. We had the tools for enabling genomics at an individual cell level but needed that big piece of enabling proteomics at the level of the individual cell. The CyTOF does that,” says Worthington.

Tanner adds it would be the dream of systems biologists to combine both genomics and proteomics at the single cell level, so that one could look at the map right from the architecture of the DNA through the machinery of the RNA to the functional performance of the proteins at the same time. “That would give you the overall picture of each individual cell and the images of each of the plethora of all the cells in the body then tells you the entire structure, the overarching biology that is making that body work.”

Fluidgim’s next steps: technology integration

Making this dream a reality and fi nding a way to integrate the CyTOF technology with its own technology thus is the next challenge going forward for Fluidigm. Specifi cally, the company hopes to answer the

“We share similar experiences and stories of hoW We came to be and i believe stories are the fabric that keeps the company real and makes it something that is approachable, human and organic as opposed to just a bland corporation. We have a lot of overlap there, for both organizations Whose primary allegiance is to doing great science, to building a company With a culture that people Want to be part of, and feel so good about that they are Willing to dedicate years of their lives to making it great.” — gajus Worthington

question of how to blend a common workflow so that the scientists can gain all of this information, both genomic and proteomic from an individual cell, rather than getting genomic information from one set of cells and proteomic information for another.

“That’s really the strength of this combined organization, not only can we provide solutions for both but we have visions for integrating those platforms. It’s not easy and straightforward to tell how that’s going to happen, but certainly we have people thinking hard about how we are going to integrate them. And therein lies the integration challenge, because both technologies ultimately destruct the cells under investigation. When one analyzes the metals in the cell using the CyTOF they vapourize the cell and look at the atomic ions. And when a researcher uses the BioMark to look at the DNA, it has to break open the cell. So that’s our task, finding a clever way to integrate both technologies so we can look at DNA, RNA and the proteins at the same time,” says Tanner.

This will be the focus of Tanner’s new role with the company as chief technology officer for Fluidigm global.

“I’m going to get to learn a whole bunch of genomics now which is actually revitalizing for me. My task is to understand the technologies thoroughly, to find out where the overlaps and integration capabilities are, and then to work with the development team to build out a roadmap for the future of expanding this platform.”

Fluidigm Canada going forward

The plans for Fluidigm Canada as whole will not deviate too much from the DVS Science’s model says Worthington. In fact, it is expected that the group at Fluidigm Canada (the Toronto branch) will continue the development and production of the proteomic platform,and continue on with its R&D and manufacturing activities, while the DVS California office will more than likely be integrated with the Fluidigm office there. The other DVS founders, Dmitry Bandura and Vladimir Baranov, and Olga Ornatsky will also continue their current roles in R&D. Essentially it will be business as usual.

“This organization has done really well and so one of the things you don’t want to do is change what’s working, rather you want to understand the main reasons that it was successful, protect and encourage it to continue being successful,” says Worthington.

Making the transition easier has been the fact that the evolutionary stories of the two companies are so similar. In a manner of speaking they are cut from the same cloth.

“We share similar experiences and stories of how we came to be and I believe stories are the fabric that keeps the company real and makes it something that is approachable, human and organic as opposed to just a bland corporation. We have a lot of overlap there, for both organizations whose primary allegiance is to doing great science, to building a company with a culture that people want to be part of, and feel so good about that they are willing to dedicate years of their lives to making it great,” comments Worthington.

He adds there are many other benefits to the deal that go beyond technological advancement and the marrying of genomics and proteomics expertise.

“There’s clearly a very highly developed skill set in the Toronto region around the technologies that are essential to our platforms. There aren’t that many places in the world where those types of skills exist in concentration like they do in Toronto. Being there gives us access to this highly developed talent pool as well. Having critical mass in an area where there are highly skilled people is a real asset. We’ve experienced that in San Francisco, Singapore, parts of Europe, so that in itself is great. The other thing of course is our business presence in Canada was fairly nascent, and this is a huge launching pad to dramatically expand our business in this locale.”

For Tanner, being part of Fluidigm is equally rewarding.

“We worked so hard to build this platform, that I think all of the founders are really happy with this next step. I don’t think any of us feel that we’re giving anything up. We always dreamed that we would be building a successful technology that was going to answer biological questions and make a difference in the world, and to do that you have to reach more people and expand your scope. I truly believe this is just one of those quantum steps that will take us to that objective.”

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