180 years ago, a doctor in the Austrian Empire conducted a radical experiment that has saved millions of children but cost him his life. This shocking, ground-breaking experiment involved doctors washing their hands. I know, I know, it sounds ridiculous, but doctors not only didn’t wash their hands back then, they were opposed to the very idea so much that the researching doctor was institutionalized and beaten to death. In this article, we’ll explore the history of handwashing, how they came up with the experiment, why people weren’t washing their hands in the first place, why the experiment worked, and how modern hand washing works. Then, we’ll dive into some nitty-gritty science.

Handwashing is old. Like, it’s really old. We have good evidence of soap from nearly 3000 years ago. Handwashing as a ritual before meals is in Abrahamic religious texts. It was recorded in ancient Egyptian and Greek civilizations and is even practiced by raccoons. But this was superficial handwashing, mostly meant to get rid of visible dirtiness because we hadn’t discovered germs yet. Instead, ideas of how disease spread were based on things like miasma – the stinkiness of a dirty thing.

Ignaz Semmelweis was a physician who, in the 1860s, got a residency in a maternity ward. In those days things were separated by gender, so there were two clinics. One was attended by male doctors and one by female midwives. Dr. Semmelweis noted that people died in the male-run clinic at a rate 300% higher than in the midwife-run clinic. He was appalled and wrote that women would have better outcomes giving birth in the street than in the hospital. The primary disease causing all the deaths was childbed fever, now known as (pew-er-per-al) puerperal fever. Luckily, Dr. Semmelweis had a shocking (shocking!) insight. He theorized that perhaps the fact that the doctors would do autopsies before going to the maternity ward was causing some of the “cadaverous particles” to infect the patients. He got this idea when a fellow doctor cut himself during an autopsy and subsequently died of childbed fever. Dr. Semmelweis concluded that doctors should wash their hands in chlorinated water upon entering the maternity clinic! Within a year the death rate plummeted from ~10% to under 2%.

Unfortunately, doctors were reluctant to change their ways. The theory that doctors could be killing their patients was seen as offensive and came with the implication that doctors were unclean, which went against the class system of the era. He was reluctant to release his findings, but when he did they were dismissed and his reputation was ruined. In his book Die Aetiologie, der Begriff und die Prophylaxis des Kindbettfiebers, he is racked with guilt. He was committed to an insane asylum where he was beaten to death by the orderlies within weeks under suspicious circumstances. It would be decades before germ theory gave an explanation for Semmelweis’s findings and brought them back into the public consciousness. He would never know how many millions of children and mothers he saved.

In Dr. Semmelweis’s day, they used chlorinated water to wash their hands. Let’s dive into modern-day hand washing. How does washing hands work? Why do we need to wash our hands, even if they look clean? Are there better ways to wash hands? Is hand sanitizer just as good? To start, let’s look at the skin as an immune organ. The skin is awesome. It’s our biggest organ and is the primary defense against invading germs; the tiny microorganisms like bacteria, fungi, and viruses. The skin has three major defense mechanisms. Our immune cells fight organisms that get too close for comfort and our skin hardens and sloughs off, taking bacteria and viruses with it. Before either of those, potential attackers have to deal with the skin microbiome. It turns out our skin isn’t just a cool canvas for tattoos but is an entire ecosystem for thousands and millions and billions of teeny little friends that make a living harvesting our sweat or whatever. Three important genera of bacteria take up the bulk of what we call the resident flora: cutibacterium, staphylococcus, and corynebacterium. These three coat our skin and enhance the immune protection skin gives us. They are commensal organisms, which is kind of like the mob. We give them food and shelter, and they promise to (mostly) do us no harm. They are called “residents” because they live with us our whole lives. They colonize our skin, making it hard for other invaders (called transient flora) to get a foothold. The defense mechanisms they have for themselves work well against the transient flora. In addition, they break down cholesterols we emit into free fatty acids which keep our skin a little acidic, killing invaders. They tend to reside deeper in the skin layers than transient bacteria, are less likely to cause infection, and are harder to remove.

This is exactly where handwashing shines. Transient flora, like MRSA, multidrug-resistant gram-negative bacteria, Vancomycin-resistant Enterococci, and “cadaverous particles” tend to be closer to the outer layers of skin and are easier to remove. Effective hand-washing removes the transient flora but keeps the residents intact. Even more effective than just soap and water are antibacterials. These attack the transients in creative ways, degrading the cell walls, DNA, and proteins. Hand sanitizer is effective at destroying many bacteria and can be applied frequently and without a sink. So next time you wash your hands between visiting the morgue and the maternity ward, think of Dr. Semmelweis and thank him for his experimental vision!

Staff Writer / Editor Benton Lowey-Ball, BS, BFA

References:

Boyce, J. M. (2021). Hand hygiene, an update. Infectious Disease Clinics, 35(3), 553-573. https://doi.org/10.1016/j.idc.2021.04.003

Edmonds-Wilson, S. L., Nurinova, N. I., Zapka, C. A., Fierer, N., & Wilson, M. (2015). Review of human hand microbiome research. Journal of dermatological science, 80(1), 3-12. https://www.sciencedirect.com/science/article/pii/S0923181115300268

Skowron, K., Bauza-Kaszewska, J., Kraszewska, Z., Wiktorczyk-Kapischke, N., Grudlewska-Buda, K., Kwiecińska-Piróg, J., … & Gospodarek-Komkowska, E. (2021). Human skin microbiome: Impact of intrinsic and extrinsic factors on skin microbiota. Microorganisms, 9(3), 543. https://doi.org/10.3390/microorganisms9030543

Semrnelweis, I. (1861). Die Aetiologie, der Begriff und die Prophylaxis des Kindbettfiebers, C. A. Hartleben’s Verlag-Expedition, Translated by K. Codell Carter. Madison, 1983 https://archive.org/details/b28064045

Widmer, A. F. (2000). Replace hand washing with use of a waterless alcohol hand rub?. Clinical infectious diseases, 31(1), 136-143. https://academic.oup.com/cid/article/31/1/136/317796

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Last month, the US Food and Drug Administration approved two gene-editing therapies to treat sickle cell disease. This made national news in a way few drug approvals have, but why? What’s the big deal, and why should we care?

Sickle cell disease is an inherited genetic disease affecting around half a million babies globally every year. People affected by sickle cell disease have genes that create malformed red blood cells that carry oxygen. These malformed cells become curved like a crescent moon (or a sickle), which results in poor oxygen delivery. Even worse, the curved cells can clump together into clots, which restrict blood flow and cause pain, organ damage, and/or death. Because it is genetic and there has been no known cure, it ranks consistently within the top 20 deaths of children. The disease is most prevalent in people of African descent, and globally the highest concentration of sufferers is in sub-Saharan Africa.

Sickle cell disease is a result of problems with genetic mutation and malformed cells, which makes it very hard to target with traditional medicine. In spite of this, innovative researchers have developed two promising treatments for sickle cell disease. These use our own cells to help cure the disease – instead of an oral, topical, or injected medication. These are both gene therapies, where the genetic code of the patient is altered. This is an understandably touchy topic. Gene-editing is different from other medical procedures in that it may be inherited: your genes are passed to your children after all! The benefit of starting gene therapy with sickle cell disease is that we are starting with mutated genes. The mutated sickle-cell-creating genes will already be passed to any children, so fixing the mutations is likely to have better outcomes. I think of it like CPR. With CPR, you are starting with a person who isn’t breathing and has no circulation; you can’t really get any worse than that. With sickle cell gene therapy, as long as the gene-editing tools are specific and target the correct genes it is hard to do worse than one of the top killers of children worldwide. So what are the therapies that were approved?

The first, Lyfgenia, is a gene-additive therapy. It uses a modified virus that can’t reproduce to infect cells and add new DNA. The virus, a lentivirus, delivers special RNA to the cells, which our cells incorporate into the DNA strand when they copy it. This genetic code tells the cells to make a different kind of hemoglobin – the protein in red blood cells that carries oxygen. This hemoglobin is a particular type that prevents sticking to the walls of bloodstreams. Note that viruses already deliver RNA that gets encoded into our genes all the time. A 2022 study looked at a protein and found that almost 10% of the human genome may be from viruses.

The second therapy, Casgevy, is gene-editing in the most fundamental way. It uses a technology called CRISPR/Cas9 to cut and change pieces of our DNA. While our DNA may be around 10% viral, bacteria have much smaller genomes, and viral insertion of new DNA is a proportionally bigger problem. To combat this, some bacteria have a gene-editing system that can find and remove bits of wayward code. This system was adapted by very smart scientists into a gene-editing tool we can use to find and correct mutations in our genetic code. The process is pretty intense. Blood stem cells are removed from the body, then the CRISPR-Cas9 system edits them outside the body. The modified cells are reinserted into the bone marrow, where they will reproduce and turn into everyday functioning red blood cells. This is mind-blowing.

Of course, there is controversy surrounding these therapies. One of the biggest is really unrelated to sickle cell disease, but instead to the very idea of gene-editing. This use of gene therapy in sickle-cell is hard to contest: we’re starting with mutated DNA in blood cells that can kill children. The what-ifs about adding new functionality like laser eyes or super strength get a lot of press and can make us question what it means to be human at a fundamental level. The second big problem is inequality. Could gene-editing be used to make a two-tiered system of wealthy people with great eyesight and perfect skill while poor people suffer? It very much looks like that, as Lyfgenia and Casgevy are both amazingly expensive, somewhere between 2-3 million dollars for treatment. But then, if we can permanently stop sickle cell for a person and all of their descendants, it may be worth it.

Staff Writer / Editor Benton Lowey-Ball, BS, BFA

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References:

Food and Drug Administration. (December 8, 2023). FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease

Milone, M. C., & O’Doherty, U. (2018). Clinical use of lentiviral vectors. Leukemia, 32(7), 1529-1541. https://www.nature.com/articles/s41375-018-0106-0

Frank, J. A., Singh, M., Cullen, H. B., Kirou, R. A., Benkaddour-Boumzaouad, M., Cortes, J. L., … & Feschotte, C. (2022). Evolution and antiviral activity of a human protein of retroviral origin. Science, 378(6618), 422-428. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10542854/

Thomson, A. M., McHugh, T. A., Oron, A. P., Teply, C., Lonberg, N., Tella, V. V., … & Hay, S. I. (2023). Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000–2021: a systematic analysis from the Global Burden of Disease Study 2021. The Lancet Haematology. https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(23)00118-7/fulltext

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It was the best of me, it was the worst of me. There are two versions of your dear author: the one who loves cookies, pizza, and video games and the one who loves surfing, cycling, and roasted vegetables. In a stroke of complete luck, I live at the beach where exercise and healthy living are trendy and encouraged. That wasn’t always the case, however. When I was younger, I went to college in Indiana. There was no beach, I had no bike, everyone had a computer, and my meal plan included unlimited pizza. Unsurprisingly, these two versions of myself have very different health outcomes. One lifestyle is associated with heart attacks, diabetes, and obesity, while the other isn’t. Which version makes it through to the end isn’t just determined by self-discipline and genetics but heavily by the community you are in.

Things that contribute to your health outcomes are called determinants of health. These include your genetics, behavior, and medical care, but also the physical place you spend time and social factors. The determinants of health aren’t insulated; they interact and influence each other. That last one is properly termed Social Determinants of Health (SDOH). These are the daily interactions with people and the area around you, but also the bigger systems that influence these interactions. Examples of the social determinants of health include:

• Availability of quality food
• Income 
• National economic stability
• Housing quality
• Access to healthcare
• Community

It was easy to see these social determinants at work during the pandemic. The “Quarantine 15” was a real phenomenon where somewhere around 48% of people in America gained weight. People were stressed, jobs and income were unstable, healthcare access was limited, exercise options dropped, and – importantly – many of us lost our community connections. Luckily, with the pandemic calming down, we are presented with opportunities to shore up our social determinants of health.

With the pandemic as a reference, we can see that social determinants of health are subject to very big forces. To improve the social determinants of health in our area, we would ideally look at inequality, structural biases, macroeconomic conditions, and government policy. On the personal level, the most productive changes we can make (other than moving halfway across the country) are at the community level. This includes your family, friends, neighbors, and people you interact with and share common ground with, such as those in a book club or church. From a healthcare perspective, “community” determines who you talk to when sick, who checks in on you, who cooks food when you have a newborn, who takes you to the doctor when you can’t drive, and so on.

Luckily, your community can expand. When you join a clinical trial at one of our ENCORE Research Group sites, you don’t just gain access to cutting-edge research, you gain a community that is committed to health. We partner with other groups, perform community outreach, and write extremely well-written, clever, and funny articles for your inbox weekly. On top of this, when enrolled in a clinical trial, we need to monitor your health and stay in touch.  We look for what will help your specific situation and if you miss an appointment we reach out to make sure you are ok. ENCORE stands for Encouraging COmmunity Research and Education, it’s right there in our name!

Staff Writer / Editor Benton Lowey-Ball, BS, BFA
With contributions from Stacey Lowey-Ball, BA Anthropology

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References:

Khubchandani, J., Price, J. H., Sharma, S., Wiblishauser, M. J., & Webb, F. J. (2022). COVID-19 pandemic and weight gain in American adults: A nationwide population-based study. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 16(1), 102392. https://doi.org/10.1016%2Fj.dsx.2022.102392

Artiga, S., & Hinton, E. (2018). Beyond health care: the role of social determinants in promoting health and health equity. Kaiser Family Foundation, 10. https://www.kff.org/racial-equity-and-health-policy/issue-brief/beyond-health-care-the-role-of-social-determinants-in-promoting-health-and-health-equity/

Baciu, A., Negussie, Y., Geller, A., Weinstein, J. N., & National Academies of Sciences, Engineering, and Medicine. (2017). The Role of Communities in Promoting Health Equity. In Communities in Action: Pathways to Health Equity. National Academies Press (US). https://www.ncbi.nlm.nih.gov/books/NBK425849/

Centers for Disease Control and Prevention. (8 December, 2022). Social determinants of health at CDC. U.S. Department of Health & Human Services. https://www.cdc.gov/about/sdoh/index.html

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You may have heard the news; earlier this month an FDA committee unanimously concluded that phenylephrine, a common decongestant, doesn’t work. What does this mean? Why is it still on shelves? Is it poison? Should I throw my medicine away? Is the FDA a scam!? What’s the point of science if they change the rules?!?

We’ll address the last two questions first. Good science is a process of change. It’s not definitive; just our best, evidence-based guess at how to predict what will happen given current best experimentation and data. As we get more data of better quality the conclusions drawn by scientists change. To be clear, when scientists update their conclusions this is good and means science is working. It means we are getting more accurate information through better practices and updated information. New technology plays a big part in this. Think of it like maps. The first explorer to document an area may have a hand-drawn map outlining the major features. Later cartographers may come along and refine the map, making it more accurate and filling in the details. Their map may show a landmark in a different, more accurate position. This doesn’t mean the original mapmaker was malicious, or that maps don’t work, but instead that we can update our information to have a more accurate view of the world.

Back to the issue at hand, let’s find out what we’ve learned. On September 11th and 12th, 2023, the Non-prescription Drug Advisory Committee reviewed the results of several clinical studies which looked into the effectiveness of oral phenylephrine at lowering nasal congestion (stuffy nose). These studies measured symptoms in hundreds of patients who took phenylephrine and/or a placebo sugar pill in controlled environments. These studies found, by and large, that the decongestant was not significantly better than the placebo at providing relief. It should be noted that in the studies, most patients found relief from both phenylephrine and the placebo! It should also be noted that participants had few or no adverse reactions to the studies, though some had headaches. In response, the committee concluded that phenylephrine is not effective at providing relief when compared with a placebo; the drug doesn’t work.

So what does this mean for me? First, note that this is an advisory committee. They provide independent advice to the FDA, but do not make policy. In the near term nothing has changed. The FDA will likely take a while to make any policy changes and may have public input. Additionally, the clinical trials did not find the medication dangerous, just ineffective. This means phenylephrine isn’t dangerous at the recommended doses; you don’t need to throw it away (unless it’s expired!). It also means that a phase-out period will probably be slow, because there isn’t a danger to the public beyond wasting money on a medicine that works no better than a placebo.

Finally, how did this happen? How did a medication that doesn’t work get past the FDA? The answer is that while oral phenylephrine doesn’t seem to provide relief, inhaled phenylephrine continues to show effectiveness! When the oral form was approved in the 1970s, scientists thought around 30% of the medication would be absorbed in the gut. It has come to light that around 1% of the decongestant medication is actually available for our body to use when taken orally. From this, it follows that we would need to take much higher doses to get significant relief, which comes with increased side effects – including to the heart! On top of this is the completely fascinating finding in 2015 that placebos are getting better. A meta-study of several placebo-controlled clinical trials found that the effects of medications stayed the same, but the effect of placebos has been increasing over time! Some scientists believe this may be because we expect medications to do more, so the placebo is more effective! This means that when clinical trials are repeated, medications have a more difficult time showing effectiveness versus placebo. Think of our map-makers. That same landmark may have been perfectly mapped by cartographers, but tectonic plates can still cause it to slowly shift position. Lucky for us this means that new medicines brought to market are virtually guaranteed to be more effective than if they were introduced last century!

Staff Writer / Editor Benton Lowey-Ball, BS, BFA

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References:

Division of Nonprescription Drugs 1 (DNPD1), Division of Inflammation and Immune Pharmacology (DIIP), Office of Clinical Pharmacology (OCP), Division of Epidemiology II (DEPI-II). (September 11, 2023). Efficacy of Oral Phenylephrine as a Nasal Decongestant. U.S. Food & Drug Administration. https://www.fda.gov/media/171915/download

U.S. Food & Drug Administration. (September 14, 2023). FDA clarifies results of recent advisory committee meeting on oral phenylephrine. U.S. Food & Drug Administration. https://www.fda.gov/drugs/drug-safety-and-availability/fda-clarifies-results-recent-advisory-committee-meeting-oral-phenylephrine

Meltzer, E. O., Ratner, P. H., & McGraw, T. (2015). Oral phenylephrine HCl for nasal congestion in seasonal allergic rhinitis: a randomized, open-label, placebo-controlled study. The Journal of Allergy and Clinical Immunology: In Practice, 3(5), 702-708. https://pubmed.ncbi.nlm.nih.gov/26143019/

Meltzer, E. O., Ratner, P. H., & McGraw, T. (2016). Phenylephrine hydrochloride modified-release tablets for nasal congestion: a randomized, placebo-controlled trial in allergic rhinitis patients. Annals of Allergy, Asthma & Immunology, 116(1), 66-71. https://doi.org/10.1016/j.anai.2015.10.022

National Library of Medicine. (March 3, 2011). Safety Study Comparing Phenylephrine HCL Extended Release Tablets 30 mg and Placebo (Study CL2007-07)(P07529)(COMPLETED).  U.S. Department of Health and Human Services.ClinicalTrials.gov ID NCT00874120. https://clinicaltrials.gov/study/NCT00874120?tab=results

Tuttle, A. H., Tohyama, S., Ramsay, T., Kimmelman, J., Schweinhardt, P., Bennett, G. J., & Mogil, J. S. (2015). Increasing placebo responses over time in US clinical trials of neuropathic pain. Pain, 156(12), 2616-2626. https://doi.org/10.1097/j.pain.0000000000000333