State of the Diagnostic Industry: Recombinants on the Rise

Discovery of a fragile foundation

Four years ago in GEN, Scripps Laboratories predicted that the clinical diagnostic industry was on the verge of a recombinant protein revolution. At the time, in vitro diagnostic (IVD) assay developers were opposed to using recombinant proteins as replacements for proteins derived from human or animal tissues, glands, organs, and fluids, so-called “native” proteins. The pushback was vigorous, even palpable.

Director, Product Research

Scripps Laboratories

Today, the transition to recombinants is underway, as they are being approved and adopted in IVD assays around the globe. My team and I witnessed firsthand the shortage of native starting materials and helped drive this shift by developing recombinants suitable for the IVD industry. Recombinants are now the most responsible option in many diagnostic areas for laboratories that care about long‑term risk management, supply chain resilience, sustainable sourcing, and price stability.

The IVD industry relied far too long on a surprisingly fragile supply network. Many of the proteins used in diagnostic assays are purified from starting materials obtained from human donors, or from abattoirs in the case of animal-sourced materials. For decades, this system appeared satisfactory: native materials were available, performance was good, and IVD assays were being produced to meet global demand. The system appeared sustainable, and there was no visible reason to change; that is, until there was.

Native sourcing becomes unsustainable

The erosion of the native starting material supply chain was not a single, isolated event. It occurred over many years, even decades. Today, native raw materials for critical proteins in several diagnostic areas are unavailable in the quantities needed to support the growing IVD industry.

Going back 10 to 15 years, human hearts and livers were becoming increasingly expensive and difficult to obtain. In addition, the quality of the donor organs made available to reagent manufacturing companies was deteriorating severely. Many organs were either resected or visibly diseased. Poor-quality hearts yielded less and less of the cardiac biomarkers creatine kinase MB (CK-MB), troponin I (TnI), and troponin T (TnT). Similarly, yields of the iron-storage protein ferritin from human livers decreased precipitously.

Pituitary glands have a similar story of declining availability and spiking costs. Pituitaries are the source of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and thyroid-stimulating hormone (TSH). These hormones are essential to testing in reproductive medicine (FSH, LH, PRL) and thyroid disease (TSH). The pituitary gland is small, the size of a pea, and each human has only one. Several thousand glands are needed, from several thousand donors, for a single pituitary gland-extraction batch. Given the growing size of the reproductive and thyroid testing markets, such large-scale consumption of this limited resource was not sustainable.

Animal-derived proteins are not immune to such supply chain disruptions. Changes in how porcine stomachs are processed at abattoirs around the world significantly reduced the intrinsic factor content available for purification. Porcine intrinsic factor has a high affinity for vitamin B12 and has been used for decades in metabolic diagnostics as the binding reagent in B12 assays. With the new stomach excision process resulting in lower yields, producing native intrinsic factor has become more challenging and expensive.

One telling indicator that some areas of the native protein model are under strain is the behavior of IVD assay manufacturers themselves. Many long-standing hormone customers have implemented a “last time buy” strategy, purchasing native hormones in quantities to last three to five years. This tactic may bridge a short-term gap, but it signals a deeper, industry-wide revelation: continuing to build assay portfolios on such vulnerable raw materials is not aligned with long-term risk management.

From skepticism to necessity

When companies began presenting recombinant alternatives to the IVD industry, the reception was cool. Many diagnostic manufacturers would not entertain a discussion about recombinants, let alone consider evaluating them. The conventional wisdom was that native proteins were inherently superior in immunoassays, particularly for structurally complex proteins, like the 24-subunit ferritin molecule, or for glycosylated, two-subunit proteins, like FSH, LH, and TSH. To be fair, the recombinants available 10 or 20 years ago were not produced with the IVD industry in mind and did not perform up to industry standards.

In only a few years, the IVD industry’s attitude toward recombinants has shifted dramatically. A willingness to evaluate them as replacements for native proteins has spread across the globe. The same diagnostic laboratories that refused to have a conversation about recombinants four years ago are now proactively soliciting their suppliers for recombinant alternatives to native proteins. Many global IVD leaders have implemented a mandate to switch to recombinant proteins wherever a native protein may be considered at risk of a raw material shortage. Furthermore, when a new assay is being developed, a “recombinant-first” approach is now the norm.

We have also witnessed a cultural element to the shift. Some of the larger IVD companies have said that their scientific staff was reluctant to switch away from native proteins, but that the transition to recombinants is happening, regardless. This, too, demonstrates a broader understanding in the industry of the fallibility of the old native model.

Recombinants taking over

The most swift and dramatic transition to recombinant hormones is occurring in the fields of reproductive biology (FSH, LH, PRL) and thyroid disease (TSH). Historically, recombinant forms of these hormones performed poorly, so the resistance to evaluating recombinants was strong. As the supply of pituitary glands contracted, however, assay manufacturers were forced to confront the vulnerability of their supply chain. Fortunately, having inside knowledge of the pituitary supply constraints, our laboratory set out early to develop recombinant forms of these hormones. By the time the supply crisis hit, we were prepared with a full line of IVD-assay-tested recombinant hormones.

The response in the industry has been decisive and far-reaching. Most customers for native hormones have now tested, approved, and switched to recombinant versions. This change did not occur because native hormones suddenly became unusable, but because their supply became incompatible with the magnitude, reliability, and planning requirements of the industry. By contrast, recombinant hormones can be produced at scale in controlled systems with consistent quality and predictable availability.

Cardiovascular diagnostics are following a similar path. Recombinant TnI, TnT, CK-MB, and myoglobin are being adopted quickly as replacements for the native forms derived from human hearts. The supply of suitable organs cannot keep pace with industry demand, as cardiovascular disease is on the rise globally and the growth of point-of-care testing continues. Recombinant cardiac markers offer a solution to organ supply shortages, meeting the industry’s high demand for these proteins, while maintaining the performance characteristics IVD laboratories expect.

In anemia and metabolic diagnostics, the switch has not been immediate, but it is underway. Recombinant apoferritin (ferritin without iron) and recombinant human intrinsic factor are available to replace the native proteins, and they are being evaluated and approved. The global supply of native ferritin and intrinsic factor is diminishing, but the situation is not as dire as with heart- and pituitary-derived proteins. Thus, the transition is progressing, but is not as far along.

Keys to producing recombinants

To justify switching to a recombinant protein, the recombinant must perform comparably to the native protein it is intended to replace. Early recombinants did not perform well, resulting in the skepticism seen initially. In antibody-based assays, even subtle structural differences can translate into poor recognition, reduced sensitivity, or altered calibrator performance. Overcoming these issues requires more than simply expressing a protein in a convenient host; it requires a project development and testing strategy tailored to the nuances of IVD assay development.

At Scripps, our intention was to devise and implement a strategy that would produce recombinants suitable for the IVD industry. The process involves appropriate gene, expression vector, and host cell line selection; tagless protein expression; early and extensive testing in antibody-based systems, including clinical analyzers; and a willingness to revisit any or all of these elements if the desired recombinant is not produced.

This development strategy addresses the concern about recombinant protein performance in the IVD industry. When a recombinant biomarker performs well and can be supplied consistently, without relying on the unstable supply framework of donor materials, the recombinant becomes not just an acceptable option, but the preferred one.

Looking ahead

The IVD industry is at an inflection point, bending toward global acceptance of recombinant biomarkers. The constraints on native tissue supply and quality will not ease; in fact, they will likely intensify. Simultaneously, industry expectations surrounding ethical sourcing, supply chain stability, risk mitigation, and long-term cost control will become more stringent. Given this environment, continued reliance on donor materials is difficult to justify and is perhaps foolish.

Recombinant proteins offer a way forward that unites consistent assay performance with sound business judgement. Disconnected from unreliable tissue supply networks, recombinants support sustainable and ethical sourcing practices, providing IVD assay manufacturers with a stable foundation for planning and growth. The experience of recent years—in reproductive biology, cardiology, and thyroid disease in particular—has shown that when recombinants are developed with clinical assay performance in mind, they can match or even exceed the standards set by native proteins.

Our team has seen the industry’s view of recombinants evolve from skepticism to necessity. Focusing on tagless expression and rigorous early testing, recombinants can be produced not as lesser-quality replacements, but as robust solutions. As assay developers and IVD executives look ahead to the next decade of innovation, recombinants are no longer a speculative option. They are the most responsible path toward assuring the continued availability of the tests that patients and clinicians rely on daily.

David A. George is director of product research at Scripps Laboratories.