According to creationists, humans are the designer’s special creation, and the Universe, Earth, and all life upon it were created solely for our benefit.
If that were the case, one might reasonably expect human design to be uniquely perfect—free from disease and physical defects. Yet, paradoxically, we are more prone to cancer than our closest evolutionary relatives, the other great apes. Recent research from the UC Davis Comprehensive Cancer Center suggests that this heightened cancer susceptibility may be linked to the very mutation that enabled us to develop our comparatively large brains.
It’s almost as though the 'designer' either deliberately endowed humans with a cancer-promoting mutation or failed to anticipate the consequences of the so-called "complex specified genetic information" (© William A. Dembski / Discovery Institute) introduced to facilitate brain growth—and then neglected to revise the design when the flaw became evident. But, of course, being omniscient, we have to assume, if we accept creationists dogma for the sake of argument, it knew full well what the consequences of its design would be and designed them with that consequence in mind.
The theory of evolution, of course, precisely predicts these kinds of suboptimal trade-offs and their consequences. As an undirected, uncaring process, evolution is concerned solely with reproductive success—not with long-term health, perfection, or ideal design.
What is the role of Fas Ligand (FasL)? Fas Ligand (FasL) is a type of protein involved in regulating the immune system and programmed cell death, also known as apoptosis. It plays a key role in maintaining cellular homeostasis and eliminating damaged or potentially dangerous cells—including those that may become cancerous. Role and Function of Fas Ligand:The UC Davis research has just been published (open access) in Nature Communications. The researchers also discuss their findings in a UC Davis ‘Newswise’ article.
- Apoptosis Induction: FasL binds to its receptor, Fas (also known as CD95), on the surface of target cells. This interaction triggers a cascade that leads to apoptosis. It is a crucial mechanism for:
- Removing infected or damaged cells
- Shaping tissues during development
- Eliminating self-reactive immune cells to prevent autoimmunity
- Immune Surveillance: FasL is expressed on the surface of certain immune cells, such as cytotoxic T lymphocytes (CTLs). These cells use FasL to induce apoptosis in virus-infected cells, tumour cells, or other targets.
- Cancer Suppression: By promoting the death of cells that exhibit abnormal growth or DNA damage, FasL helps protect against cancer. A malfunction in this pathway can lead to:
- Immune evasion by cancer cells
- Excess survival of genetically unstable cells
- Increased cancer risk
Relevance to the UC Davis Study:
The study suggests that a small human-specific genetic change in FasL may have reduced its effectiveness in inducing apoptosis. While this change may have supported brain development (e.g. by allowing more neural progenitor cells to survive), it inadvertently made humans more susceptible to cancer by impairing a key tumour-suppressive mechanism.
In short: Fas Ligand is a crucial part of the body's ability to eliminate harmful cells. A mutation that weakens its function could help brain growth but at the cost of higher cancer risk—a classic evolutionary trade-off.
A Single Genetic Mutation May Have Made Humans More Vulnerable to Cancer Than Chimpanzees
New research from UC Davis Comprehensive Cancer Center has uncovered an evolutionary change that may explain why certain immune cells in humans are less effective at fighting solid tumors compared to non-human primates. This insight could lead to more powerful cancer treatments.
The study was published in Nature Communications. It revealed a tiny genetic difference in an immune protein called Fas Ligand (FasL) between humans and non-human primates. This genetic mutation makes the FasL protein vulnerable to being disabled by plasmin, a tumor-associated enzyme. This vulnerability seems unique to humans and is not found in non-human primates, such as chimpanzees.
The evolutionary mutation in FasL may have contributed to the larger brain size in humans, but in the context of cancer, it was an unfavorable tradeoff because the mutation gives certain tumors a way to disarm parts of our immune system.
Associate professor Jogender Tushir-Singh, senior author
Department of Medical Microbiology and Immunology
University of California Davis, Davis, CA, USA.
Tumor environment neutralizes key immune protein
FasL is an immune cell membrane protein that triggers a programmed cell death called apoptosis. Activated immune cells, including CAR-T cells made from a patient’s immune system, use apoptosis to kill cancer cells.
The UC Davis team discovered that in human genes, a single evolutionary amino acid change — serine instead of proline at position 153 — makes FasL more susceptible to being cut and inactivated by plasmin.
Plasmin is a protease enzyme that is often elevated in aggressive solid tumors like triple negative breast cancer, colon cancer and ovarian cancer.
This means that even when human immune cells are activated and ready to attack the tumor cells, one of their key death weapons — FasL — can be neutralized by the tumor environment, reducing the effectiveness of immunotherapies.
The findings may help explain why CAR-T and T-cell-based therapies can be effective in blood cancers but often fall short in solid tumors. Blood cancers often do not rely on plasmin to metastasize, whereas tumors like ovarian cancer rely heavily on plasmin to spread the cancer.
Plasmin inhibitors may enhance immunotherapy
Significantly, the study also showed that blocking plasmin or shielding FasL from cleavage can restore its cancer-killing power. That finding may open new doors for improving cancer immunotherapy.
By combining current treatments with plasmin inhibitors or specially designed antibodies that protect FasL, scientists may be able to boost immune responses in patients with solid tumors.
Humans have a significantly higher rate of cancer than chimpanzees and other primates. There is a lot that we do not know and can still learn from primates and apply to improve human cancer immunotherapies. Regardless, this is a major step toward personalizing and enhancing immunotherapy for the plasmin-positive cancers that have been difficult to treat.
Associate professor Jogender Tushir-Singh.
Publication:
AbstractCreationists frequently claim that the presence of "complex specified information" (a term coined by William Dembski) in the human genome is evidence of intentional design by an intelligent agent. They point to features such as our large brain and cognitive abilities as examples of purposeful engineering. But if this genetic information is indeed the result of deliberate design, then intellectual honesty demands an explanation for the harmful consequences that come with it. The same small genetic modification to Fas Ligand that may have enabled increased brain size also compromises our ability to eliminate potentially cancerous cells. If the positive trait—the large brain—is cited as evidence of design, then the negative outcome—heightened cancer risk—must logically be part of the same design. Yet creationists tend to celebrate the former as intentional while dismissing the latter as somehow unrelated or a result of ‘the Fall’, thereby invoking theological special pleading rather than scientific reasoning. This contradiction highlights a central flaw in the argument from design: it is selectively applied. Beneficial traits are attributed to divine foresight; harmful traits are either ignored or excused through post hoc theological rationalisations. But if the genome is to be viewed as a product of intelligent agency, then the designer must be held accountable for all its consequences—good and bad alike. A more consistent and evidence-based explanation is that these traits evolved through natural selection, with no foresight or moral intent, only reproductive utility. So, which is it? Is complex specified information truly the signature of a designer? And if so, what does it say about the nature of that designer when the same information causes both intellect and illness, cognition and cancer? Creationists cannot have it both ways.
Despite sharing >98% genomic similarity, humans are more likely to develop cancers than our closest living ancestors, the nonhuman primates. Here, we unexpectedly discover that, unlike chimpanzee and other primates, a critical embryonic development, immune homeostasis, and general cell-death regulator protein called Fas Ligand (FasL) contains a Pro153-Ser153 evolutionary substitution in humans. The latter renders human FasL preferentially susceptible to cleavage by plasmin, an overly elevated protease in solid tumors. Since FasL-mediated killing of tumor cells by activated T-lymphocytes and chimeric antigen receptor T-cells (CAR-T) is critical for therapeutic efficacy, we find that elevated plasmin levels in certain ovarian tumors interfere with the T-lymphocyte-expressed FasL death signaling. Either targeted inhibition or blocking plasmin accessibility to membrane FasL rescues the FasL cell-death function of activated T-lymphocytes in response to immune-checkpoint receptor targeting antibodies. These findings of evolutionary significance highlight that elevated plasmin in metastatic tumors potentially contributes to differential outcomes of T-cell-based immunotherapies in solid tumors.
Introduction Clinical data indicate that antibodies that help eliminate tumor cells by activating and harnessing the power of a patient’s immune system are highly effective against hematological cancers1. The core of immunotherapy primarily relies on strategies that potentiate, prolong, and maintain T-cell function, either using T-cell activating monospecific and bispecific antibodies against checkpoint blockade receptors or via chimeric antigen receptor (CAR)-T cells2. Regarding clinical response rates, T-cell-based immunotherapies, unfortunately, have a significant disparity in hematological liquid vs solid tumors3. On the one hand, various regulatory mechanisms intrinsic to T-cell priming and activation are influenced by solid tumor microenvironment (TME)4. At the same time, the tumor’s inherent factors contributing to limited efficacy include the loss and downregulation of target antigen (antigen escape), resulting in high tumor heterogeneity, further influencing the outcome5. Moreover, before everything, limited T-cell and general immune penetration remains a significant bottleneck in dense solid tumor stroma. Hence, alternate strategies that debulk solid tumors independent of immune effector cells are highly critical.
For the past few decades, most alternatives have focused on targeting death receptor-activating agonist antibodies, as the latter has the potential to shrink tumors via extrinsic apoptotic cytotoxicity independently of limitedly solid tumor stroma penetrated immune effector cells6. TRAIL-R2/DR5 remains the essential targeted TNFα-superfamily death receptor in various solid tumor trials; however, tested DR5 agonists have shown limited clinical success7. More recently, TNFα-superfamily death receptor named Fas (CD95) has become the focus of attention due to the critical role of Fas ligand (FasL) on the surface of CAR-T cells in instigating bystander killing of antigen−/FasR+ cancer cells in leukemia clinical trials8,9,10. The bystander killing is critical for CAR-T and other T-cell-based immunotherapies against antigen-escaped tumors11. Hence, circumstantially, a higher FasL signaling against the tumors in TME, independent of its activity by tumor-infiltered T-cells (in response to immunotherapies), natural killer cells, stromal cells, or engineered CAR-T cells should indicate a better antitumor outcome8,9,10. Contrarily, despite the higher FasL/Fas mRNA and protein ratio, the prognostic effect of Fas signaling remains inconclusive in tested solid tumor studies12,13,14. Besides, the differential and temporal regulation of FasL-mediated extrinsic apoptosis is also a hallmark of the T-lymphocyte self-suicide program15 in the spleen and lymph nodes. Indeed FasL/Fas signaling is critical to maintaining immune homeostasis and is solely responsible for monitoring lymphoproliferative disorders16. The latter indicates a discrepancy in operating optimal FasL signaling in healthy organs such as in spleen and lymph nodes vs aggressive solid tumors. A key difference between T-cell homeostasis and metastatic solid tumors is upregulated proteolysis17,18, which degrades the extracellular matrix and promotes metastasis19. Hence, in this work, we sought to investigate whether distinctive regulatory mechanisms predispose FasL to differential proteolytic degradation in tumors and if targeting the latter could improve T-cell-based immunotherapies.
Fig. 1: Proline to serine substitution at position 153 in HuFasL.
a Amino acid alignment of the FasL membrane proximal ECD from different primates. b Ribbon depiction of FasL monomer. c FasL A and H beta-strands are highlighted along with their connecting loops. R144, K145 (red), S153/P153 (left/right red), F269 (green), E271 (blue) are shown as sticks. d SEC chromatograms of indicated FasL are shown with different colors.
Wamba, B.E.N., Mondal, T., Freenor V, F. et al.
Evolutionary regulation of human Fas ligand (CD95L) by plasmin in solid cancer immunotherapy. Nat Commun 16, 5748 (2025). https://doi.org/10.1038/s41467-025-60990-0
Copyright: © 2025 The authors.
Published by Springer Nature. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
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