Are Robots More Dangerous Than Cholesterol? No.

When I think of the most dangerous things in modern society, the things most likely to kill me, robots are pretty much at the top of the list. When I examine the statistics, however, OSHA reports only two deaths a year from robots.^[1] The leading cause of death in the U.S., on the other hand, is the same as it has been since 1921, heart disease.^[2,3] A significant cause of this burden is high cholesterol. While cholesterol-targeting medications like statins have led to major advances, there are still far too many people suffering from cholesterol-exacerbated heart disease.^[3,4]  New technologies (not robots!) are using nucleic acids such as RNA and DNA to boost our body’s ability to get rid of dangerous proteins and molecules.

Unlike robots, each of us is unique, as shown in our DNA, the code that defines what we are. DNA on its own doesn’t do much. Proteins are the robots machines in our bodies that get things done. To make proteins, the body first transcribes DNA into messenger RNA (mRNA). The mRNA then carries the instructions to cell structures that build proteins. This is essential to translate the genetic code (nucleic acids - the “NA” in DNA and RNA) into amino acids, the building blocks of proteins. The amino acids are assembled and folded into the final protein which, in the case of high cholesterol, can cause problems. Nucleic acid-based approaches lower cholesterol by interfering with the body’s ability to turn specific pieces of DNA into functional proteins that would normally increase cholesterol in the blood.

There are many proteins that contribute to dangerous cholesterol levels. Before we jump into those, a quick refresher on cholesterol. Cholesterol is a necessary component of all cells, but excess cholesterol that our body doesn't need, travels in the bloodstream where it can accumulate and cause damage. Particularly dangerous carriers of cholesterol include triglyceride-rich chylomicrons, LDL (low-density lipoprotein), and lipoprotein(a), also called Lp(a). Luckily, new technology (still not robots!) and epidemiological data have identified several specific genes and proteins that are associated with higher cholesterol levels.^[4] Some of these, such as Lp(a),  have been previously impossible to target.^[4] A few of the key proteins follow:

• APOC-III, Apolipoprotein C3

  • Free triglycerides in the blood are frequently carried by large chylomicrons, which are broken down into remnants and packaged into safe forms or destroyed by the liver.^[4] APOC-III binds to the chylomicrons  and prevents them from being cleared effectively. Medications that target APOC-III show promise for people with high triglycerides without other cholesterol markers.^[4]

• PCSK9, Proprotein convertase subtilsin/kexin type 9

  • The liver absorbs LDL through special proteins on the surface of liver cells called LDL receptors. These bind to LDL particles, pull them into liver cells to be destroyed, then move back to the surface to gather more.^[4] PCSK9 can also bind to LDL receptors. This has a double-whammy effect; it keeps the receptor from binding and recycling LDL particles and causes the receptor itself to be destroyed.^[4] Lowering PCSK9 would allow the body to remove LDL particles at a higher rate.^[4]

• APOA/Lp(a), Apolipoprotein a/lipoprotein a

  • APOA binds to cholesterol to form Lp(a), a special LDL-like particle that has all the bad effects of LDL on overdrive. Lp(a) carries cholesterols in the bloodstream and deposits them, causing damaging plaques and inflammation.^[5] More than one in four adults with atherosclerotic cardiovascular disease (ASCVD) have Lp(a) levels above the danger threshold.^[6] Even worse, Lp(a) levels are determined by genetics, and medicines like statins do not affect this dangerous particle.^[4,5]

Nucleic acid-targeting medicines are effective at lowering levels of proteins by a few different methods of interfering with gene expression.. Each method works by targeting RNA or DNA to reduce or silence the production of specific proteins associated with disease. 

Antisense oligonucleotides (ASOs) are short, single-stranded bits of synthetic RNA (or DNA).^[4] These bind with molecules inside a cell’s nucleus and destroy mRNA that’s on its way to be turned into a protein.^[4,7] It’s like cutting the cable between a laptop and a printer. The end result is that RNA doesn’t make it to production and the final protein (in this case, APOC-III, PCSK9, or APOA) doesn’t get built.^[7] There are many medications which use antisense oligonucleotides, including those that target:

• APOC-III

  • Volanesorsen has undergone many clinical trials, including the COMPASS and BROADEN trials, which found significant 71% and 88% reductions in triglycerides after three months.^[8,9]

  • Olezarsen, which has recently shown topline results from the CORE and CORE2 trials showing 49872% reductions in triglycerides after six months.^[10,11]

• APOA/Lp(a)

  • Pelacarsen is an antisense oligonucleotide medication in phase 3 HORIZON clinical trials, which targets APOA to reduce Lp(a) levels by up to 80%, depending on dose and frequency.^[5,12]

Small interfering RNA (siRNA) is a technology that mimics the body’s natural regulatory mechanisms.^[4] The body uses them to selectively reduce the amounts of specific genes and to defend against viruses.^[4] siRNAs are different from antisense oligonucleotides because they recruit a special machine (not a robot!) in the cell nucleus that hangs around and lowers levels of the target gene/protein for a prolonged period of time.^[5,7] Medications that use siRNA to limit cholesterol target:

• PCSK9

  • Inclisiran was the first FDA-approved siRNA cholesterol medication in 2021.^[4] The ORION studies showed a 50% drop in LDL levels after 18 months, and VICTORION trials are ongoing for additional uses.^[4,13]

• APOA/Lp(a)

  • Olpasiran is currently undergoing phase 3 trials, though the OCEAN(a)-DOSE trials showed Lp(a) reductions of up to 90% after 3-6 months.^[5]

These ongoing clinical trials need people to make them happen; robots simply won’t cut it. Heart disease may be the most likely cause of death in America, but with the help of clinical trial investigators, staff, and participants it may become less dangerous than robots. Especially if the robots have an uprising.

Creative Director Benton Lowey-Ball, BS, BFA

References:

[1] Occupational Safety and Health Administration. (2025). Accident search results: Keyword “Robot”. U.S. Department of Labor. Accessed 3 September, 2025. https://www.osha.gov/ords/imis/AccidentSearch.search?acc_keyword=%22Robot%22&keyword_list=on&Fatal=fatal

[2] U.S.Centers for Disease Control and Prevention. (2019). Leading causes of death, 1900-1998. U.S. Department of Health and Human Services. https://archive.cdc.gov/www_cdc_gov/nchs/data/dvs/lead1900_98.pdf

[3] Murphy, S. L., Kochanek, K. D., Xu, J., & Arias, E. (2024). Mortality in the United States, 2023. In NCHS Data Briefs [Internet]. National Center for Health Statistics (US). https://www.cdc.gov/nchs/products/databriefs/db521.htm

[4] Makhmudova, U., Steinhagen-Thiessen, E., Volpe, M., & Landmesser, U. (2024). Advances in nucleic acid-targeted therapies for cardiovascular disease prevention. Cardiovascular Research, 120(10), 1107-1125. https://doi.org/10.1093/cvr/cvae136

[5] O'Donoghue, M. L., López, J. A. G., Knusel, B., Gencer, B., Wang, H., Wu, Y., ... & Sabatine, M. S. (2022). Study design and rationale for the Olpasiran trials of Cardiovascular Events And lipoproteiN (a) reduction-DOSE finding study (OCEAN (a)-DOSE). American Heart Journal, 251, 61-69. https://www.sciencedirect.com/science/article/pii/S0002870322000862

[6] Nissen, S. E., Wolski, K., Cho, L., Nicholls, S. J., Kastelein, J., Leitersdorf, E., ... & Nordestgaard, B. G. (2022). Lipoprotein (a) levels in a global population with established atherosclerotic cardiovascular disease. Open Heart, 9(2), e002060. https://openheart.bmj.com/content/9/2/e002060

[7] Damase, T. R., Sukhovershin, R., Godin, B., Nasir, K., & Cooke, J. P. (2024). Established and emerging nucleic acid therapies for familial hypercholesterolemia. Circulation, 150(9), 724-735. https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.123.067957

[8] Oral, E. A., Garg, A., Tami, J., Huang, E. A., O'Dea, L. S. L., Schmidt, H., ... & Tsimikas, S. (2022). Assessment of efficacy and safety of volanesorsen for treatment of metabolic complications in patients with familial partial lipodystrophy: Results of the BROADEN study: Volanesorsen in FPLD; The BROADEN Study. Journal of Clinical Lipidology, 16(6), 833-849.

[9] Gouni-Berthold, I., Alexander, V. J., Yang, Q., Hurh, E., Steinhagen-Thiessen, E., Moriarty, P. M., ... & Yataco, A. (2021). Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. The lancet Diabetes & endocrinology, 9(5), 264-275.

[10] Bergmark, B. A., Marston, N. A., Prohaska, T. A., Alexander, V. J., Zimerman, A., Moura, F. A., ... & Sabatine, M. S. (2024). Olezarsen for hypertriglyceridemia in patients at high cardiovascular risk. New England Journal of Medicine, 390(19), 1770-1780.

[11] Ionis Pharmaceuticals, Inc. (2 September, 2025). Olezarsen significantly reduces triglycerides and acute pancreatitis events in landmark pivotal studies for people with severe hypertriglyceridemia (sHTG). [Press release]. Accessed 3 September, 2025. https://ir.ionis.com/news-releases/news-release-details/olezarsen-significantly-reduces-triglycerides-and-acute

[12] Cho, L., Nicholls, S. J., Nordestgaard, B. G., Landmesser, U., Tsimikas, S., Blaha, M. J., ... & Nissen, S. E. (2025). Design and rationale of Lp (a) HORIZON trial: Assessing the effect of Lipoprotein (a) lowering with Pelacarsen on major cardiovascular events in patients with CVD and elevated Lp (a). American heart journal, 287, 1-9. https://doi.org/10.1016/j.ahj.2025.03.019

[13] Ray, K. K., Troquay, R. P., Visseren, F. L., Leiter, L. A., Wright, R. S., Vikarunnessa, S., ... & Landmesser, U. (2023). Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. The Lancet Diabetes & Endocrinology, 11(2), 109-119. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(22)00353-9/fulltex