The End of Chromatography?
Chromatography-free techniques can speed up analysis time from minutes to seconds while also eliminating 95 percent of organic waste (in the right applications), argues Jeffrey Zonderman. Will anyone be doing chromatography in a decade’s time?
| 7 min read | Interview
Credit: Supplied by Interviewee
With Jeffrey Zonderman
Why did Bruker decide to explore chromatography-free?
Chromatography-free mass spectrometry (MS) isn’t entirely new to Bruker – MALDI has been very successful, which is essentially a form of chromatography-free analysis. Bruker has developed and commercialized the most successful clinical mass spectrometer ever, the MALDI Biotyper. The challenge is to make these technologies suitable for more widespread use in the routine lab environment, where experts aren’t required to operate them.
Chromatography-free delivers a strong sustainable profile. Traditional chromatography generates a lot of organic waste that needs to be disposed of as hazardous material. Chromatography-free techniques remove up to 95 percent of that waste in the right applications. Chromatography-free methods like direct analysis in real-time (DART) can meet the criteria of return on investment (ROI), ease of use, robustness, and sustainability. Once we establish that DART is quantitative, there’s no reason not to switch to it. And, as new assays are developed, we’ll see a shift toward this technology.
What are some of the common pushback points you hear when you suggest getting rid of chromatography?
Chromatography is only applicable for the right workflow. For example, if someone is looking to run a 1,000-pesticide screen, chromatography isn’t going to be removed in that context. But if you’re dealing with high-throughput triple quad quantitative assays that focus on discrete panels, like drugs of abuse or therapeutic drug monitoring, then you can remove the chromatography. You can do the analysis quantitatively, reduce the process from minutes to seconds, and eliminate most of the organic waste.
As it’s a new approach, the main pushback is skepticism. When we mention chromatography-free or sustainability, people are interested. But like with any new technology, there’s an adoption curve. To help resolve this, we’re currently working with key opinion leaders (KOLs) and early adopters who are investing in this technology.
Looking ahead 10 or 20 years, how much chromatography do you think people will still be doing?
I think chromatography will still be around and improving in areas where complex separations are necessary. For instance, in proteomics, where nanoflow chromatography is required, these systems are highly complex, expensive, and require expert operation.
It’s important to note that "chromatography" is a broad term. In many high-flow quantitative assays, traditional chromatography is a secondary sample prep after the initial process, creating a peak for quantitation. However, you don't necessarily need a peak to quantitate; there are other methods. By optimizing processing software, you can remove the need for certain chromatography steps and move towards chromatography-free solutions.
That said, there are still applications where chromatography is essential. For example, one of our collaboration partners uses gas chromatography-mass spectrometry (GC-MS) to develop methods for dioxins and persistent organic pollutants (POPs) using a combination of GC, trapped ion mobility spectrometry (TIMS), and high-resolution (HRMS). These complex experiments require chromatography paired with ion mobility.
In fact, when ion mobility was first introduced, many ion mobility technologies didn’t take off because they lacked efficiency and speed. However, when TIMS was introduced, it quickly gained traction due to its high efficiency, speed, and quantitative capabilities. Ion mobility has become a valuable separation technique in HRMS, and I see it playing a role in routine analysis as well.
In some areas, like protein analysis, we've seen that chromatography-free approaches can be highly effective. For example, in clinical MS, removing chromatography can simplify the process and reduce the need for specialized expertise. While chromatography remains crucial for certain applications, there’s a significant market for high-throughput, quantitative analysis where chromatography might not be necessary. It’s about finding the right technology for the application.
What are some of the most trending and important application areas for mass spectrometry right now?
Drugs of abuse testing is a massive area, especially in the United States (US) where the need for testing is enormous. Crime labs at the city, state, and federal levels are all equipped with mass spectrometers to test for drugs, both for public health and safety and for prosecution. Clinically, there’s also a need to monitor whether patients are taking the correct amount of prescribed opiates. The US opiate crisis has been devastating but analytical technology can help.
Currently, a typical (liquid chromatography-mass spectrometry (LC-MS) system can process a limited number of drug panels per day. We can increase that capacity by at least ten times on a single mass spectrometer per day. Most US state or crime labs are backlogged with GC, LC, and affinity assays – and sample loads are skyrocketing. Drugs of abuse testing can be accelerated dramatically using chromatography-free testing. These labs currently manage around 100 to 200 samples a day with LC-MS systems. Now, we have the potential to process 1,500 samples a day – moving from methods that take minutes per sample to those that take seconds.
Our value proposition lies in providing high-throughput, quantitative assays that are robust, offer better ROI, and can be run by a broader range of technicians. This makes the technology more accessible to labs, as they won’t need a specialized LC-MS expert to operate, maintain or troubleshoot it. There’s a shortage of skilled personnel in this field, which is another reason chromatography-free methods resonate. For those running high-throughput assays on triple quad mass spectrometers, chromatography is often a challenge.
Meet the Expert
Did you ever see yourself doing what you're doing now?
No – does anyone? I got a BSc in biology, where I learned a little about everything but not enough about anything specific. I entered a world that was just starting to explore DNA and synthetic DNA synthesis, and even had the chance to meet Watson at the time.
I became a DNA synthesis chemist and, through this, got involved in matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) MS. Later, I sold MS equipment, and I really fell in love with MALDI. I liked it because I could run it myself – and it offered unique insights that other methods couldn’t provide.
For instance, if I wanted to check whether I had synthesized a pure and correct DNA sequence, traditional chromatography could tell me the retention time, but it wouldn't reveal specific issues. The detection using mass spectrometry is better. With MALDI-TOF, I could immediately see problems like depurination or nucleotide misincorporation. I could diagnose what went wrong in my synthesis protocol in seconds, without waiting or developing a method. That’s when I really got hooked on MS.
I’ve been fortunate to work for both large companies and small startups. I ventured into a few startups that were eventually acquired, but I remained passionate about MS. I joined a company called IonSense, which had DART technology, and I realized I wanted to develop a total solution rather than just selling niche products.
That’s how I joined Bruker. IonSense was looking for a MS partner to help fund the vision and we realized that it made sense for Bruker to acquire IonSense, to focus on applied markets and on developing chromatography-free MS.
You've worked at various companies over the years – are there any key lessons you've learned about how to deliver on innovation or how to innovate effectively?
Absolutely. One of the biggest lessons I've learned is the importance of staying close to KOLs and customers. Invest in those relationships because they provide invaluable guidance.
When I first moved from the lab into sales, marketing, and general management, I quickly realized that the most important asset I had was a network of customers who trusted me and whom I could trust to give honest feedback. For instance, our work with chromatography-free solutions came directly from listening to what our customers needed.
We’ve worked with Professor Matthias Mann, for example, and having someone like that involved in your work is incredibly valuable. The key is to take risks, get your technology into the lab, and listen carefully to the feedback, especially the criticisms. That’s how you improve and come out with something better – by letting your customers’ needs guide your development.
Jeffrey Zonderman is Senior Vice President of Bruker Applied MS
