Can plastic eating super-enzymes solve our destructive plastic problem?

Rumiana Tenchov, Information Scientist, CAS

The production of cheap, durable and adaptable plastics has exploded in the last few decades as they infiltrate every part of our lives; but this once desirable polymer has a dark side. Plastics may take hundreds of years to degrade and with production at astronomic levels (globally over 350 million tons each year), plastic pollution is one of the most pressing environmental concerns facing the world today.  

A staggering 150 million tons of plastic finds its way to landfill or is released into the environment annually and over 8 million tons are transported by rivers into the world’s oceans. Most of this does not degrade but simply breaks down into microparticles. These well-documented microplastics are found in ocean water, within marine animals and even deep inside the gastroenteric systems of humans. Plastic pollution is one of the most critical environmental issues facing humankind today and researchers have been busy looking for answers to this perplexing plastic problem.

Depolymerization: Solving the polymer recycling conundrum 

Plastics are made of polymers – long chains created by repeating monomer blocks. Most of the widely used plastics are either thermoplastic or thermosetting. Thermoplastics, such as acrylic, polyamide and polyethylene, become soft and moldable at high temperatures and harden when cooled. This property makes them relatively easy to recycle because they can be softened and remolded into new products, although quality decline limits benefit. Thermosetting plastics, like polyurethane, epoxy resin and melamine resin, harden when heated and are almost impossible to recycle. The challenges faced by recycling both thermoplastics and thermosets mean that all plastics will eventually be destined to contribute to environmental contamination.

To attain real recycling, with subsequent reuse in new products, waste plastics need to be returned to their original monomers through a process called depolymerization. This is a critical technical advance needed to enable a global circular materials economy.  In biological systems, complete depolymerization to monomers can be necessary for microbial uptake and growth. 

To achieve depolymerization, scientists have looked to nature, searching for microbial enzymes that can break down plastics. In 2012, researchers at Osaka University discovered an enzyme in a compost heap that can break down one of the world’s most used plastics: polyethylene terephthalate (PET, CAS Registry Number 25038-59-9, formula (C10H8O4)n).  

The enzyme, known as leaf-branch compost cutinase (LLC), breaks the bonds between PET monomers, but it is intolerant to the 65°C softening temperature of PET, denaturing after a few days of working at this temperature and limiting its industrial practicability. Since depolymerization can only take place in molten plastic, enzymes must be stable at increased temperatures

Double-action PET depolymerization from a little-known soil bacterium 

PET is a thermoplastic and one of the most widely used polyesters. Worldwide PET production grew from 42 million tons in 2014 to 50 million tons in 2016 and is set to reach 87 million tons by 2022

This synthetic polymer is manufactured from petroleum-derived terephthalic acid (TPA) and ethylene glycol (EG). PET is a versatile polymer that can be made transparent, opaque, or white in color, depending on its crystal structure and particle size (Fig. 1). It is widely used to produce clothing fibers and containers, including water bottles, and non-oriented PET can be thermoformed (or molded) to manufacture other packaging products, such as blister packs1. Finding an effective way to depolymerize PET will be an important milestone in the journey towards true plastic recycling and resulting environmental protection.

PET products and structural formula
Figure 1. PET Products (A) and Structural Formula (B)

PET biodegradation has been extensively studied because esterase enzymes (enzymes that split esters into an acid and an alcohol) are abundant in nature2. Reports on the biological degradation of PET or its utilization to support microbial growth are, however, infrequent. Some organisms from the filamentous fungi group, Fusarium oxysporum and Fusarium solani, have been grown on a mineral medium containing PET yarns3.   

In 2016, Yoshida et al4 reported the discovery and characterization of the soil bacterium strain, Ideonella sakaiensis 201-F6, found growing in PET-contaminated sediment near a plastic recycling facility in Japan. This gram-negative, aerobic, rod-shaped bacterium has the remarkable ability to use PET as its major carbon and energy source for growth.   

I.sakaiensis employs a two-enzyme system to depolymerize PET to its building blocks, TPA and EG, which are further catabolized to a carbon and energy source. One of the two enzymes, ISF6_4831 protein, hydrolyzes and breaks ester linkages. With a preference for aromatic rather than aliphatic esters, and a specific inclination towards PET, it is designated as a PET hydrolase (PETase). The PETase enzyme in I. sakaiensis is a cutinase-like serine hydrolase that attacks the PET polymer, releasing bis(2-hydroxyethyl) terephthalate (BHET), mono(2-hydroxyethyl) terephthalate (MHET) and TPA. PETase further cleaves BHET to MHET and EG. The second enzyme, ISF6_0224 protein, MHET hydrolase (MHETase), further hydrolyzes the soluble MHET to produce TPA and EG (Fig. 2). Both enzymes are required, likely synergistically, to enzymatically convert PET into its two environmentally benign monomers, TPA and EG4, making it possible to fully recycle PET. 

PET depolymerization scheme

Fig. 2.  PET depolymerization scheme:  PETase catalyzes the depolymerization of PET to bis(2-hydroxyethyl)-TPA (BHET), mono(2-hydroxyethyl) terephthalate (MHET), and terephthalic acid (TPA). MHETase converts MHET to monomers TPA and ethylene glycol (EG). 


PETase mutant’s supersize PET degradation capability  

Sequence and structural studies of PETase enzyme highlight similarities to cutinase enzymes, evolved by many bacteria to break down cutin, a natural, waxy polymer that forms part of the protective cuticle in many plants. Crystal structural analysis and biochemical tests reveal that the PETase in I.sakaiensis 2 has an open active-site architecture in the binding site and that it likely operates along the canonical serine hydrolase catalytic mechanism5.   

Based on structural modifications in PETase and a homologous cutinase active-site cleft, PETase variants have now been produced and tested for PET degradation, including a mutant with a double mutation distal to the catalytic center. This area is hypothesized to be capable of amending important substrate-binding interactions6. This double mutant, based on cutinase architecture, was found to exhibit enhanced PET degradation capacity relative to wild-type PETase6 and a patent has now been filed7

By narrowing the binding cleft via the mutation of two active-site residues in cutinases, researchers observed improved PET degradation, suggesting that PETase does not exhibit the optimum structure for degradation of crystalline PET, despite evolving in a PET-rich environment. The mutant enzyme takes just a few days to start breaking down the plastic – significantly faster than the centuries it takes in the oceans. 

From double mutant to a double enzyme cocktail  

When MHETase enzyme is added to the reaction, the enzyme mixture breaks down PET twice as fast as PETase on its own. The degradation trend observed within the tested enzyme loadings range shows increasing levels of constituent monomers as the concentration of both enzymes increases. This indicates that the reactions are enzyme, rather than substrate, limited. The synergy analysis also indicates that degradation rates increase with PETase loading and that the presence of MHETase, even at low concentrations relative to PETase, improves total degradation. The current experiments do not indicate an optimal ratio of PETase to MHETase.

Creating a super-enzyme triples PET degradation  

In further experiments exploring the properties and scope of PET degradation, researchers have engineered a new super enzyme by stitching MHETase and PETase into one long chain. The chimeric proteins covalently linking the C terminus of MHETase to the N terminus of PETase, using flexible glycine-serine linkers, were generated and assayed for degradation of amorphous PET (Fig. 3).  When comparing the extent of degradation achieved by different enzymes, the chimeric proteins outperform both PETase and MHETase, as well as the unlinked enzyme mixture.  

diagram of three chimeric enzymes
Fig. 3.  Sketches of three chimeric enzymes, with linkers connecting the C terminus of MHETase to the N terminus of PETase


Interestingly, the super-enzyme not only depolymerizes PET but also works on PEF (polyethylene furanoate), a sugar-based bioplastic used in beer bottles.  
The enzymatic deconstruction of some natural polymers, such as cellulose and chitin, is achieved in nature by mixtures of synergistically acting enzymes secreted from microbes8. These natural microbial systems have evolved over time to optimally degrade such polymers.  It appears that some soil bacteria, such as I. sakaiensis, have evolved in a similar way to utilize a polyester substrate with a two-enzyme system4,9. Unlike natural degradation, which can take centuries, the super-enzyme can convert PET back to its monomers in just a few days, although this is still too slow to be commercially viable

Endless recycling with plastic degradation 

By converting PET back to its original, monomer building blocks, the super-enzyme would allow plastics to be made and reused endlessly, reducing dependence on fossil resources. And the breakthroughs don’t stop here… 

In 2020, a major advance saw scientists identifying another enzyme that could degrade PET in just 10 hours10. The research screened a large variety of bacteria and enzymes for potential candidates, including the leaf-branch compost cutinase, LCC, that was first discovered in 2012.  Hundreds of mutant PET hydrolase enzymes were then produced by varying amino acids at the binding site and improving thermal stability. Bacterial mutants were then screened to identify efficient PET decomposers. After running this process for multiple rounds, a mutant enzyme was isolated that is 10,000 times more efficient in degrading PET than the native LCC. It is also stable at 72°C, close to the melting temperature of PET. This finding contributes significantly towards attaining the infinite recycling of PET and is already at a pilot industrial stage10

We are only seeing the tip of the iceberg of possibilities that these microorganisms and their enzymes can offer. Most plastics are derived from fossil fuels, finite in their creation yet ubiquitous in our environment. Plastic pollution will continue to be a growing problem unless we can find a way to form a circular economy. In just a few decades, we will be unable to produce the plastic items on which we depend unless we can find a way to recycle the waste that already exists. Traditional recycling is not effective or sustainable and, unless we can reduce plastics to their monomer constituents on an industrial scale, we cannot hope to solve this problem. Thankfully, with the help of nature, some skillful evolution and a dash of scientific ingenuity, there is a hope that this problem might be solved.  

Interested in learning more about ‘green’ innovations? 

In the hunt for novel species to drive innovation, nowhere contains greater biodiversity than the rainforests of Brazil. Learn how data is being collected and mined for public use and how this might help to protect the 15-20% of the Earth’s biodiversity.  

(Read Organizing Vital Data to Unlock Innovation from Brazil’s Biodiversity


(1)    Pasbrig, E.; Claessens, P.; Walker, R. I.; Walker, R. Peelable cover film for pharmaceutical packaging, e.g. blister packs, comprises paper, aluminum foil or heat-resistant plastic, a layer of special plastic film, mesh or fabric, a layer of aluminum foil and a heat-sealing layer. EP1767347-A1; WO2007038488-A2; EP1928654-A2; AU2006294788-A1; US2008251411-A1; CN101316702-A; CA2623586-A1; JP2009509874-W; TW200727887-A; MX2008004201-A1; IN200801248-P2; ZA200802826-A; BR200616412-A2; WO2007038488-A3; EP1928654-A4. 

(2)    Han, X.; Liu, W. D.; Huang, J. W.; Ma, J. T.; Zheng, Y. Y.; Ko, T. P.; Xu, L. M.; Cheng, Y. S.; Chen, C. C.; Guo, R. T., Structural insight into catalytic mechanism of PET hydrolase. Nature Communications 2017, 8. DOI: 10.1038/s41467-017-02255-z 

(3)    Nimchua, T.; Eveleigh, D. E.; Sangwatanaroj, U.; Punnapayak, H., Screening of tropical fungi producing polyethylene terephthalate-hydrolyzing enzyme for fabric modification. J. Ind. Microbiol. Biotechnol. 2008, 35 (8), 843-850. DOI: 10.1007/s10295-008-0356-3 

(4)    Yoshida, S.; Hiraga, K.; Takehana, T.; Taniguchi, I.; Yamaji, H.; Maeda, Y.; Toyohara, K.; Miyamoto, K.; Kimura, Y.; Oda, K., A bacterium that degrades and assimilates poly(ethylene terephthalate). Science 2016, 351 (6278), 1196-1199. DOI: 10.1126/science.aad6359 

(5)    Rauwerdink, A.; Kazlauskas, R. J., How the Same Core Catalytic Machinery Catalyzes 17 Different Reactions: the Serine-Histidine-Aspartate Catalytic Triad of alpha/beta-Hydrolase Fold Enzymes. Acs Catalysis 2015, 5 (10), 6153-6176. DOI: 10.1021/acscatal.5b01539 

(6)    Austin, H. P.; Allen, M. D.; Donohoe, B. S.; Rorrer, N. A.; Kearns, F. L.; Silveira, R. L.; Pollard, B. C.; Dominick, G.; Duman, R.; El Omari, K.; Mykhaylyk, V.; Wagner, A.; Michener, W. E.; Amore, A.; Skaf, M. S.; Crowley, M. F.; Thorne, A. W.; Johnson, C. W.; Woodcock, H. L.; McGeehan, J. E.; Beckham, G. T., Characterization and engineering of a plastic-degrading aromatic polyesterase. Proc. Natl. Acad. Sci. U. S. A. 2018, 115 (19), E4350-E4357. DOI: 10.1073/pnas.1718804115 

(7)    Beckham, G. T.; Johnson, C. W.; Donohoe, B. S.; Rorrer, N.; McGeehan, J. E.; Austin, H. P.; Allen, M. D. New modified polyethylene terephthalate -digesting enzyme comprising amino acid mutation of an active site residue, is used to degrade a polymer e.g. polyester, aromatic polymer or semi-aromatic polymer and polyethylene terephthalate. WO2019168811-A1. 

(8)    Payne, C. M.; Knott, B. C.; Mayes, H. B.; Hansson, H.; Himmel, M. E.; Sandgren, M.; Stahlberg, J.; Beckham, G. T., Fungal Cellulases. Chem. Rev. 2015, 115 (3), 1308-1448. DOI: 10.1021/cr500351c 

(9)    Taniguchi, I.; Yoshida, S.; Hiraga, K.; Miyamoto, K.; Kimura, Y.; Oda, K., Biodegradation of PET: Current Status and Application Aspects. Acs Catalysis 2019, 9 (5), 4089-4105. DOI: 10.1021/acscatal.8b05171 

(10)    Tournier, V.; Topham, C. M.; Gilles, A.; David, B.; Folgoas, C.; Moya-Leclair, E.; Kamionka, E.; Desrousseaux, M. L.; Texier, H.; Gavalda, S.; Cot, M.; Guémard, E.; Dalibey, M.; Nomme, J.; Cioci, G.; Barbe, S.; Chateau, M.; André, I.; Duquesne, S.; Marty, A., An engineered PET depolymerase to break down and recycle plastic bottles. Nature 2020, 580 (7802), 216-219. DOI: 10.1038/s41586-020-2149-4 

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The Science Behind Performance-Enhancing Drugs

Zach Baum, Information Scientist, CAS
performance enhancing drugs CAS blog thumbnail

The Summer Olympics reveal amazing stories of triumph, determination, and athletic feats. While athletes always look for an edge within the rules (from diets to hyperbolic chambers, to cryotherapy), performance- enhancing drugs (PEDs) are a line that should not be crossed. Performance-enhancing drugs are constantly scrutinized, tracked, and tested for by the International Olympic Committee, US Anti-Doping Agency and World Anti-Doping Agency. While the drugs and methodologies have evolved, anabolic-androgenic steroids (AAS) are still key performance enhancers from the Olympics to the Tour De France, Ironman Triathlons, and even more niche sports like CrossFit Games. This blog will provide details on some common performance enhancing drugs and measures to detect these drugs. 

What Are Performance-Enhancing Drugs?

A structural understanding of steroids, their metabolites, and testosterone is central to developing analytical protocols for their detection. Testosterone (T) is a naturally produced hormone and the native ligand for the androgen receptor. When this receptor binds to an androgen such as testosterone or a synthetic steroid, it becomes activated, resulting in desirable performance-enhancing effects including increased muscle strength, bone density, and red blood cell production. While stronger muscles and bones are an obvious advantage for an athlete, the increased red blood cell production provides more oxygen to muscles and organs, which fuels energy production and recovery. Testosterone (both synthetic and natural), therefore, is the basis for anabolic steroids. 

Anabolic steroids fall mainly into three categories (Figure 1 below):

  • Testosterone derivatives
  • 5α-dihydrotestosterone (DHT) derivatives
  • 19-nortestosterone derivatives

three main categories of anabolic steroids

Figure 1: The structure of testosterone in comparison to common anabolic-androgenic testosterone derivatives, 5α-dihydroxytestosterone derivatives, and 19-nortestosterone derivatives.

The differences in structure, substrate activities, and half-life affect the biological profiles of these anabolic-androgenic testosterone derivatives. These differences are the foundation for designing methods to detect these compounds, especially since we all possess testosterone naturally. 

How Are Performance-Enhancing Drugs Detected?

For each drug, identifying its major metabolites is the first step in developing a direct urine, blood, or saliva diagnostic test. The human body produces natural (endogenous) testosterone (T) and epitestosterone (E) in a ratio of approximately 0.4-2 (Figure 2A)1. One of the first detection methods simply measured the ratio of testosterone and epitestosterone in urine samples. If the T/E ratio exceeds 4, doping with an exogenous testosterone product is suspected. To confirm the presence of exogenous T, the laboratory can measure the isotope ratio of 13C:12C in T, as laboratory-made T has a slightly lower 13C:12C ratio than endogenous T2. This methodology was used in the prosecution of Floyd Landis surrounding his performance in the 2006 Tour de France, proving that he had, in fact, used exogenous testosterone.

testing parameters for anabolic steroid detection

Figure 2. Testing parameters for anabolic-androgenic steroid detection. A: Structures of testosterone (T) and epitestosterone (E), which are produced in a ratio between 0.4-2 in the human body. T/E values above 4 are considered evidence of AAS doping. B: Metabolism and analytical procedures necessary for detection of stanozolol by urinalysis.

When a steroidal drug first finds its way onto the competitive scene, the onus is on regulators to understand its properties and metabolism for its detection and analysis. Such was the case in the 1988 Seoul Olympic Games, when sprinter Ben Johnson set a world record in the 100m dash but was stripped of his gold medal after testing positive for stanozolol. To develop a detection method for this drug, researchers had to understand the metabolism of stanozolol and how it could be detected most sensitively. The major route for stanozolol metabolism is shown in the vertical pathway of Figure 2B, along with the sample treatment required to detect metabolites by the time-tested gas chromatography-mass spectrometry (GC-MS)3. However, stanozolol produces another metabolite in smaller amounts called 17-epi-stanozolol-N-glucuronide, shown in the horizontal pathway of Figure 2B. This metabolite is long-lived and can be detected 28 days after administration! To detect stanozolol from this metabolite, a complex combination of methods involving electrospray ionization (ESI) and liquid chromatography mass spectrometry (LC-MS) was more recently developed. Simply put, these techniques create ions which can be separated and identified by their mass to characterize and identify the metabolites present. 

Why Are Performance-Enhancing Drugs a Continual Problem?

While scientists were busy improving techniques to detect the anabolic-androgenic steroids they knew about in the early 2000s, Barry Bonds was busy hitting home runs. Little did the MLB know that behind the scenes, Bonds and other athletes had been using a newly synthesized steroid, tetrahydrogestrinone (THG), designed specifically for potent anabolic effects and with anti-doping testing protocols in mind. Dubbed “The Clear”, THG could not be detected in urine initially because the anti-doping program had no knowledge of its existence or metabolites. During an investigation, a sample of THG was extracted from the residue of a spent syringe and identified, after which an LC-MS/MS method could be easily developed for screening4.

The baseball scandal typifies some of the issues surrounding direct detection of AAS in anti-doping programs. First, the screening process is looking for known metabolites of known substances; a well-equipped organization can therefor feasibly synthesize “designer steroids” that have not yet been seen to avoid detection. Even when a testing protocol is in place, infrequent testing (such as in the MLB, where testing occurs twice per year) can allow steroid use to go undetected; longer periods between tests allow the concentrations of steroid metabolites to decrease below the limits of detection more easily. It is also possible for an athlete to deploy masking agents and diuretics to avoid detection5, which places an additional burden on testing administrations.

Anti-doping agencies were aware of these problems and the continued use of performance enhancing drugs despite their efforts to contain them. As early as the 1990s, research had shown that in the absence of exogenous agents, concentrations and ratios of testosterone, its precursors, and its metabolites remain remarkably stable in an individual’s urine, and anabolic-androgenic steroids have a lasting effect on these otherwise stable values. However, it wasn’t until 2007 that researchers adopted Bayesian inference to formalize the detection of abnormal values in these ratios. These ratios together with a hematological profile constitute an Athlete Biological Passport (ABP). This passport is a powerful benchmarking tool to enhance our ability to detect performance enhancing drugs. 

Future Developments in Monitoring for Performance Enhancing Drugs

In vitro bioassays are another promising nontargeted approach for detecting androgens. By altering cells with reporter proteins under regulation of androgen response elements, these assays can detect androgen receptor activation regardless of its source6. This makes bioassays useful for detecting androgens in samples of unknown composition, such as in dietary supplements, which have in recent years caused athletes to inadvertently ingest banned substances. The further development of nontargeted bioactivity-based detection methods will likely assist researchers in characterizing emerging androgens, whether they be steroidal in nature or part of the emerging class of selective androgen receptor modulators, which bear no resemblance structurally to testosterone and are not as metabolically understood7 (Figure 3).

androgen receptor modulators

Figure 3. Chemical structures of popular selective androgen receptor modulators (SARMs) of abuse.


Looking toward the Olympic games and beyond, there will no doubt be scandals involving doping by individuals, sometimes at the behest of their organizations. Such is the apparent nature of elite sport. In cases when designer drugs are used to avoid detection, such compounds would not have been clinically tested for safety by their very nature and would therefor pose a risk to athletes’ health. But as sports organizations continue to be creative with the pharmacology they deploy, science will continue to equip anti-doping authorities with the knowledge and analytical capabilities needed to detect performance enhancing drugs. Maximizing these capabilities will serve as a deterrent to minimize doping, promote health in sport, and preserve a semblance of fairness.


1. Donike, M., Nachweis von exogenem Testosteron. Dt. Ärzte-Verl.: Köln, 1983; p S. 293-298.

2. Polet, M.; Van Eenoo, P., GC-C-IRMS in routine doping control practice: 3 years of drug testing data, quality control and evolution of the method. Anal Bioanal Chem 2015, 407 (15), 4397-409.

3. Schänzer, W.;  Opfermann, G.; Donike, M., Metabolism of stanozolol: identification and synthesis of urinary metabolites. J Steroid Biochem 1990, 36 (1-2), 153-74.

4. Catlin, D. H.;  Sekera, M. H.;  Ahrens, B. D.;  Starcevic, B.;  Chang, Y. C.; Hatton, C. K., Tetrahydrogestrinone: discovery, synthesis, and detection in urine. Rapid Commun Mass Spectrom 2004, 18 (12), 1245-049.

5. Alquraini, H.; Auchus, R. J., Strategies that athletes use to avoid detection of androgenic-anabolic steroid doping and sanctions. Molecular and Cellular Endocrinology 2018, 464, 28-33.

6. Lund, R. A.;  Cooper, E. R.;  Wang, H.;  Ashley, Z.;  Cawley, A. T.; Heather, A. K., Nontargeted detection of designer androgens: Underestimated role of in vitro bioassays. Drug Testing and Analysis 2021, 13 (5), 894-902.

7.Thevis, M.; Schänzer, W., Detection of SARMs in doping control analysis. Molecular and Cellular Endocrinology 2018, 464, 34-45.


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Tackling the Global Vaccine Distribution Challenge

Rumiana Tenchov, Information Scientist, CAS
microfluidics for improved production of lipid nanoparticles for vaccines

A breakthrough in nanotechnology accelerates vaccine production

While COVID-19 hotspots have continued to emerge driven by the Delta variants, the data still shows that vaccinations are effective at preventing hospitalizations and deaths. While over 4 billion vaccine doses have been administered worldwide, only 27% of the world’s population and only 1.1% of people in low-income countries have received at least one dose of a COVID-19 vaccine. While there are many supply chain challenges for the production and distribution of these vaccines (refrigeration, costs, and transportation), one in particular is the production of lipid nanoparticles for vaccines.

Percentage of vaccinated people by country - July 2021

Figure 1: A breakdown by country and continent of the share of vaccinated people

Why are lipid nanoparticles essential for mRNA therapeutics?

Delivery of mRNA therapeutics into the human body has been a major challenge caused by the nucleic acid’s inherent instability and properties: 

  • The negative charge and hydrophilicity prevent passive diffusion across bio-membranes
  • The association with serum proteins, uptake by phagocytes, and degradation by endogenous nucleases obstruct efficient delivery
  • Delivery vectors are required to protect them from degradation and to deliver them to the target cells for efficient uptake.  

Lipid nanoparticles (LNPs) have proven successful at effectively protecting and transporting mRNA into cells as seen in the recent mRNA COVID-19 vaccines

Vaccine production is limited by the output of lipid nanoparticles

Scaling the production of any therapy is difficult, but production of these lipid nanoparticles to fulfil the worldwide demand for vaccines is a major challenge. The synthesis of the proprietary ionizable cationic lipids especially developed and optimized for these vaccines is a complex multistep process. But there is even a bigger challenge in producing the LNP on a large scale – the task of combining the lipids and the mRNA into nanoparticles.

Indeed, for efficient production of a pharmaceutical formulation, the manufacturing technique is of utmost importance. Traditional methods for LNP manufacture including but not limited to thin film hydration, reverse phase evaporation, solvent injection, and detergent removal, commonly result in large (>100 nm) and heterogeneous particles with a low encapsulation yield, requiring an additional downsizing step, such as extrusion or sonication. Moreover, these methods are difficult to scale-up and are not consistently reproducible. 

Microfluidics is new approach 

Recently, microfluidics has proven successful in producing LNPs. In microfluidic focusing method, a stream of lipid solution in alcohol is forced through a channel that is intersected and sheathed by a coaxial stream of an aqueous phase (Figure 2A). Reciprocal diffusion of alcohol and water across the alcohol/water interface causes the lipid to precipitate and self-assemble into LNPs. Microfluidic techniques are robust, scalable, and highly reproducible. For mRNA vaccine formulations, the lipid mixture includes an ionizable cationic lipid, along with a PEG-lipid and helper lipids (phosphatidylcholine, cholesterol), while the aqueous phase contains the nucleic acid. The cationic lipid interacts with the negatively charged nucleic acid, resulting in LNPs with high encapsulation efficiency. LNPs of defined sizes and narrow size distribution can be produced by precisely controlling the microfluidic operating parameters, such as flow rate and component ratios. However, the throughput of the process is limited (<10 mL/h), thus creating a bottleneck for a large-scale production of mRNA vaccines.

schematic of microfluidic devices

Figure 2.  A single-channel microfluidic device (A) and a novel parallelized microfluidic device (B) containing 128 micromixing channels working in parallel

Early results are promising

А recent manufacturing technology breakthrough enabled over hundred-fold increase in the current microfluidic production rates. A microfluidic device has been constructed containing 128 micromixing channels working in parallel – a parallelized microfluidic device, utilizing a very large scale microfluidic integration (VLSMI) platform technology. The channels mix precise amounts of lipid and mRNA, crafting lipid nanoparticles of accurately controlled size and amount of encapsulated mRNA. The device has over hundred times the throughput of a single channel microfluidic device (18.4 L/h) and provides an excellent possibility for even further scaling up, thus allowing mass-production of RNA-carrying lipid nanoparticles. Published results indicate that the parallelized microfluidic device produces lipid nanoparticles effective for use in siRNA- and mRNA-based therapeutics and vaccines.  

Lipid nanoparticle production will enable more mRNA therapies

The development of such vaccines and therapies has the potential to revolutionize medicine by gene editing and protein replacement therapeutics. Currently, LNP-based mRNA vaccines have entered clinical trials against a variety of infectious diseases, such as nucleoside-modified mRNA vaccines for Zika virus, cytomegalovirus, tuberculosis, and influenza. mRNA therapeutic vaccines have great potential in cancer immunotherapy against melanoma, ovarian cancer, breast cancer, and other solid tumors. 

The use of mRNA for the expression of therapeutic proteins bears great promise in treating a wide range of diseases by applying protein replacement therapy. This newly developed microfluidic fabrication technology addresses the clinical need of scalable, highly precise, and reproducible LNP production, thus enabling rapid formulation of LNPs for a broad range of RNA therapeutics and vaccines. While this may not solely solve the global distribution challenge, it is a critical advancement in a new era of potential cures and vaccines that mRNA may unlock. 


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COVID-19 vaccine boosters: what does the research show?

Janet Sasso, Information Scientist/CAS
Nurse administering booster vaccine

With the announcement of newer mRNA booster recommendations, many are asking whether they or their loved ones should get a COVID-19 booster and what science shows. This blog will explain the basics of boosters, review current expert recommendations, and examine the emerging research that has been published.  

What is a COVID-19 booster shot?

A COVID-19 booster is simply an additional dose of vaccine after an individual is fully vaccinated, with two doses of Pfizer-BioNTech’s or Moderna’s mRNA vaccine or one dose of Johnson & Johnson’s viral vector vaccine and has a typical immune response. Booster vaccines work as their name suggests by boosting the protective effect of the initial vaccine. They stimulate an individual’s immune system to produce additional antibodies and memory B cells and T cells. 

An adult booster vaccine that many individuals are familiar with is the Tdap (diphtheria, tetanus, and acellular pertussis (whooping cough) booster. The Centers for Disease Control (CDC) recommends an adult booster once every 10 years, but special scenarios also encourage the use of boosters. For example, parents and caregivers of infants are encouraged to get a Tdap booster to provide a protective vaccine bubble for vulnerable newborns and infants against the disease whooping cough. A Tdap booster is also encouraged after an injury with potential Clostridium tetani exposure to “boost” the immune system to respond to the bacterial toxins that cause a tetanus infection. 

The COVID-19 booster dose strengthens both the humoral and cellular immunity provided by the initial vaccines, helping the immune system respond more quickly to the SARS-CoV-2 virus when encountered.

Why are COVID-19 vaccine boosters being recommended?  

Especially for certain segments, there is clear evidence that an additional dose for the immunocompromised and a booster for high risk populations would be beneficial. The data below shows that the effectiveness of the COVID-19 vaccines is decreasing with the emergence of variants, waning immunity, and exposure to higher viral loads. The highly transmissible Delta variant became the dominant strain in most areas during summer 2021, changing how vaccine effectiveness looks with the resulting higher case counts. Another aspect to note is that many COVID-19 public health orders such as universal masking ended in the U.S. before or during summer 2021.  

  • CDC researchers show that mRNA vaccines drop from 74.7% effective against infection in March 2021 to 53.1% in July 2021 for nursing home populations.
  • Israeli researchers showed the risk for infection was significantly higher for individuals vaccinated earlier compared to those vaccinated later. Individuals vaccinated in January 2021 had a 2.26-fold increased risk for breakthrough infection compared to individuals receiving vaccinations in April 2021. Like the U.S., Israel vaccinated their most vulnerable populations first, based on age and health status. Therefore, the first vaccinated were at the highest risk for COVID-19 infection. Seventy-eight percent of Israel’s population age 12 and older are vaccinated for COVID-19 with the Pfizer-BioNTech BNT162b2 vaccine.
  • New York researchers also found vaccine effectiveness against infection to decline from 91.7% to 79.8% for all New York adults from May to July 2021, as Delta became dominant.
  • UK researchers analyzed data collected in Britain’s ZOE COVID study. They found that the Pfizer-BioNTech vaccine fell from 88% effective one month after full vaccination to 74% five or six months after full vaccination for the Delta variant. The Oxford-AstraZeneca viral-vector vaccine fell from 77% effective one month after full vaccination to 67% at four or five months after full vaccination.
  • The University of California San Diego Health (UCSDH) researchers saw a sharp decrease in vaccine effectiveness in its healthcare workers from June to July 2021. Vaccine effectiveness exceeded 90% from March through June but fell to 65.5% in July. The Delta variant represented 95% of UCSDH cases by the end of July.

US Vaccine Manufacturer’s Booster Vaccine Administration Recommendations

Vaccine Recommendation
Pfizer-BioTech BNT162b2 Booster dose given 6-12 months after full vaccination
Moderna mRNA-1273 Booster dose given 6 months after full vaccination
Johnson & Johnson COVID-19 vaccine Booster dose given 8 months after full vaccination

Currently Pfizer-BioNTech and Johnson & Johnson (ages 18-64) are recommending the standard dose of their current vaccine, while Moderna is recommending a lowered dose of 50 µg vs. its standard 100 µg dose. Johnson & Johnson is recommending a lower booster dose for individuals 65 years and older.

What does the CDC and FDA say about the COVID-19 vaccine boosters?

There is strong evidence about the need for an additional dose especially within immunocompromised populations who can have a reduced immune response and are more vulnerable to serious illness, hospitalization, and death from COVID-19. While experts agree that a booster would be valuable for at-risk populations, there are differences in government agency recommendations for front-line workers and the general population.  

Agency At Risk Populations* Front-Line Workers General Population
CDC Recommends Recommends Not Recommended
HHS Recommends Recommends Recommends
FDA Recommends Recommends Not Recommended

*Immunocompromised and those over 65.

In mid-August, the Food and Drug Administration (FDA) authorized an additional Pfizer-BioNTech (BNT162b2) or Moderna COVID-19 (mRNA-1273) vaccine dose for immunocompromised individuals. Within a week, the U.S. Department of Health and Human Services (HHS) announced that they recommended COVID-19 booster vaccines for all individuals, pending approval and recommendations from the FDA and the U.S. Centers for Disease Control and Prevention (CDC). The CDC currently recommends a third dose of vaccine for moderately and severely immunocompromised individuals who received the Pfizer-BioNTech or Moderna COVID-19 vaccines to better protect this population. 

However, after the FDA Advisory Committee meeting on September 17, 2021, they concluded that the scientific evidence does not support booster vaccines for the general population at this time; because the current vaccination is still highly effective at preventing severe disease, hospitalization, and death from COVID-19.  Scientifically, the news was positive in that the vaccines are working according to their design, even amongst new variants. However, this FDA Advisory Committee recommendation will be revisited when more scientific evidence supporting widespread boosters is available. 

Most recently on September 22, the FDA officially recommended a Pfizer-BioNTech's COVID-19 booster vaccines to individuals who are 65 and older or at high risk of severe disease and received their second dose at least six months ago. They also specified that health care workers, first responders, and those whose jobs put them at special risk should also be eligible for a booster. This group includes professions such as teachers. 

On September 23 the CDC's Advisory Committee on Immunization Practices(ACIP) voted to recommend a Pfizer-BioNtech Covid-19 vaccine booster to people 65 years or older, long-term care facility residents, and people ages 18 to 64 with underlying medical conditions. However, they voted against offering a booster dose to people 18 to 64 whose occupational or institutional setting put them at high risk for COVID-19 infection such as health care workers, first responders, and teachers.  The committee will revisit this recommendation when more evidence is available.  

Hours later, CDC Director Dr. Rochelle Walensky signed off on her official recommendation for the Pfizer-BioNtech Covid-19 vaccine booster. However, it differed from the advisory committee’s results. Instead, she aligned with the FDA, to include boosters for individuals 18 to 64 whose occupational or institutional setting put them at high risk for COVID-19, citing the best interest of the nation’s public health.

Should the booster be the same vaccine as the first one? 

The CDC currently recommends individuals who received either Pfizer-BioNTech or Moderna’s COVID-19 vaccine series receive the same mRNA vaccine for their third dose. If the mRNA vaccine given for the first two doses is unavailable or is unknown, either mRNA COVID-19 vaccine is appropriate as a booster.

However, there are some early results from the UK, Germany, and Spain that have shown mixing vaccine types produced a higher number of antibodies than those who received two doses of the viral vector vaccine. They used the Oxford-AstraZeneca viral vector vaccine to “prime” the immune system with the first dose and then the Pfizer-BioNTech mRNA vaccine to “boost” with the second dose. Each vaccine type stimulates a different area of the immune system creating a more robust immune response than the viral vector vaccine alone.

The National Institutes of Health (NIH) is currently conducting a Phase 1/2 clinical trial to examine a mixed COVID-19 vaccine schedule to determine the safety and immunogenicity of mixed booster regimens.  

CAS COVID-19 Resources:

While boosters may help individuals evade symptomatic infection, they are in no way a means out of the COVID-19 pandemic. Staying ahead of COVID-19 viral variants with the prevention of large outbreaks through global vaccination, boosters, masks, and social distancing will still be critical to minimizing transmission and continued viral mutations. To stay informed on the latest COVID-19 vaccines, technology, and breakthroughs, visit our COVID-19 Resources page for all of our publications, data sets, and insights.



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The next growth wave: lithium-ion battery recycling technologies

Zach Baum, Information Scientist, CAS
lithium ion battery recycling

Just over 10 years ago, a paper published in Nature asked, “is lithium the new gold?” This was based on the metal’s use in lithium-ion batteries (LIBs) coupled with uncertainties about reserves and demands. Today, ‘black mass,’  the metal rich material from the recycling of lithium-ion batteries could be the new “gold” of the lithium-ion market. In total, the global LIB market is worth USD 41 billion–with an expected increase to over USD 116 billion by 2030. 

It is anticipated that in 2040, 58% of all cars sold worldwide will be electric cars–and the total amount of universal waste generated could be as much as 8 million tons. Despite this, only around 5% of LIBs are thought to be recycled globally with alarming implications for the environment and the earth’s mineral reserves. 

As we explore in our white paper, this is because LIB recycling is limited by various factors, including the fluctuating financial values of battery materials, lack of technological convergence in battery designs and materials (and associated recycling labor costs), as well as within recycling plants. The lack of monetization of recycling benefits (including material security, safety, and environmental benefits), and absence of recycling regulations across much of the world also play a part.

Are we up for the lithium-ion battery recycling challenge?

The challenges of lithium-ion battery recycling come with substantial opportunities for growth. For instance, from the estimated 500,000 tons of batteries which could be recycled from global production in 2019, the following raw materials could be recovered: 15,000 tons of aluminum, 35,000 tons of phosphorus, 45,000 tons of copper, 60,000 tons of cobalt, 75,000 tons of lithium, and 90,000 tons of iron–offering material security and significant economic and environmental benefits.

As we discuss in our white paper, interest in lithium-ion battery recycling is understandably under rapid growth–evident by the soaring popularity of ‘black mass’ in general interest. The CAS Content Collection™ has enabled unique views into past journal and patent publications for lithium-ion battery recycling, identifying emerging trends in rechargeable batteries, repurposing of single-use materials, and projecting future opportunities ahead. 

What lithium-ion battery recycling methods are used today? 

In most cases, combinations of hydrometallurgical and pyrometallurgical methods are used to process LIBs, yet direct recycling is enjoying increased popularity (as we explore later). Hydrometallurgy uses solutions (primarily aqueous) to extract and separate metals from battery resources. Pyrometallurgy uses heat to convert the metal oxides used in battery materials to either metals or metal compounds. Direct recycling is the removal of cathode material for reuse or reconditioning.

The three methods used for LIB recycling
Figure 1. An outline of the three methods used for LIB recycling. 

Increasing research trends in the Li-cycle

While the global scientific publication volume has been steadily increasing in the past decade, we found that the annual volume growth in publications for the topic of Li -cycle (32%) far exceeds that of overall scientific publications (4% annually), suggesting an emerging interest. 

Consistent with this, publications involving all three methods of LIB recycling have increased overall in the last decade and have grown significantly in recent years (Figure 2), with China in the lead with the highest volume by far both in journals and patents (roughly 90% of publications; Figure 3). 

Publication volume for each respective recycling method during the years 2010-2021
Figure 2. Publication volume for each respective recycling method during the years 2010-2021.


Li-ion battery recycling publications by country/region during the years 2010-2021
Figure 3. Li-ion battery recycling publications by country/region during the years 2010-2021.

In terms of the specific processes used, hydrometallurgy has outgrown pyrometallurgy considerably after 2015, and, encouragingly, direct material recycling has also seen substantial recent growth (Figure 2). Considerable research effort has also been made towards previously lesser-studied LIB components (suggestive of an emerging, more holistic recycling management view) and towards LIB disassembly (Figure 4). This is preferable because it maximizes the amount of recyclable material. 

Publications studying recovery of non-cathode materials and process optimization for recycling.
Figure 4. Publications studying recovery of non-cathode materials and process optimization for recycling.

Battery recycling capacity around the world

Current LIB recycling capacity is concentrated in East Asia, with China possessing more than half of the world’s current recycling capacity–Europe possesses most of the remaining LIB recycling capacity (Figure 5). Proposed LIB recycling facilities will increase recycling capacities by approximately 25%, with most of the defined new capacity concentrated in North America. The location of current recycling capacity is consistent with the effect of LIB recycling regulations, while the location of future capacity is more consistent with economic motivations. 

Established and planned global li-ion battery recycling facilities as of November 2021.
Figure 5. Established and planned global li-ion battery recycling facilities as of November 2021.


Lithium-ion battery recycling regulations around the world

Overall, lithium-ion battery recycling regulations are increasing; many countries fund research into recycling methods, and a variety of countries have lithium-ion battery recycling laws, with China and the European Union having or enacting comprehensive regulatory frameworks for LIB recycling. Coupled with the increasing interest in lithium-ion battery recycling management, these findings are encouraging for the future as the world’s use of lithium-ion battery continues to grow (e.g., electric vehicles, cell phones).

Read our CAS Insights Report for an overview of the trends in lithium-ion battery recycling research, where we assess the global regulations and economic benefits, and provide insights into the current and future state of LIB recycling globally.

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A greener future: Lithium-ion batteries and Hydrogen fuel cells

Zach Baum, Information Scientist, CAS
picture of car being fueled with hydrogen

Since the mid-late 20th century, the atmospheric concentration of greenhouse gases has been increasing, contributing to ongoing contemporary warming to the extent that climate change can now be detected from any single day of weather. Today, owing to their heavy reliance on fossil fuels, the world’s largest economies still produce vast quantities of CO2 (Figure 1). 

graph showing rise of carbon dioxide emissions over time
Figure 1. a) The continued rise of global CO2 emissions over time. b) CO2 emissions from the six nations generating the highest levels of this gas worldwide. Source:

In the ongoing pursuit of greener energy sources, lithium-ion batteries and hydrogen fuel cells are two technologies that are in the middle of research boons and growing public interest. The li-ion batteries and hydrogen fuel cell industries are expected to reach around 117 and 260 billion USD within the next ten years, respectively.

A key driver for interest in lithium-ion batteries is their explosively growing uses in electric vehicles as well as in consumer electronics among other applications, while H2, as both an energy source and storage medium,– finds uses in transportation, energy supply to buildings, and long-term energy storage for the grid in reversible systems. Both technologies are expected to play key roles in the decarbonization of electricity supplies.

As analyses using our CAS Content Collection™ have shown, much of the research over the past decade on lithium-ion batteries and hydrogen fuel cells has focused on solving contemporary challenges and barriers to their use–some of which we will discuss here. If these technologies are to transform our energy use and transition us into a greener future, this research will be critical.

Lithium-ion batteries vs Hydrogen fuel cells: which are more promising?

On the surface, it can be tempting to argue that hydrogen fuel cells may be more promising in transport, one of the key applications for both technologies, owing to their greater energy storage density, lower weight, and smaller space requirements compared to lithium-ion batteries. Hydrogen-powered vehicles can also be refuelled more quickly than vehicles powered with lithium-ion batteries. However, hydrogen  fuel cells are not without disadvantages: an estimated ~60% of stored H2 energy is lost in the process of packaging energy from H2,which amounts to around three times as much lost energy when compared with lithium-ion battery use.

Clearly, however, both technologies have numerous applications and direct comparisons are therefore complicated. Furthermore, this perspective ignores the ongoing research, as well as the wider costs and benefits of the technologies. Our CAS Content Collection search allows us to delve beneath the surface and gain a deeper understanding of how lithium-ion batteries and hydrogen fuel cells are used today and might be used in the future.

Challenges in lithium-ion battery use

The manufacturing and disposal of li-ion batteries have always been the subjects of political and environmental concerns, with their considerable associated pollution and non-renewable energy sources of lithium and other key resources remaining highly pertinent.

With explosively growing numbers of electric cars (and increasing battery size) in tandem with the rapid disposal of lithium-ion batteries in smartphones and other consumer electronics, energy waste and reliance on non-renewable resources are becoming more significant. Indeed, it is anticipated that in 2040, 58% of all cars sold worldwide will be electric cars, and the total amount of waste generated could be as much as 8 million tons. Much recent research on lithium-ion batteries, therefore, has focused on how to recycle them, with the aim of reducing pollution and easing pressure on mineral reserves.

Today, only around 5% of lithium-ion batteries are recycled globally because of limitations, such as fluctuating financial values of battery materials, lack of technological convergence in battery designs and materials (and associated recycling labor costs) as well as within recycling facilities, lack of monetization of many recycling benefits (including material security, safety, and environmental benefits) and absence of recycling regulations across much of the world.

Challenges in hydrogen fuel cell use

Although costs of hydrogen fuel cells are significant, largely owing to the use of platinum, the greatest challenge is the difficulty in storing (and transporting) H2. Indeed, the success of H2 as a consumer fuel directly depends on finding robust H2 storage materials and developing a refined, safe system for its transportation. 

Key research trends: lithium-ion batteries

As discussed, recycling is of major interest in li-ion battery research since it could help address contemporary issues with pollution, waste, and limited mineral reserves associated with LIBs. The annual publication volume growth on this topic (32%) far exceeds that of overall scientific publications (4% annually), suggesting an emerging interest (Figure 2). 

graph showing publication data for lithium battery recycling
Figure 2. Journal articles and patent publications on lithium-ion battery recycling (Data for 2021 is partial).

Encouragingly, considerable research effort has been made towards previously lesser-studied lithium-ion battery components (suggestive of an emerging, more holistic recycling management view) and towards disassembly (Figure 3), which is preferable environmentally because it maximizes the amount of recyclable material. Direct recycling, the removal of cathode material for reconditioning followed by reuse in new batteries, has also seen increased interest (Figure 4) and is likely to have lower energy costs and reagent costs than other recycling methods.

graph showing publications studying recovery of non-cathode materials for battery recycling
Figure 3. Publications studying recovery of non-cathode materials and process optimization for recycling.
graph showing publication volume for battery recycling methods from 2010-2021
Figure 4. Publication volume for each respective recycling method during the years 2010-2021. Pyrometallurgy is the use of heating to convert the metal oxides used in battery materials to either metals or metal compounds. Hydrometallurgical methods use solutions to extract (leach) and separate metals from battery materials. Direct recycling is the removal of cathode material for reconditioning followed by reuse in new batteries.

Key research trends: Hydrogen fuel cells

There has been a steady increase in the volume of patents in the H2 fuel space since 1997, demonstrating the growing global interest in this technology (Figure 5). Encouragingly, H2 storage has remained the leading topic of interest over the last decade (Figures 6 and 7); the development of a H2 economy is highly dependent on the ability to store and transport the gas, since it is not feasible to establish a supply chain without this capability.

graph showing timeline of patent publication in the hydrogen fuel space
Figure 5. The timeline of patent publication in the hydrogen fuel space. The number of filing organizations is represented by the color and thickness of the sparkline. Source: CAS Content Collection.


chart showing trends in the focus of publications in the hydrogen fuel space
Figure 6. Trends in the focus of journal articles and patents within the hydrogen fuel space. Source: CAS Content Collection. 


chart showing main areas of innovation in the hydrogen fuel space
Figure 7. The main areas of innovation in the hydrogen fuel space across a range of industrial sectors. Source: CAS Content Collection


Hydrogen storage is followed by dehydrogenation (Figure 6), which has been established as the second leading area of innovation since 2012. With dehydrogenation methods, it is possible to extract H2 gas from liquid H2 carriers such as ammonia–chemicals for which the storage and transportation infrastructure already exists. Thus, this topic could represent a key solution in efforts to utilize H2 more widely. Ongoing research seeks to increase the efficiency of costly processes such as the Haber-Bosch process, required to extract H2 from its carrier (in the case of an ammonia source), or find more energy-efficient alternatives. 

Looking ahead

The CAS Content Collection has allowed us to investigate key research trends in the ongoing pursuits to harness the potential of lithium-ion batteries and hydrogen fuel cells–two key technologies that could help transform global energy use for a greener future.

Moreover, research appears to be focused on solving key contemporary issues associated with these technologies–in the case of lithium-ion batteries, recycling is undergoing a research boon, while H2 storage remains the principal topic of interest in hydrogen fuel cell work. 

See our lithium-ion battery recycling and hydrogen fuel cell white papers for deeper insights into the evolving economic, political, environmental, and research landscapes of these two key technologies.

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Is nuclear energy critical in solving climate change?

Gilles Georges, Vice President Content Operations, CAS
photo showing nuclear power plant stacks

While green energy’s footprint continues to increase as the fastest growing segment within the global energy mix, it still trails significantly behind conventional, high-carbon energy options due to efficiency and capacity hurdles. These limitations are preventing green energy from becoming a predominant, mainstream energy option. What other scalable, non-CO2 emitting form of energy could help us close the gap until green energy becomes a large-scale reality for us? Could nuclear energy’s carbon-free profile, proven efficiency and scalability make nuclear power a transition candidate, and possibly another viable, widely accepted energy option for the future? 

In addition to their zero-emission blueprint, the approximately 450 nuclear power plants operate today at full capacity greater than 90% of the time compared to 50% for coal and 25% for solar plants. However, only 10% of the total electricity demand worldwide is supplied by nuclear power plants (Figure 1). Why hasn’t nuclear energy grown faster over the years? 

chart showing source of electricity production in 2021
Figure 1. Share of electricity production by source 2021. 

Although a proven and economical option for energy production, nuclear energy carries a controversial image due to the risks associated with radioactivity and its impact on the environment. The Chernobyl and Fukushima events reminded us that atomic fission requires flawless control and vigilance and that small incidents can turn into major catastrophes. 

Nuclear Reactions and Radioactivity 

With over 18,000 reactor-years of experience, nuclear reactor technology is well established, diversified, and benefits from decades of technological improvements making reactors safer, more reliable, durable, and efficient. 

To generate electricity, nuclear power plants use a mixture of uranium isotopes, mainly 238U and 235U as fuel. Most commercial nuclear power plants use low enriched uranium (LEU) fuel, which is uranium with 235U enriched between 3-5%, as opposed to highly enriched uranium (HEU) which has the 235U concentrations of ~90% needed for weapon grade applications.  

illustration of uranium enrichment reaction
Figure 2. Uranium enrichment – Uranium-235 isotope concentration increases from 0.3% to 3%.

Once in the reactor as the LEU fuel, 235U and 238U take two different atomic transformation paths as Figure 3 illustrates. Through the capture of a neutron, and in the case of 238U which transmutes to fissile 239Pu, both 239Pu and 235U fission into smaller nuclei, i.e., fission products. The fission reactions each also release three neutrons and a significant amount of energy in the form of heat and ionizing radiation.

illustration of nuclear fission reactions
Figure 3. Nuclear fuel fission reactions.

This atomic transformation or decay is a blessing and a curse.  A blessing because in relation to the small quantity of fuel involved, it produces enormous amounts of energy that will be extracted through heat exchangers and high-pressure water turbines to produce electricity. It is a curse because transmutation associated atomic decay also produces ionizing radiation and particles, collectively called radioactivity. The radioactivity in the reactor for electricity production is desired, but this radioactivity persists within the fuel waste, called “spent fuel”, and can be harmful if not contained and controlled. 

After 3-5 years of continuous nuclear activity in a reactor, the fuel concentration in fissile isotopes eventually falls below the minimum level to maintain a chain reaction for electricity production purposes. The spent fuel is unloaded from the reactor and categorized as “high-level” radioactive waste (HLW). HLW represents only 3% of the total radioactive waste volume but it accounts for 95% of the waste’s total radioactivity. Thus, HLW is a major focus of radioactive waste management strategies worldwide.   

An average nuclear power plant with a capacity of 1000 MWe (sufficient to supply the needs of more than one million people), produces 25-30 tonnes of HLW per year and zero carbon emissions. A coal-fired plant releases 300,000 tonnes of ash and more than 6 million tonnes of CO2 to the atmosphere annually. However, reducing the footprint and the radioactive potency of nuclear waste through reprocessing and reuse of spent fuel would address a complex hazardous waste management challenge. 

Nuclear spent fuel recycling options 

Nuclear spent fuel reprocessing technology has existed since the late 1940’s. It is well understood and technically proven but only a few countries have invested in reprocessing. France and Russia are the two main countries reprocessing and reusing spent fuel. On average, about 95% of spent fuel waste is uranium (the majority is 238U), 1% is plutonium, and the rest are a wide variety of fission products with a lower atomic number and minor actinides (Figure 4). Spent fuel reprocessing technology allows the separation of uranium and plutonium isotopes from other actinides and fission products.  

illustration of PUREX nuclear separation process
Figure 4. PUREX separates the spent fuel into three phases. 

The predominant reprocessing option is called PUREX (plutonium and uranium reduction extraction). PUREX uses hydrometallurgical separation technology to separate the spent fuel into three phases:  

  1. Uranium isotopes
  2. Plutonium isotopes
  3. Fission products with minor actinides 

This third phase is considered HLW because of the presence of these minor actinides and the highly radioactive, medium-lived fission products (i.e. 90Sr and 137Cs with radioactive half-lives of about 30 years). The primary advantage of PUREX is the recycling of large amounts of usable uranium that would otherwise be considered as waste and the significant reduction in the HLW volume. 

While PUREX reduces waste volume, it doesn’t address its radioactivity. Also, the separation of 239Pu from other actinides generates nuclear weapons proliferation concerns. 

PUREX process variants have been proposed and implemented around the world to address HLW radioactivity and plutonium proliferation risks. These PUREX variants consist in blending 239Pu with minor actinides that would prevent it from being weaponized while creating an acceptable reprocessed actinide fuel blend. Other variants consist in blending uranium, plutonium, and all transuranics (elements with a higher atomic number than uranium) together, leaving fission products as the only waste. 

HLW recycling makes sense when one considers that more than 90% of the uranium is “unburned” when spent fuel rods are unloaded from the reactor. Recycling unused uranium and plutonium allows the generation of ~25-30% more electricity. At the end of 2020, 400,000 tonnes of used fuel had been generated globally from commercial nuclear power reactors, of which about 120, 000 tonnes (30%) has been reprocessed and reused as nuclear fuel.  

Advances in nuclear reactor designs 

Recent advances in the design of nuclear reactors have improved energy production’s efficiency and safety. The CAS Content Collection™ shows a significant increase in patent and journal activity since 2018 indicating a renewed interest, primarily driven by organizations in Asia (Figures 5a and 5b).  

top patent assignees for nuclear energy technology
Figure 5a. Top patent assignees for nuclear energy technology since 2000.
organizations with most nuclear energy journal publications since 2000
Figure 5b. Organizations with most journal publications on nuclear energy since 2000.

Figure 6 shows the publication volume associated with new, advanced nuclear reactor designs. The data confirms increasing research activity around these new nuclear reactor technologies.  

graph of publication volumes for types of nuclear reactor design
Figure 6. Advanced nuclear reactor designs and their association with publication volumes


Nuclear Energy's Future Potential 

The renaissance of nuclear energy has been an enduring theme, but several obstacles and challenges still make it difficult for nuclear energy to fulfill the hope and promise it generated decades ago. The large upfront capital, changing regulations, cost overruns, and political polarization have made nuclear power plant deliveries a decade-long, tortuous journey. This has been a serious deterrent for governments and investors to consider nuclear energy even if its advantages and potential are proven and undeniable. A recent Wall Street Journal article also addresses some of these challenges as well as recent developments in the field of nuclear energy technologies.

The need for carbon-free sources of energy, advances in new reactor technologies, and new spent fuel recycling and reuse alternatives could propel nuclear energy as a key tool in the arsenal to combat the global climate change challenge. 

Acknowledgement to Elaine McWhirter for scientific consultation.

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Lithium Ion Battery Recycling

Lithium Battery Recycling white paper thumbnail

A Review of the Current Methods and Global Developments

Today, only 5% of the world’s lithium-ion batteries are thought to be recycled across the globe, with dramatic environmental and financial implications for the projected 8 million tons of waste.  While the challenges of recycling will range from financial, to policy-making, this white paper dives deep into the scientific challenges and the emerging research landscape around this huge opportunity.  

Lithium Battery Recycling white paper cover

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Bio-Based Polymers As An Alternative to Fossil Fuel Plastics


With almost 10% of the world’s fossil fuels going towards plastic production, a viable alternative to fossil fuel-based plastics has been a key goal for the past 20 years. Bio-based polymers, obtained from renewable biomass resources, have received wide attention as the ideal replacement. These polymers have been used to create bioplastics, which are a promising and sustainable alternative to oil-based plastics and could even benefit countries that are heavily reliant on foreign oil.

This journal manuscript in ChemRxiv details the three types of bio-based polymers, their strengths and weaknesses, the latest research progress, and the trends in this field of study. Because bioplastics often face skepticism from the public, likely attributed to misinformation, this article aims to clarify the confusions and raise the awareness of bio-based polymers’ importance to sustainability.

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Predicting New Chemistry: Impact of High-Quality Training Data on Prediction of Reaction Outcomes

Predicting New Chemistry White Paper thumbnail

Machine learning models supporting synthesis planning applications are largely limited to the chemistry seen in training, and the accuracy and diversity of their predictions are often diminished in sparsely populated chemical subspaces. By measuring how different datasets affect the performance of trained models, we can make stronger assertions regarding the expected coverage and novelty of synthesis planning solutions, and design datasets that will open up previously difficult areas of science. 

In this study, scientists at Bayer demonstrate the significant impact that scientist-curated reactions from the CAS Content Collection have on the predictive power of a synthesis planning model. Accuracy in prediction of outcomes in rare reaction classes increased significantly – a boost of 32 percentage points – expanding understanding into new, useful chemistry.

Predicting New Chemistry white paper cover

Request the CAS Insights Report or contact our Custom Services Team to design a dataset to open up challenging areas of science.

This CAS Insights Report is published in collaboration with scientists from Bayer.


  • Miriam Wollenhaupt, Ph.D., Computational Chemist, Bayer AG
  • Martín Villalba, Ph.D., Expert Applied Mathematics, Bayer AG
  • Orr Ravitz, Ph.D., Synthesis Planning Solutions, CAS

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