The Mystery of Non-Targeted Effects

The health impact of heavy ion radiation remains the biggest unknown in sending human beings to Mars

Imagine that one morning I hit you with a stick, then a golf club, and then a baseball bat.

Later that day, from the comfort of your hospital bed, you might come up with the concept of an ‘impact equivalent dose’ to quantify and relate the effects of the three blows you received. Maybe getting hit with the stick gave you an absorbed impact of 100 microcegłowskis, the golf club was 300 µCg, and the baseball bat was 550 µCg.

Once you’ve defined such a scale, you can use it to calculate the relative harm of other beatings by tallying up the various kinds of blows and where they land on your body. You might even derive some occupational exposure limits—perhaps 1200 µCg is the single-dose limit for a TikTok influencer, while office workers can only tolerate chronic daily beatings of 200 µCg, and small children shouldn’t be beaten at all.

This is the rationale behind units of effective radiation dose like the Sievert. They calculate the biological damage done by different kinds of ionizing radiation (gamma rays, protons, electrons, heavy ions) by applying a scaling factor to the energy that different parts of your body absorb¹. The effective radiation dose will depend on what kind of ray or particle zapped you, how much of it hit you, and which specific tissues it passed through.² And that final number will give you an idea of how likely you are to get radiation-induced cancer.

Effective dose models are calibrated against radiation exposures humans have encountered on Earth in the past (atomic bomb survivors are a favorite yardstick), and give a probabilistic measure of future bad outcomes like cancer and cardiovascular disease. The model in widest use today, called the Linear No-Threshold model (LNT), assumes that the relationship between dose and risk is linear, that the fundamental mechanisms of damage at the cellular level are the same no matter the type of radiation, and that there is no threshold value below which radiation exposure becomes harmless.

But to continue with my metaphor, imagine that one day instead of hitting you with a stick, I poke you with its pointy end. Now your effective dose model becomes less predictive. Because the mechanism of harm from stabbing is so different from blunt impact, the ‘effective impact dose’ you calculate may not capture the severity of the damage. You might even find that an otherwise light impact is rapidly fatal if it happens in the wrong place (like the jugular).

This is the situation scientists find themselves in with heavy ion radiation. Models of radiation equivalent dose assume that ionizing radiation either damages DNA directly, by barreling through a cell and breaking the strands, or through near misses, by creating reactive chemicals in close proximity to DNA strands. While this certainly happens with heavy ions (we observe some spectacular chromosome damage on astronauts returning from ISS), it leaves out an additional mechanism of damage that we are just beginning to discover, one that affects neighboring and distant cells that the ion didn’t pass through at all.

Non-Targeted Effects

“Non-targeted effects” is the catchall term for radiation-induced changes to cells that are not on the ionizing radiation track. They are a kind of ‘spooky action at a distance’ in the field of radiation biology.

One type of non-targeted effect is called the bystander effect, where cells in the local neighborhood of a cell hit by ionizing radiation will display levels of DNA damage similar to the cell that actually got hit. Just like you wouldn’t expect to find yourself in the hospital after seeing your neighbor got hit by a bus, the fact that this can happen is surprising. Bystander effects are also observed when irradiated cells are transplanted into new tissue (imagine losing your ability to walk because someone with a broken leg moved in next door to you), and when growth medium from irradiated cells is fed to a culture of pristine cells (imagine the same happening because you shared a burrito).

A second non-targeted effect is genomic instability, the tendency for the progeny and neighbors of an irradiated cell to show persistently higher mutation rates and chromosomal aberrations down the generations. This effect is different than the point mutations we expect to find in the classic model of radiation damage, and is also seen affecting cells far from the radiation track. It appears to involve changes in the epigenetic bookkeeping system that cells use to keep track of what genes they are supposed to be expressing.

Finally, there are abscopal effects that show up in remote parts of the body, hundreds or thousands of cell diameters away from the radiation track. Radiation oncologists since the fifties have observed cases where targeted radiation therapy in one body part will shrink or eliminate tumors far from the irradiated site, even though those tumors did not receive any radiation dose. Careful recent research has shown that abscopal effects are real, and are sensitive to factors (like what kind of ion is used in radiation therapy) that the standard model of radiation damage insists shouldn’t matter.

The conjectural mechanism behind all these effects is disruption to chemical signaling that affects whole cellular neighborhoods.

In some ways, the cells that make up our bodies are just like us—they are chatty, nosy, and susceptible to peer pressure. Something about heavy ion radiation disrupts the way they keep track of one another’s activities in a way that affects their development and gene expression. In the case of abscopal effects, it’s been shown that these disruptions are further mediated by the immune system, which can broadcast them to distant parts of the body.

Researchers are just beginning to map some of the complex chemical bookkeeping around gene expression that is responsible for these effects. As our understanding improves, the mechanism around non-targeted effects may grow clearer. But right now, we are stuck with a double riddle. We don’t know how epigenetic signaling and regulation work in healthy cells, and we don’t know how chronic exposure to heavy ion radiation in space would disrupt these mechanisms.

The uncertainty around the contribution of NTEs to radiation hazard is the main obstacle to calculating the radiation risk of a Mars mission.

Risk of cancer on a 940 day Mars mission for a baseline model (TE) and three different parameters of NTE model. Note that shielding doesn’t help much, and that there is a threefold difference in risk depending on model assumptions. See #2 in ‘Further Reading’ for more.

Implications for Mars

There are five pieces of bad news about NTEs as they relate to exploring Mars.