Hi Reader, what does it take for a sustainable innovation to make it into the lab?
Today, I have a really exciting story for you.
We’ll walk through first-hand experiences of building a sustainable startup from scratch.
Along the way, you might also pick up a few ideas on how to improve the quality of your research data:
Today's Lesson: From Innovation to Application
The entrepreneurial journey of more sustainable products
Number of the Day
It was in 1958 that Puck et al. introduced fetal bovine serum (FBS) as a supplement to support the growth and division of cultured cells. Since the 2010s, approximately 600 000 liters of FBS have been produced each year. Remember, we normally use it at a 2–10% dilution - just to put this number into perspective. However, it seems that nobody knows exactly how much FBS is actually produced or precisely where it is sourced from. And its environmental impact as well as the scientific challenges it poses are greater than one might think.
600 000
A Sustainability Journey
I got in touch with Dr. Katie Bashant Day a few months ago.
As one of the few science sustainability advisors worldwide, I frequently connect with startups but she was up to something special:
A solution for cell culture medium that avoids the use of FBS.
Although most scientists have heard of FBS and its ubiquitous use, few are aware of the limitations and challenges associated with it.
That obviously raises ethical dilemmas. However, there are two more major issues:
The Overlooked Shortcomings of FBS
Its production leaves a significant footprint.
Although depending on the analysis method, FBS can account for a larger fraction of the entire footprint of cell culture medium:
This is data from Wali et al. outlining the footprint contribution of medium components, however, please note that these include the impacts from the cattle. Analyses such as the one from Tuomisto et al. that do not, arrive at much smaller impacts between 0.2–13%. This is because the latter follows the approach of Bier and colleagues, arguing that FBS is generated from blood as a byproduct of slaughter.
The second issue is scientific: FBS is not standardized.
In other words, it contains hundreds of compounds that vary by batch. Therefore, concerns about contamination risks due to mycoplasma or viruses have been raised. But there is more:
Katie got involved with the topic through a journal club.
She presented a paper that makes you rethink FBS because it showed that when culturing cells in the serum of different species, inflammatory responses change fundamentally.
Click to enlarge. In essence, depending on the medium, cells show differences in inflammatory responses. These are graphs from Warren et al., showing: A) LPS and peptidoglycan associated lipoprotein (PAL) 20% human whole blood and in 20% mouse whole blood (n=5). B) Human monocytes in 10% mouse serum (open triangles) or 10% human serum (closed squares) (n=4). C) Concentration of TNF in culture supernatants from elicited mouse peritoneal macrophages incubated with 20ng/ml LPS for 18h in the presence of 20% serum.
She went on to work in laboratories where she dealt with cell culture.
In one of them she created specialized, chemically defined culture media for ethical and consistency-related reasons.
Medium without FBS - that sparked a passion.
A Journey Starts
Katie worked at a startup focused on cultured meat. But let's imagine you were in her position:
You see how a small company grows tenfold. In her words, “you manage a large team and direct tech strategy, which gives you a front-row seat to the journey from idea to product on the market.”
And now you have this itch to do it yourself. With your long-lasting passion.
In our previous lesson, we dove deeper into the alternatives to FBS. Notably, Weber et al. also provide a fantastic categorization and explanation of FBS alternatives. These media use other factors or recombinant molecules instead of fetal bovine serum to provide cultured cells with the necessary nutrients, especially growth factors.
Maybe you are like Katie - initially too shy. But as she advises, at some point you have to make the jump.
But what challenges do you face when you want to bring a new sustainable innovation to market?
The R&D Phase
First, you spend an incredible amount of time in the laboratory.
This is what you will have to work on – how to replace FBS because whether we like it or not, we often still need growth factors for our cell culture. These pictures come from a preprint, showing micrographs of ZEM2S cells on day 3 of culture, with the pictures in theright column being 20X enlarged. PS: For Katie, that meant so much time that even when her baby was born, there were only eight days in the year that she wasn’t in the lab. You have to come up with a formulation of the new medium.
In contrast to academic research, it is not just about making it work.
It’s about reaching a high-quality standard. We know that many scientists are very protective of their methods, so any reduction in quality is not going to be accepted.
Moreover, time is money.
You have competitors who have solutions but, of course, do not share their secrets.
Remember, as you develop your product, you are not yet earning money, while giants like ThermoFisher or PanBiotech already have their own solutions behind them. You know they have weaknesses, but the psychological pressure is on. Additionally, when you are in Katie's shoes, you will have to build your own lab. Seeing how labs grow is very different from building and coordinating them yourself. As every newly appointed group leader will tell you, doing science and managing the organization is a huge burden.
Therefore, you have to test different conditions without knowing what to change if something doesn’t work.
First Tests
After many long nights, you come up with a few trial formulations and find partner labs that will try them out.
Finally, the first round of trials!
But poor results...
You realize, just as Katie did, that culture techniques and cell lines vary significantly between labs, and therefore your formulations have to become more robust.
Moreover, without practical user guidelines, people come up with the weirdest ideas.
Another thing you need to take care of is industry standards.
Yes, you even have to pay just to access the standard you’re expected to follow. Not all ISO standards are certifiable, but for those that are, there’s yet another step involved. And of course, once you want to bring a product to market, you still need approval from your national authorities, which adds another layer of complexity and paperwork.
You have to work according to guidelines like ISO to assure your customers. Persistence, resilience, and stamina will get you there.
Growing Production
Challenge number two is production.
In the laboratory we rarely see this, but producing a product in large quantities is not simple.
You build the infrastructure, you must keep quality high, and you must ensure that your products remain sustainable.
This graph stems from Islam et al., with each data point representing the findings of a different study, and filled markers indicating cradle-to-gate versus open markers indicating cradle-to-grave studies. (PS: The first four plastics are bioplastics, the last four are conventional ones). Several sustainable innovations really struggle at this stage and essentially lose their sustainability label. The problem is that even though advantages might appear on paper, you need to maintain them throughout the production cycle. Just think about biobased plastics: even though, in theory, producing them from plant material is great, if you need a lot of energy you will release carbon during manufacturing, the use of acids and solvents might contribute to acidification, and waste streams to eutrophication. So, how do you get your resources, how do you manufacture, how do you deliver?
All of this, of course, leads many startups to initially have only small batches available and to sell at a higher price.
And this leads us to the final challenge.
Getting Your Solution into Laboratories
Often underestimated but essential, marketing.
The higher price of new products is one thing to consider.
However, beyond this, there is something I especially often encounter as a consultant and advisor: doubts from the scientists themselves.
This is data from Katie – viability is good and with their solution you maintain doubling times typically within 18–30 hours, depending on cell line and conditions. Please note that even if you don’t want to allow for the smallest trade-off, you can use 9% FRS + 1% FBS.
As we discussed, one of the major problems with FBS is its variability.
In other words, you do have batch-to-batch variations and unquantifiable effects on your cells.
However, the scientific community is so used to using FBS that having the ability to use a chemically defined option is accepted but not seen as a necessary change.
Again, Katie is able to assure that each batch is similar to the previous one.
In other words, you can have the more sustainable solution - even one that improves the underlying science - but that doesn’t mean you will see automatic uptake.
“Never change a running system.”
You invested months on end into developing a fantastic solution, and many are not even ready to give it a try.
Therefore, you need to invest a lot of effort in convincing people to test it in order to build case studies proving your product is safe.
Find some of the data Katie has put together here and even more examples of data sheets right here.
And once you have mastered all of that, you must figure out how to make people aware.
Advertisements? Word of mouth? Conferences?
Applying The Knowledge
Imagine, Katie went through all of that.
How?
The same things that unite us all: a passion for science, a more sustainable future, and a few people in our community who motivate you again and again.
A huge shout out to Dr. Katie Bashant Day and her co-founder Dr. Christopher Day. Fingers crossed!
So, if you work with cell lines, consider giving it a try even if you do a 1% FBS + 9% FRS solution as mentioned above!
As Katie has repeatedly mentioned, contrary to what many scientists believe that serum-free medium works for a large number of cell lines!
That means:
If you have bought a batch of FBS only to find that it doesn’t work,
If you struggle with variability across experiments or collaborating laboratories,
If you develop cell therapies that face regulatory pressure,
Or if you simply want to use a more sustainable solution
My tip as a consultant is to really start with one experimental line.
Begin when you finish a project and start a new one.
Do not try to change methods during an ongoing project. Only then will your data stay consistent and you will have the headspace needed to make it work.
However, it might be worth it.
As shown in this paper, FBS contains extracellular RNA species that can interfere with your sequences and affect your cellular responses. Neither filtration, nor ultracentrifugation gets completely rid of those. Again, switching truly makes your data more robust. Therefore, if you stumble upon confusing data from cell culture, you might now have an idea. P.S. Interestingly, in the original paper from 1958, the authors even discussed outright deleterious batches that could harm cell lines.
The problem is that nobody knows how much FBS is going to be produced.
Some countries have prohibited the transport of animals in the last third of gestation raising the concern that shortages of FBS could halt the research activities of tens of thousands of labs.
And still, it's a single journal club that can shape your life and eventually change how we do science around the globe.
How We Feel Today
References
Puck, T.T., et al., 1958. Genetics of somatic mammalian cells. III. Long-term cultivation of euploid cells from human and animal subjects. Journal of Experimental Medicine, 108(6), 945–956. doi:10.1084/jem.108.6.945.
Brindley, D.A., et al., 2012. Peak serum: implications of serum supply for cell therapy manufacturing. Regenerative Medicine, 7(1), 7–13. doi:10.2217/rme.11.112.
Warren, H.S., et al., 2010. Resilience to bacterial infection: difference between species could be due to proteins in serum. Journal of Infectious Diseases, 201(2), 223–232. doi:10.1086/649557.
Islam, M., et al., 2024. Impact of bioplastics on environment from its production to end-of-life. Process Safety and Environmental Protection, 188, 151–166. doi:10.1016/j.psep.2024.05.113.
Wali, M.E., et al., 2024. Life cycle assessment of culture media with alternative compositions for cultured meat production. International Journal of Life Cycle Assessment, 29, 2077–2093. doi:10.1007/s11367-024-02350-6.
Tuomisto, H.L., et al., 2022. Prospective life cycle assessment of a bioprocess design for cultured meat production in hollow fiber bioreactors. Science of The Total Environment, 851(1), 158051. doi:10.1016/j.scitotenv.2022.158051.
Bier, J.M., et al., 2012. An eco-profile of thermoplastic protein derived from blood meal Part 1: allocation issues. International Journal of Life Cycle Assessment, 17, 208–219. doi:10.1007/s11367-011-0349-8.
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