So said John Kenneth Galbraith in his book, The Affluent Society, published in 1958. Science in general, and Medical Science in particular, are no strangers to clinging to conventional wisdom. As Galbraith himself pointed out, and Richard Smith (a former editor of the BMJ), echoed in an article during the COVID-19 pandemic (2), “vested interest in understanding is more preciously guarded than any other treasure.” Indeed many pivotal moments in Medical Science, and drug discovery, have been born from challenging conventional wisdom.

Six years ago, I was party to a debunking of conventional wisdom (what you might describe as a ‘mic drop moment’). One of those junctures where conventional wisdom was swept away through great science. But before I get to that, I need to describe the conventional wisdom around growth differentiation factor-15 (GDF15): a secreted circulating polypeptide associated with mammalian energy balance.

It was known that secreted GDF15 is released from peripheral tissues in response to cellular stress and tissue damage and that animals deficient in GDF15 had increased body weight and fat, while overexpression lead to a leaner phenotype and diminished impact of a calorie-rich diet in driving obesity. These observations led to a flurry of interest in the potential of GDF15, or potential analogues, as a therapeutic strategy for ‘diabesity’.

These observations were not the ‘conventional wisdom’. This was an accumulation of opinions on the role of GDF15 in cancer. Many studies had demonstrated that GDF15 levels were markedly elevated (10–100 fold) in cancer patients compared with patients with benign conditions of the same organ system. Furthermore, intermediate levels were observed in pre-cancerous conditions, and higher levels were seen in more advanced diseases and in patients with metastases compared with earlier and confined diseases. Levels of GDF15 had also been shown to have prognostic value in different tumour types. Studies also elevated levels of GDF15 gene expression, mRNA, or protein in tumour tissue derived from patients compared with healthy tissue.

It had also been established that GDF15 played a significant role in the cachexia seen in cancer patients: a role that fitted with its (somewhat distant) membership of the extended TGFb family. Beyond these data in man, overexpression of GDF15 appeared to promote tumorigenic behaviour in many cancer cell lines and appeared to promote tumour growth in many in vivo models.

Conventional wisdom at this point was therefore that GDF15 was a ‘bad actor’ in cancer. In common with TGFb, it was believed to promote tumorigenesis, tumour growth and metastasis, as well as driving cachexia. Seemingly a very poor choice for an approach designed to aid weight loss and more normative metabolism. However, one vital piece of the equation was missing. It was understood where GDF15 was derived from (multiple tissue sources), but it was not understood by which pathway(s) it exerted its effect. This is where we come to the ‘mic drop moment’. During a meeting with multiple experts in the field (at which I was present), where much of the evidence I describe above was reviewed and discussed, it was revealed (at the end) that the singular receptor for GDF15 had been found: the glial cell line-derived neurotrophic factor family receptor alpha-like (GFRAL) receptor. In fact, four laboratories had independently made this discovery at a similar time, with their findings published later that year (3-6).

This was however not the actual mic drop: that was the finding that the GFRAL receptor is expressed only in the area postrema of the brain in mice, rats, non-human primates and man. This key finding – consistent with many studies – means that it is highly unlikely that GDF15 is a promoter of cancer at all, as GFRAL is not expressed on any of the cell types that are precursors for tumours, or indeed on any tumour cells. As I was aware of what was about to be presented, I studied the response in the room. As I am sure you can imagine, the collective experts were lost for words at an observation that cast doubt on several decades-worth of research.

This was indeed a moment where conventional wisdom was challenged and superseded. There are a number of explanations for the findings from in vitro cell lines and in vivo cancer models (which I shall not review here), and increased scrutiny of the literature base overall revealed a more complex mixture of ‘positive’ and ‘negative’ studies, and as might be expected, a degree of publication bias (“vested interest in understanding is more preciously guarded than any other treasure”). The story becomes even more complex, because evidence gathered after these studies suggest that GDF15 may act via another receptor in the tumor microenvironment. One study suggests that this is CD48, which is mostly expressed on dendritic cells, responsible for presenting tumor antigens to T cells. (7) GDF15 has been shown to interfere with LFA-1/ICAM-1-dependent immune cell extravasation, inhibiting immune cell infiltration into the tumor microenvironment. It also promotes regulatory T-cell activity, resulting in a more suppressive tumor microenvironment. Overall, evidence suggests that GDF15 may indeed have a role in promoting the development and metastasis of tumors, but that this is an indirect effect on the immune response to the tumor, not a direct effect on tumor cells themselves. (8) This has prompted the development of the GDF-15 binding antibody visugromab, with encouraging data from early-phase clinical development (in combination with an anti-PD-1 antibody) in recently published. (9)

The plot thickens further from the recent observation that hyperemesis gravidarum (HG) – severe (and possibly life-threatening) nausea and vomiting in pregnancy – is the result of fetal and placental GDF15 secretion, and maternal sensitivity to it, leading to speculation that GDF15 should be targeted as a therapeutic strategy for HG. (10)

Overall though, this is a salutary reminder that conventional wisdom can be built through reinforcement of a singular perspective (“conventional wisdom…should be a term that emphasizes this predictability”), and – as Galbraith himself further and aptly put it – “The enemy of the conventional wisdom is not ideas but the march of events”.

References

1. John Kenneth Galbraith, The Affluent Society (1958), chapter 2.

2. Richard Smith. Beware the snares of “Conventional Wisdom,” with implications for the pandemic and much else. BMJ: October 9, 2020

3. Hsu, JY et al. Nature 550, 255–259 (2017)

4. Yang, L et al. Nat. Med. 23, 1158–1166 (2017)

5. Mullican, SE et al. Nat. Med. 23, 1150–1157 (2017)

6. Emmerson, PJ et al. Nat. Med. 23, 1215–1219 (2017)

7. Wang, Z et al. J. Immunother. Cancer 9, e002787 (2021)

8. Haake, M et al. Nature Communications, 14: 4253 (2023)

9. Melero Bermejo I et al. Journal of Clinical Oncology 41 Suppl; abstract 2501 (2023)

10. Fejzo, M et al. Nature. 2023 Dec 13. doi: 10.1038/s41586-023-06921-9