Currently a #1 new release in Biotech on Amazon!

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One of the more surreal parts of this process has been seeing how others respond to my story. This recent review on Love for the Page captures it quite succinctly:

“5/5 stars” — you can read it here:
https://fortheloveofthepageblog.wordpress.com/2026/04/14/5-5-%e2%ad%90-mud-microbes-and-medicine-how-a-curious-anthropologist-got-to-the-boardroom-by-elizabeth-reed-aden-phd

For those of you in the Bay Area, I’ll be at Book Passage in Corte Madera tomorrow, Wednesday April 22 at 6:00 pm, in conversation with Priya Hutner and Sheri T. Joseph—talking about paths that don’t go as planned. Join me if you can.

More soon—but for now, thank you for being part of this.

— Betsy

This was not entirely planned, but I found the letters, the memories and then….

Currently a #1 new release in Biotech on Amazon!

Buy on Bookshop.org

Buy on Barnes & Noble

Buy on Amazon

My story begins with a naïve young anthropology grad student looking for beaches and French food in the South Pacific… reality intervenes and the journey twists its way from anthropology, to epidemiology, biotech, and Big Pharma. Along the way, there were a number of decisions that, in hindsight, were brave or ill-advised or just ignorant.

Possibly both.

Early reactions include:

Of course, I’m choosing to focus on the “fascinating autobiography” part and yes, I met Diamond first in Honiara, Solomon Islands (1976) and since then have had two long (5-hour) in-person conversations with him at his home in LA (2025).

Also:

As you can gather, this is not a linear success story. It’s more of a trial-and-error, learn-as-you-go experience, a case study of indulging curiosity rather than following a conscious career path. There is no deciding what happens next rather it’s building a life without a clear blueprint. There are candid descriptions of fieldwork, culture shock, reinvention, and occasional moments of clarity.

On Wednesday April 22, 6:00 pm, I’ll be speaking at Book Passage in Corte Madera with Priya Hutner and Sheri T. Joseph on journeys that don’t proceed as expected. Join me if you can either in person or watch the event posted on my website.

Also, this recent piece in CanvasRebel offers a glimpse into the backstory (a curated version, naturally) of the memoir that I think you might enjoy.

I’ll share more as publication approaches—including a few stories that didn’t quite make it into the book. (Some for good reason.)

As always, many thanks for reading and hope you’ll read Mud, Microbes & Medicine.

— Betsy

The IAN Awards honor excellence across genres, with entries judged by a panel of industry professionals on narrative quality, originality, and impact, so this recognition means a great deal!

Thank you to everyone who has read the book, reviewed, and shared it with the world. Your support makes this journey so rewarding.

— Betsy

Medical Thriller
Most Likely to Inspire a Sequel
New Fiction (First Time Published)

The Firebird Book Awards, hosted quarterly by Speak Up Talk Radio, celebrate storytelling across all genres while giving back in meaningful ways. Entry fees go toward projects that support women and children in long-term shelters — including donations of books and handmade pillowcases through Enchanted Makeovers.

I loved their mission and the chance to share my book all while helping a deeply worthwhile cause, so I’m very honored that The Goldilocks Genome resonated with the judges.

— Betsy

Over a cup of virtual tea, we talked about my godmother Eunice’s novels, finding treasures in your family home, living through history, and remembering family stories. Eunice was an award-winning mystery writer during the Golden Age of Agatha Christie and her books were intelligent, cozy whodunnit murder mysteries with many twists and turns. As her literary executor, I recently re-published her books decades after they were written to make them fresh and accessible again.

If you’d like to listen in, you can find the full episode here:
🎧 Sunday Tea with V — The Hystery Chronicles Podcast

Pour yourself a cup of something warm, settle in, and join us for a conversation about science, conscience, and the stories that connect them.

— Betsy

My mother’s history, coupled with my memories of the hype Merck generated about the dangers of high cholesterol, made me wonder whether high cholesterol/high LDL was really the issue. Their promotional campaign emphasized the association between high cholesterol/LDL and cardiovascular disease (notably atherosclerosis) and the benefits of low LDL. Theirs was the first statin.[2] But, there were skeptics who questioned the strength of the association between high cholesterol and cardiovascular disease. Lovastatin’s approval in 1987 and its market success paved the way for the next generation of block-buster statins that followed, namely Lipitor® (atorvastatin) and Crestor® (rosuvastatin).[3]^,[4] Over the subsequent decades, the statins became the one of the best-selling class of drug with annual sales exceeding $16 billion globally of which US sales account for 25-30 percent.[5] In the US, sales are expected to grow even more since an estimated 70% of adults have high cholesterol (LDL >160 mg/dL).

[1] Lampert 2012 American College of Cardiology

[2] Mevacor® (lovastatin) was approved by the FDA in 1987.

[3] The mechanism of action of the statins is to inhibit HMG-CoA reductase which is an enzyme that regulates the production of cholesterol. HMG-CoA is an abbreviation for hydroxymethylglutaryl-coenzyme A. The statins lower total cholesterol by lowering triglycerides and LDL while increasing HDL, the “good” cholesterol.

[4] High cholesterol is defined as: (i) total cholesterol levels above 200 mg/dL; or (ii) LDL-cholesterol level above 190 mg/dL.

[5] https://www.imarcgroup.com/statin-market

Figure 3
The Global Statin Market

How does one get high cholesterol and especially high LDL? One way is by diet, and another is through our genes. Diet can lead to obesity and there are two different ways our genes can be involved: first is though complicated multi-gene interactions that affect the metabolism of cholesterol; and second is the monogenic dominant trait of familial hypercholesterolemia (FH).

People with FH have a single point mutation in either the LDL receptor, apoB (apolipoprotein B) or PCSK9 (proprotein convertase subtilsin/kexin type 9) genes. Each of these genes is intimately involved in the regulation of cholesterol. A mutation in any one of these genes prevents normal cholesterol processing resulting in high blood levels of LDL. All this sounds pretty bad…but FH is the most prevalent monogenic disorder in humans, with 1 out of 250 people having the disorder. Furthermore, there are more than 2,000 known variants of FH. [1] Most people are heterozygous for the mutation which is always dominant. The rare individuals who are homozygous have LDL levels ranging from 400-1000 ng/dL—a potentially life-threatening condition.

These facts raise an interesting question…if high LDL is associated with atherosclerosis and cardiovascular disease, why is FH so prevalent? Is there a benefit to having high LDL? If so, is—or was—there a selective advantage to having one copy of the gene? Could this be an example of a balanced polymorphism like sickle cell anemia where the heterozygote is more likely to survive than either the normal or FH homozygotes? Further investigation was warranted.

The numerous FH variants seem to have evolved in Eurasia with varying frequencies. Comparisons with ancient DNA suggest some of these variants arose 50,000 years ago and others as recently as 1,000 years ago.[2] If the gene for FH was as deleterious as it seems to be today, how has it survived and why has it become so prevalent?

[1] https://familyheart.org/genetic-testing-and-fh/overview-of-genetic-testing-for-fh#:~:text=There%20are%20currently%20over%202%2C000,causes%20the%20condition%20or%20disease.

[2] Lithuania reference

Figure 4

Familial hypercholesterolemia molecular heterogeneity worldwide. Only papers where patient origin was clearly stated were considered. Color scale indicates the number of different variants reported by country.[1]

The biology of LDL suggests that people with FH have sensitive proinflammatory cells leading to highly responsive immune systems—which in today’s population results in atherosclerosis. However, there is a flip side to this hyper immunovigilance—greater ability to fight infection. There is evidence that high LDL levels are more effective in preventing or resolving gram-negative bacterial infections than are people with low/normal LDL levels.[1]

In historic and prehistoric times, the gram-negative bacterial infections that were common and often deadly included: cholera (Vibrio), typhoid fever (Salmonella), dysentery (Shigella), and sepsis (Escherichia, Klebsiella, Enterobacter, Proteus). Furthermore, it is possible that FH has protective benefits against tuberculosis and leprosy (Mycobacterium) as

1] From: Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis.

[2] Gram-negative and gram-positive bacteria refer to whether or not the cell wall absorbs the Gram stain. In general, gram-negative bacteria are considered more difficult to treat.

well as tetanus (Clostridium) because these gram-positive bacteria have notable gram-negative features.[1] In modern clinical settings, patients with high LDL have been shown be less likely to develop sepsis in a hospital setting and, if over 60 years of age, likely to live longer than the non-FH controls.[2]^,[3],[4]

Perhaps the most interesting data suggesting a selective advantage comes from an eight generation Dutch pedigree with 412 descendants many of whom have or had FH. The study was probability based in terms of figuring out the likelihood of an FH positive ancestor based on the heterozygous status of the living persons. Interestingly, from 1840-1915 the mortality ratio of the FH individuals was less than the non-FH family members. During the twentieth century the mortality ratio changed dramatically with the FH individuals have a substantially higher mortality ratio. The mortality ratio then began to improve when the statins were introduced.[5] Since 1964, their life expectancy has been increasing and is now likely to reach the average (1.0) (Figure 5).

[1] Grin et al 2015 Nature; add sepsis paper

[2] Mani et al 2023 Cureusl Chidambaram et al 2021 Frontiers in Cardiovascular Medicine

[3] Guirgis et al 2016 Critical Care

[4] Ravnskov et al 2016 BMJ

[5] Sijbrands, EJC 2001 BMJ

Figure 5

Mortality from Familial Hypercholesterolemia Over Time

These data are suggestive of an environmental/dietary change that occurred around 1900 and worsened dramatically between 1920 and 1960. Some of these changes include increased processed foods, a shift from saturated fat to unsaturated fats, reduced physical activity, increased sugar consumption. These changes were facilitated by industrial food production and refrigeration technology along with ubiquitous marketing and advertising campaigns.[1] It appears that a once adaptive trait has become a significant liability and cause of mortality in our modern environment.

With increased mortality and complications of atherosclerosis seen in FH patients, what has been done for them other than offering statins? A lot. One of the genes directly involved in FH is PCSK9. The gene was discovered in 2001 and shown to be implicated in FH. Soon after its discovery, people were found genetic mutations that led to a loss of function of the PCSK9 gene. These individuals had low LDL and a reduced risk of coronary heart disease.[2] This finding, coupled with an analysis of the PCSK9 protein, led to development of monoclonal antibodies that bind to the protein.[3] These monoclonals are used to treat people with FH as well as individuals whose LDL is still high despite statin treatment.[4]

As with CCR-5 D32, the FH/PCSK9 story is complicated with plusses and minuses both of which are context dependent. Genes that were adaptive for our ancestors may function differently depending upon the environment. When we know our genes, we understand both the risks and potentially the rewards in developing ways and/or treatments to manage the risks as well as take advantage of the benefits.

[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC8805510/

https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2021.748847/full

https://maxinesheavenly.com/blogs/maxines-heavenly/1922-2022-what-s-changed-over-100-years-of-health-baking

https://www.ers.usda.gov/amber-waves/2010/march/guess-who-s-turning-100-tracking-a-century-of-american-eating/

[2]https://www.mayoclinic.org/medical-professionals/cardiovascular-diseases/news/pcsk9-inhibition-a-game-changer-in-cholesterol-management/mac-20430713#:~:text=%22PCSK9%20inhibitors%20fill%20an%20obvious,Mayo%20Clinic%20in%20Rochester%2C%20Minnesota.

[3] Alirocumab (2015 approval) and Evolucumab (2016 approval) are both fully humanized monoclonal antibodies.

[4] The two FDA-approved PCSK9 inhibitors are alirocumab (Praluent) and evolocumab (Repatha)

• Winner of the Next Generation Indie Book Awards in the Suspense category

• Finalist in the Mystery/Suspense category at the International Book Awards 2025

• Finalist in the Mystery/Suspense category at the American Fiction Awards

When I set out to write The Goldilocks Genome, my hope was to create a story that not only entertained but also sparked deeper conversations about how we approach health, medicine, and the ways science intersects with our lives. To see these efforts being recognized on such a broad scale is deeply rewarding.

If you haven’t had a chance to read The Goldilocks Genome yet, now might be a great time to dive in. I’m always looking for feedback!

All the best,

Betsy

My Memoir Mud, Microbes, and Medicine --Coming April 2026

The Goldilocks Genome - now on Audible

Amazon Best Seller; 2024 International Impact Award

2025 Winner American Legacy Awards

2025 Winner Next Generation Indie Book Awards

2025 American Fiction Awards -- Finalist

2025 International Book Awards -- Finalist

2024 Winner Best Thriller Books Award

2024 Best Books Award -- Finalist

The Genome Killer - serial podcast

This recognition means so much to me, not just because of the award itself, but because I hope it reflects the conversations we’re having around personalized medicine, pharmacology, and the very real consequences of medications that aren’t tailored to the individual. The Goldilocks Genome has always been about exploring these themes, and I’m so thankful that it’s resonated with so many readers,

To everyone who has read the book, shared their thoughts, and supported me along the way—thank you!

If you haven’t read The Goldilocks Genome yet, I invite you to take a look.

All the best,

Betsy

My Memoir Mud, Microbes, and Medicine --Coming January 2026

The Goldilocks Genome - now on Audible

Amazon Best Seller; 2024 International Impact Award

2025 Winner American Legacy Awards

2024 Winner Best Thriller Books Award

2024 Best Books Award -- Finalist

The Genome Killer - serial podcast

For those of you interested in the intersection of medicine, pharmacology, and high-stakes drama, my book explores the dangerous consequences of medications that are not personalized, dramatizing the “Goldilocks Effect”—the phenomenon where drugs are “just right” for only about 40% of patients, leaving the rest with ineffective or potentially harmful results. With over 21 million Americans struggling with depression, this dilemma is more relevant than ever, as antidepressants often fail to work for a significant portion of patients.

Thank you in advance for your support!

All the best,

Betsy

My Memoir Mud, Microbes, and Medicine --Coming January 2026

The Goldilocks Genome - now on Audible

Amazon Best Seller; 2024 International Impact Award

2024 Winner BestThriller Book Award

2024 Best Books Award -- Finalist

The Genome Killer - serial podcast

Recently, many news outlets have been advising people to delete their 23andMe data following the company’s bankruptcy filing. If you choose to delete your data, make sure to take the necessary steps to download your raw data first (see the instructions below for more details).

I have had two sets of data generated by 23andMe: one in 2012 and another in 2024. The most recent analysis provides far more information, all obtained using the updated Illumina chips (used by most companies and laboratories offering SNP—single nucleotide polymorphism—genetic data). My data contains information on more than 950,000 SNPs. That’s a lot of data, and much of it relates to general traits, such as whether I’m more likely to have curly hair (I am!).

What I Like About 23andMe

The website is well-designed and easy to navigate. It shows where I have genetic variants in different genes, which is useful. However, interpreting this information often requires visiting third-party websites. For example, I want to understand whether I am at risk of a "Goldilocks effect" in terms of how I respond to prescription drugs (i.e., not too little, not too much). I also want to ensure that my genotype is accessible in case of a medical emergency.

When Would I Delete My Data?

If I had genetic results indicating near certainty of developing a disease like Huntington's disease, Tay-Sachs disease, or Alzheimer’s disease, I would probably download my data and then delete it. I believe information is knowledge.

What About Privacy?

In the U.S., the Genetic Information Nondiscrimination Act (GINA) protects against the use of genetic data for employment or insurance discrimination (at least in theory). However, some information will be retained by the company, the laboratories that conducted the testing, and any third parties involved. Their website has been hacked in the past, but there have been no reported significant impacts to those 8.5 million users. In today’s digital world, privacy is a tough illusion. With so much data floating around, it’s nearly impossible to do anything meaningful with genetic information, which may be a good thing in the end. Furthermore, most serious genetic diseases have early-onset symptoms and for many there are treatments.[1] Knowledge of one’s risks helps plan for the future.

The Future of 23andMe

The future of 23andMe is uncertain. It’s likely that the company will be purchased, and its data will continue to be used like a BioBank resource. If the company is sold, the sale conditions will probably require that existing customer agreements are honored, or that an option to delete data is made available.

I remain hopeful that the service and website will stay operational and continue to be updated. Although I have not subscribed to any of their premium services, I do appreciate the occasional updates, even if they’re rarely relevant to me. I choose not to participate in their optional genetics research services because I find the information gathered tends to be subjective. But for now, I’m keeping this “baby” in its bathwater.

[1] These include: cystic fibrosis, Duchenne Muscular Dystrophy, hemochromatosis, neurofibromatosis type 1, Sickle Cell disease, Ehlers-Danlos syndrome, achondroplasia, Angelman syndrome, congenital cataracts, MUTYH associated polyposis, familial thoracic aortic aneurysm, and aortic dissection. https://www.healthdirect.gov.au/genetic-disorders

How to Download Your 23andMe Data:

1. Open the hamburger menu and sign in.

2. Follow the login instructions.

3. Click your profile name in the top right corner.

4. Select “Resources” from the dropdown menu.

5. Choose “Browse Raw Genotyping Data.”

6. Click “Download” at the top of the page.

7. Confirm the information requested, scroll through the warnings and disclaimers, and submit.

8. Wait for the *.txt file to be sent to you. Download and save it in a safe place.

   ---

   All the best,

   Betsy

   ---

   My Memoir Mud, Microbes, and Medicine --Coming January 2026

   The Goldilocks Genome - now on Audible

   Amazon Best Seller; 2024 International Impact Award

   2024 Winner BestThriller Book Award

   2024 Best Books Award -- Finalist

   The Genome Killer - serial podcast

Monogenic traits, resulting from single point mutations in a gene, can lead to disease or provide insight into how to treat a disease. The normal, wild-type, gene and its variants elucidate the biology of the disease process which can encompass responses to environmental stresses. Protective variants may lead to new therapies in addition to providing a window into our ancestral genetic past where these variants survived because they protected our ancestors. If we understand the gene, its variants and their protein product(s) it is possible to design and tailor therapies that treat some of our deadlier and insidious diseases.

Two genetic variants that served us well in the past may be a mixed blessing in today’s environment. My family’s history features one important variant and one wild-type gene—both for better and for worse.

From Mutation to Medicine—CCR-5-delta (D)32

In 1979, I attended an afternoon lecture at the Institute for Cancer Research (ICR) near Philadelphia. The speaker was Hungarian. He told us that after his talk we would all know the correct way to pronounce Kaposi (kah-pō-she) sarcoma.[1] At the time, it was a rare and obscure cancer that was becoming almost common in San Francisco. The lecturer added that the cancer was found disproportionately in homosexual men. He went on to describe the disease and possible treatments—none of which offered much hope for the patient. At the time, it seemed “obvious” that this new disease was likely the consequence of a blood-borne viral infection. Why? The epidemiology was very similar to the parenterally transmitted virus, hepatitis B, which was the subject of my dissertation and a focus of research at ICR. Hepatitis B virus could lead to hepatocellular cancer.

[1] The first person to characterize Kaposi Sarcoma was Moritz Kohn who changed his last name to Kaposi after the Kapos River that ran through the city Kaposvár, Hungary, where he was born. He made the change to distinguish himself from other German scientists who also had the name Kohn. Dorland’s illustrated medical dictionary, 31st ed. Philadelphia: Saunders; 2007; http://www.hemoctoday.com/article.

Two years later, in San Francisco, my brother underwent a 13-hour operation requiring multiple blood transfusions. Local epidemiologists suspected the donated blood supply harbored the uncharacterized pathogen associated with Kaposi sarcoma. Without the means to test for the virus, it was a crap shoot. Throughout the year following his surgery, I wondered whether he would come down with the disease later named Acquired Immune Deficiency Syndrome (AIDS).

The following year, I was seriously exposed to hepatitis B virus (HBV) in Vanuatu doing field research. Upon my return to San Francisco, I rushed to UCSF and took the recently approved HBV vaccine. The vaccine was made from plasma collected from “otherwise healthy” carriers of HBV. In theory, the virus was inactivated but would still trigger antibody formation which could protect me if I had been exposed as well as provide lifetime immunity. The plasma was collected locally and from New York City where HBV was prevalent. This also meant the plasma was from “otherwise healthy” donors asymptomatic for AIDS. I trusted that HBV had been inactivated and hoped that the unknown pathogen had been as well. I took the first two doses but chickened out for the third. I did not complete the full vaccination schedule because I was worried about the potential of being injected with the mysterious AIDS virus.

Neither my brother nor I got AIDS. Soon after our respective exposures to donated blood and the HBV vaccine, the human immunodeficiency virus (HIV) was identified and demonstrated to cause AIDS. This discovery led to a diagnostic test for HIV and a better understanding of AIDS epidemiology. In the late 1980’s, if a person tested positive for HIV, the fatality rate was nearly one hundred percent within ten years. But, scientists noted, there were some exceptions—a small number of people seemed “immune” to HIV and never came down with ADS despite partaking in all the high-risk behaviors and living the risky lifestyle including homosexual sex with numerous partners and/or intravenous drug use.

Intrigued, and enabled by advances in molecular biology and genetics, researchers discovered that these “should be positive HIV-outliers” had a mutation in the receptor for CCR-5 (C-C chemokine receptor type 5). This mutation, the CCR-5 D32 deletion prevented HIV-1 from entering the T-lymphocytes (T-cells).[1] A person, who was homozygous (footnote def) for this deletion, was fully protected from infection with HIV-1 and never developed AIDS. The heterozygous individuals, with only one copy of CCR-5 D32, developed disease but its progression was much slower, and they lived longer. These observations around the D32 mutation led to research on both the origin of the variant as well as its benefits and liabilities. Understanding the genetic modification and its biology led to drugs that blocked the CCR-5 receptor, providing an effect equivalent to having the D32 mutation.

Why are T-lymphocytes so important? They are the critical first line of defense against pathogens—either viruses or bacteria. In theory, the mutation should be harmful, but it wasn’t. This led to investigations of where the D32 mutation was found. Unexpectedly, 8-15 percent of Europeans had this mutation, and it was unique to Europe. Since the prevalence was so high, it also meant that many people were homozygous for the variant, having two copies of the gene.

Why? What selective pressure(s) had occurred over the millennia that conferred a survival benefit for D32? A reasonable hypothesis was the mutation was protective against pathogens other than HIV. There was an obvious pathogen known to ravage Europe over the millennia—the plague.

[1] The D32 signifies a deletion of 32 base pairs in the DNA of the CCR-5 gene.

Figure 1

Spread of bubonic plague in Europe from 1348 to 1353 (48, 51–54).

If this was the case, then the distribution of the gene should overlap with the geography of the bubonic plague that decimated Europe in the 14^th Century—and it does (see Figure 2). Moreover, the plague is an ancient scourge, documented in Roman times and likely earlier and would have a distribution pattern similar to that seen for the later plague.

Figure 2

CCR5- D32 Allele Frequency Distribution

In addition, there is evidence that the D32 variant is also protective against smallpox. Plague and smallpox are both highly infectious and deadly diseases that could have provided strong selective pressure favoring the differential survival of people with the D32 mutation. Moreover, there is genetic evidence from burial remains of plague victims in England confirming those who died had the wild type CCR-5 gene. Similarly, archaeologist and pathologists found that survivors of that pandemic were more likely to be D32 positive.

Subsequent analyses have shown other benefits of being a carrier of the CCR-5 D32 mutation. They have a milder course of HBV infection and progression, recover from faster from strokes due to reduced neuronal inflammation, and are resistant to the lethal sequelae associated with Staphylococcus aureus infections.

The D32 mutation is the equivalent of blocking the CCR-5 receptor on the T-cell. Receptors are a favorite target of the pharmaceutical industry because they have defined structure and, being on the cell surface, are accessible to either small molecule chemical compounds—the bread and butter of the pharmaceutical industry—or monoclonal antibodies. In the case of CCR-5, the receptor configuration was a target that could be blocked only by a small molecule. Medicinal chemists synthesized compounds that bound to the receptor. Compounds can be either rationally designed or discovered through high throughput screening of hundreds of thousands of compounds followed by an analysis of which bind to the receptor. This approach can lead to a rationally developed structure-activity-relationship (SAR) to optimize the binding affinity to and specificity for the receptor. When successful, the result is a medicine that maximizes efficacy and minimizes side effects.

For pharma, CCR-5 was a perfect target for new drug development. Blocking the receptor was expected to have few side effects since the D32 homozygotes were “normal.” The benefit was obvious—a safer treatment for AIDS. Pfizer developed such a drug, maraviroc, which was approved by the FDA in 2007. Although the drug has some side effects and is not recommended for those patients where HIV uses both CCR-5 and CXCR4 co-receptors, it is a viable therapy.

So far, D32 has shown many positive benefits. But is there a downside to having this variant? The answer…it depends. People with the mutation are more likely to have serious consequences when they get influenza. They are also thirty times more likely to develop encephalitis when infected with West Nile Virus which can lead to death.[1]

So how does my brother’s and my close brushes with HIV fit into this picture? Thirty years later, our experiences made sense. In 2013, everyone in our family spat into 23andMe test tubes. When our results came back, it was clear my brother’s genes protected him from possible HIV infection. In our family, my brother, mother and I were all homozygous for the D32 deletion. We escaped one disaster but, in 1957, my young, healthy mother was hospitalized with “the Asian flu” (H2N2). I remember well the day my godmother, who was taking care of me, told me that my mother might die. My stepfather, a Professor of Medicine, stayed at her bedside micro-managing her care. She survived. Years later, my brother was incapacitated for weeks with encephalitis caused by West Nile Virus. He survived. Me? I’m fine.

Just kidding, I keep flu antiviral medicines on hand and never travel without them.

The bottom line…we won a big one and scraped by with others. Our big win was unexpected but became relevant when the infectious disease environment changed.

[1] O’Brien, S.J., 2024 “Legacy of a magic gene—CCR5 D32: From discovery to clinical benefit in a generation.” PNAS—Genetics (121(12).

All the best,

Betsy

My Memoir Mud, Microbes, and Medicine --Coming January 2026

The Goldilocks Genome - now on Audible

Amazon Best Seller; 2024 International Impact Award

2024 Winner BestThriller Book Award

2024 Best Books Award -- Finalist

The Genome Killer - serial podcast

Best wishes,

Betsy Aden

Best wishes,

Betsy

Best wishes,

Betsy

While researching her debut mystery novel, Berkeley author Elizabeth Reed Aden reached out to her mother and brother for advice. They are both psychiatrists, and she asked them how her killer might go about the grisly business of disposing of his victims through combinations of malicious pharmacology.

“As I’m running ideas by them,” Aden recalled, “they were like: ‘We’re not going to help you.’ ”

Here’s the link to the full spread.

Best wishes,

Betsy

A British friend in Valencia sent me the article, "‘Like a Bad Dream’ Pain Killer Linked to Deaths of Brits & Scandinavians in Spain.”[1] She asked if I knew why a readily available pain killer, Nolotil® (metamizole also known as dipyrone[2]) seemed to preferentially kill Brits and Swedes in Spain[3]. There are historic connections between Scandinavia[4] and Britain so I answered with the “obvious”— genetics.  A hundred journal articles later, the “obvious” became an adventure into the world of hypersensitive drug reactions—where I discovered that no one knows how to predict why a Brit will have a potentially fatal reaction to Nolotil and why a Spaniard will not. The literature offers clues about risk factors that result in hypersensitivity to the drug.

Hypersensitivity is when the immune system, the body’s army, mounts an exaggerated response to a foreign substance either real or perceived.  When it senses an enemy, it goes to war and does battle. The tactics used by the immune army depend on the nature of the assault. Generally, the army wins and the invader (pathogen, antigen) is conquered and peace reigns. Sometimes the enemy wins and the body succumbs. “Friendly fire” is another possible, albeit unfortunate, outcome. When the army aims its guns on itself, the result is an autoimmune response.

[1] https://www.theguardian.com/world/2024/jan/20/alarm-over-death-toll-of-britons-in-spain-linked-to-painkiller-nolotil-metazimole#:~:text=6%20months%20old-,'Like%20a%20bad%20dream'%3A%20Briton's%20death%20in%20Spain,heightens%20fears%20about%20painkiller%20Nolotil&text=On%20an%20October%20evening%20last,systems%20could%20be%20switched%20off.

[2] Pronounced [die-per-one] and [meh-tam-i-zol]

[3] https://www.theguardian.com/world/2024/jan/20/alarm-over-death-toll-of-britons-in-spain-linked-to-painkiller-nolotil-metazimole

https://www.theguardian.com/society/article/2024/jun/16/eu-drugs-watchdog-probes-painkiller-linked-to-deaths?CMP=share_btn_url

[4] https://www.history.org.uk/primary/resource/3867/the-vikings-in-britain-a-brief-history

The Vikings (Sweden, Norway and Denmark) invaded Britain, the British Isles, France (they became the Normans), and Russia. They settled in Canada, Iceland, and Greenland and traded extensively with the Muslins.  The period of greatest activity was between 800-1150 AD.

(Cont.)

Hypersensitivity Reactions

There are four types of  hypersensitivity[1] each of which recruits a different battalion of highly trained “soldiers” within the immune system. Types I, II, and III are extracellular reactions that generate antibodies against blood-borne antigens/pathogens—this is also described as humoral immunity. Type IV reactions are intracellular and use thymus-derived cells (T-cells) to attack antigens that have infiltrated organs such as the lymph nodes or spleen.

Metamizole is associated with Types I and IV hypersensitivity. The four types of hypersensitivity responses are described below.

Type I Hypersensitivity (Allergic, Anaphylactic and Atopic Reactions): Type I allergic reaction that is the most common and is triggered by exposure to common, generally harmless things in the environment, like dust mites, cats, and pollen. In susceptible people, exposure can initiate a two-step process if the trigger substance is recognized as foreign by the body. When this happens, an allergen-specific immunoglobulin E (IgE) antibody is formed and attaches itself to mast cells and basophils where it lies in wait. If re-exposure to the trigger allergen happens, the second step is initiated with the allergen-specific IgE leading an attack lobbing its histamine-filled mast cell grenades at the re-introduced allergen. The body’s response varies from allergic rhinitis, atopic dermatitis, hives and eczema. Anti-histamines offer some relief. The most serious Type I hypersensitivity response is anaphylaxis, which can be life-threatening and is often alleviated by an injection of epinephrine. Allergies to bee stings, peanuts, and penicillin are common examples as well as the rare reactions to non-steroidal anti-inflammatory drugs (NSAIDs) and metamizole.

Metamizole itself is inert, but as it travels down the digestive tract, it morphs into a biologically active metabolite MAA.[2] This transformation occurs within minutes of taking the drug which makes MAA the likely candidate to trigger a Type I response in susceptible individuals who had previously taken metamizole.

Type II Hypersensitivity (Classical Antibody-Dependent Cytotoxic Reactions):  Antibody-dependent cytotoxicity brings out the general fighting troops. They take a day or two to mobilize. These are the big guns and the first line of defense against plasma-borne pathogens.[3] The short-lived “advance troops” are immunoglobulin M (IgM) which are followed by the “standing army” of immunoglobulin G (IgG) which can remain vigilant indefinitely.

[5] https://www.ncbi.nlm.nih.gov/books/NBK562228/

[6] MAA = 4‐methylaminoantipyrine

[7] specifically the plasma complement system

(Cont.)

“Friendly fire” happens when the IgM/IgG response mistakes a self-protein for a foreign invader. Rheumatic fever, following a strep throat infection, is a classic example. The strep antigen has a configuration almost identical to a self-antigen which the IgM/IgG soldiers attack mercilessly. Their misguided effort destroys the body’s cells long after the invading bacterium has been vanquished. Drugs can also cause Type II hypersensitivity by binding to the surface of a cell which is destroyed when the IgM/IgG army mounts its attack. An example is hemolytic anemia, caused by blood transfusions containing foreign proteins or when an Rh negative mother gives birth to her second Rh positive child.

Type III (Immune Complex Antibody Reactions): When the invaders and the IgM/IgG army are equal in numbers, they engage in “hand-to-hand” combat. The result is formation of antigen-antibody complexes which clump and are deposited in tissues, vessels and joints. The diseases caused by this “stalemate” include lupus erythematosus, rheumatoid arthritis, and serum sickness. 

Type IV (Delayed Cell-Mediated Reactions): T-cells are the exquisitely honed “special forces” of the immune system. They rely on scavenger cells like the macrophages to gobble up foreign antigens the antibodies missed. Macrophages incorporate antigen into the Major Histocompatibility Complex (MHC) which then presents the antigen in a configuration that can be recognized by T-helper cells. The MHC comes in two complementary regiments: Class I which handles intracellular antigens; and Class II which specializes in extracellular antigens.

The MHC is comprised of human leukocyte antigens (HLA) genes which code for proteins that help the immune system differentiate between self and non-self.  The HLA genes are sensitive, specific, complex, and diverse with over 40,000 known variants. This diversity explains why some people survive disastrous pandemics while others don’t.

One scenario, likely to be important for metamizole, is when a low molecular weight antigen (hapten) binds with a self-protein and if that conjugate is recognized as foreign by the MHC/HLA complex, then all hell can break loose. T-cells are recruited and empowered to search and destroy the “foreign” antigen. If this conjugate configuration is similar to a cell type in the body, such as a granulocyte, then the T-cells will attack depleting the neutrophils/granulocytes—a potentially lethal side effect of taking metamizole.

Type IV drug-induced hypersensitivity is likely caused by a metabolite of MAA as it transits through the liver where the highly polymorphic cytochrome P450 enzymes convert MAA into AA.[1]^,[2] In addition, other polymorphic molecules such as the Constitutive Androstane Receptor (CAR) and NAT2 may play a role in this process.[3] AA is both biologically active and a hapten. [4]^,[5] It’s possible that AA combines with a protein (AA + protein) in a shape that resembles a granulocyte. Once formed, if the MHC/HLA complex recognizes it as foreign, then the AA + protein conjugate is presented to the T-cells which scurry off to eliminate the granulocytes. 

How this happens is both fuzzy and complicated. Numerous studies have been done on patients with metamizole-induced agranulocytosis (MIA) and no HLA-smoking gun has been found. There have been associations in small studies but the results have not been replicated. HLA expression also can be modulated by other factors including diet, infections, concomitant drugs (which protein + hapten combines with), and the way the hapten + protein is presented to the MHC/HLA complex.  Comparisons between Swedish and Spanish populations have been done that highlight differences in HLA alleles and diet but prediction of who develops MIA remains elusive.[6]

However, it is reasonable to think the HLA genes are involved. A classic example of Type IV drug-induced side effects occur when Southeast Asians are given carbamazepine to treat neurologic disorders. Patients with the HLA-B*15:02 allele are at high risk of developing life-threatening side effects.[7] As a result, people with this ethnic heritage are tested prior to taking the drug. Carbamazepine also interacts with the HLA-A*31:01 allele which is found in diverse populations worldwide. Testing for this gene is not standard, but, if our genotypes were part of our medical record, the answer could be known quickly—potentially life-saving.

What is Agranulocytosis?

Agranulocytosis is a Greek-based medical term describing a disease (‘osis’) caused by a lack of (‘a’) white blood cells (“cytes”) containing granules (‘granulos’). Granulocytes produce

[8] CYP3A4 and CYP1A2 (Lutz 2019)

[9] AA = 4-aminoantipyrine

[10] NAT2 =N-acetyltransferase 2

[11] Metamizole is a Moderate Cytochrome P450 Inducer Via the Constitutive Androstane Receptor and a Weak Inhibitor of CYP1A2; Fabio Bachmann1,2, Urs Duthaler1,2, Henriette E. Meyer zu Schwabedissen3 , Maxim Puchkov4 , Jörg Huwyler4 , Manuel Haschke5,6 and Stephan Krähenbühl1,2,*

[12] NAT2= arylamine N-acetyltransferase; Genetic determinants of metamizole metabolism modify the risk of developing anaphylaxis” García-Martín, Elena et al Pharmacogenetics and Genomics 25(9):p 462-464, September 2015. 

[13] Advances in methods for characterizing dietary patterns: A scoping review [2024]

[14] Steven-Johnson Syndrome (SJS) associated with HLA-B*15:02  and , HLA-A*31:01 has been associated with toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) (Dean 2015),

(Cont.)

three different types of cells.[1] The most abundant and important are the neutrophils which comprise between 50-70 percent of our white blood cells[2]. Neutrophils protect the body from pathogens and are a key part of an immune response. Clinical chemistry panels report the number of neutrophils with the normal range being between 2,000-7,000 per microliter (ml). A count below 500/ml is described as neutropenia and a cell count of ≤100/ml is life threatening. Agranulocytosis is a recognized risk in patients receiving chemotherapy. As such, patients  are regularly monitored and treated with granulocyte-colony stimulating factor when their neutrophil count gets too low so the complications of agranulocytosis—infections, sepsis—are prevented.

Drug-induced agranulocytosis (DIA) also occurs with a wide range of drugs not used in chemotherapy.[3] The disease is rare and often undiagnosed. The reported average is 7.2 cases per million people per year, with the high end of the range at 15.4 cases per million.[4] To put these cases into perspective, physicians in San Francisco would expect to see 3-18 patients with DIA  per year. Of these cases, the fatality rate would be 5 percent or one death in this city of 800,000 people.

One reason MIA may be under diagnosed is it can be self-limiting, especially if the patient stops taking the drug. Neutrophils are replenished quickly so the flu-like symptoms can disappear within three to four days. However, if the drug is continued and the symptoms persist, then sepsis or other life-threatening infections can develop.

The relative rarity of MIA means it is often not a consideration when taking Nolotil for the first time. Unless, you are British or Swedish and in Spain.[5] A study done in Marbella found an average of 8.33 cases per 106 inhabitants per year. Based on verified cases within the British population, it was estimated that the incidence of MIA among the Brits could be 20.4 cases/106 inhabitants/year.[6] The British are the largest group of visitors and foreign residents in Spain with Marbella being a favorite Andalucian town for ex-pats and tourists.[7] In addition, the city’s

[15] Eosinophils, basophils, and neutrophils

[16] Lymphoblasts produce B-lymphocytes, T-lymphocytes, and Natural Killer Cells which comprise the other components of our white blood cells/leukocytes.

[17] https://www.acpjournals.org/doi/10.7326/0003-4819-146-9-200705010-00009

[18] Rattay, B and Benndorf, RA. 2021. “Drug-induced idiosyncratic agranulocytosis –Infrequent but dangerous.” Frontiers in Pharmacology, 202:727717article number); pp 1-11 “Review”

[19] Or other countries where metamizole is on the market.

[20] Mérida Rodrigo, L, Faus Felipe, V, Poveda Gómez, F, García Alegría, JG 2009. [Agranulocytosis from metamizole: a potential problem for the British population.” Ver Clin Esp 209(4):176-9.

[21] https://www.ifema.es/en/fitur/news/british-market-tourist-spending-spain

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demographics skew on the older side which favors the use of metamizole for pain management due to its immediate pain relief and its generally good safety/tolerability profile.[1]

 What do we know about metamizole?

The History of Metamizole/Dipyrone

The drug, which has more than sixty brand names, was developed by the German pharmaceutical company Boehringer Ingleheim. It is effective in treating pain, fever and spasms. It is used preferentially for post-operative pain, migraines, and headaches because its analgesic benefits combine rapid and sustained relief.

Metamizole was first marketed in the mid-1920’s. At that time, the primary analgesics were aspirin and opioids. As such, this new drug fit nicely between these two options. It was more effective than aspirin and not addictive like the opioids. For decades, the novel analgesic enjoyed worldwide market success and was literally in a chemical class by itself.  The first case of an MIA death was reported in 1936. It was a cause of concern, but the risk was considered acceptable.  

For the next forty years, metamizole remained widely available. Then in the 1950s acetaminophen (Tylenol®)/paracetamol was introduced as a safer-than-aspirin alternative. Its market success spurred development of a new class of medicines, the NSAIDs which entered the market between 1969-1976. The NSAIDs—diclofenac, ibuprofen and naproxen—dominated the world markets. By this time, MIA had reached a level of unacceptable risk in some countries and was banned in those markets (see map below). In Sweden, the reported incidence of MIA was 1:1439 prescriptions.[2] Today, metamizole is banned in many countries, especially those with Viking/British ancestry or presence like the United Kingdom, Sweden, Norway, and the United States of America.[3]

Metamizole is available in Spain—with or without a prescription—as well as throughout Asia, Africa, Latin America, much of Western Europe, and most of Eastern Europe. In these countries, the pharmacist is the go-to drug dispenser. If you’re sick, the pharmacy is often your

[22] https://everythingmarbella.com/marbella-demographics-and-population/#:~:text=The%20average%20resident%20age%20sits,flock%20for%20plentiful%20job%20prospects.

[23] https://pubmed.ncbi.nlm.nih.gov/12136373/

[24] These countries included: the Scandinavian countries (Sweden, Denmark, Norway, Iceland, and Greenland, but not Finland), the English-speaking countries (Canada, UK, USA, Australia, Zimbabwe), the Arab countries (Saudi Arabia, Iran, Morocco, excluding Egypt, Turkey, and Yemen), the Indian sub-continent (India, Pakistan, Nepal, Sri Lanka with the exception of Bangladesh) and the seeming “outliers” of Greece, and Japan.

(Cont.)

first stop. There, the pharmacist listens as you describe your symptoms and then suggests treatment options. You buy the recommended drug(s) and try it/them. If problems arise, you either return to the pharmacy or seek medical advice. In Spain, the package insert suggests the drug not be sold to tourists.

Despite the ban in many countries, metamizole continues to generate healthy sales. Recently, perhaps due to the opioid crisis and/or the aging of the baby boomers, sales have increased dramatically, most notably in Germany. Metamizole has become a go-to analgesic among the elderly.

So What Is the Answer?

The biological complexity of both the drug and the patient’s immune system is an example of conditional probability. For example, if 50 percent of people are Blood Group O and 6 percent are Rh negative (Rh(-)) then the probability that a person is O Rh(-) is 3 percent. Each factor adds an additional multiplication step that makes the likelihood of finding a person with a specific constellation of traits increasingly rare. When we examine all of the variables that can affect a patient’s response to metamizole it becomes understandable why MIA is rare. Since the drug is banned in countries where the incidence of MIA is relatively high, it is even harder to identify specific risk factors.[1] For now, we have to settle for the uncomfortable knowledge that Brits and Swedes are at higher risk without knowing which Brits or Swedes.

Do we give up? Never! Help is on the way. Companies are developing rapid, self-test diagnostics to monitor neutrophil count at home or quickly in an emergency room.[2] Analyses of each step from gene to metabolite are providing new and actionable data. Incorporating basic genetic information into our medical record is critical. Additionally, anonymized records, used for research purposes in biobanks, can help define individual hypersensitivity risk factors. Ultimately, it will be possible to know which medicines a person needs to avoid.

For now, the bottom line is…an ounce of prevention is truly worth the British pound of cure.[3]

[25] CYP3A4, CYP1A2, NAT2, CAR and the 40,000-plus HLA alleles

[26] https://nhscep.com/2024/03/12/new-finger-prick-test-detects-sepsis-in-cancer-patients-at-home/

[27] https://www.allelefrequencies.net/hla-adr/adr_report.asp - is a reference resource for HLA frequencies

(Cont.)

Figure 1: Drugs Associated with Agranulocytosis

Figure 2: Median treatment time to occurrence of agranulocytosis
(N.B. metamizole speed of onset may be due to multiple past exposures)

Figure 3: HLA Associations with Metamizole

Figure 4: Cold-Medicine Induced STS/TEN with SOC

Associated with Concomitant use of NSAIDs & Metamizole[1]-- Meta-Analysis Review Article (Tanganmornsuksan et al 2020)[2]

[28] Some authors classify metamizole as an NSAID

[29]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324363/pdf/41598_2020_Article_67610.pdf

I am truly grateful for this wonderful community and look forward to sharing more exciting updates with you.

Best wishes,
Betsy Aden

Starting today, August 27, through August 29, you can purchase my medical thriller, The Goldilocks Genome, on Kindle for just $0.99! 📚 If you haven't had the chance to dive into the book yet, now's a perfect opportunity to try it out at a fantastic price! Just click on the image below.

Best wishes,

Betsy

I hope you enjoy my recommendations for the most compelling medical nonfiction books this summer, just published on Shepherd.com: https://shepherd.com/best-books/compelling-medical-nonfiction-books

Best wishes,

Betsy

I want to share interesting findings in Personalized Medicine. This recent article highlights the importance of population-based genetics in identifying new variants that may have health consequences: A recent genetic study of Japan’s population found there were three ancestral populations: Jomon hunter-gatherers; people from China’s Yellow River region; and previously unknown group who contributed primarily to the Northeastern Japanese population. This tri-ancestral model helps to place specific founder mutations unique to the Japanese population in context.  Some of these founder mutations are pathogenic.

Of anthropological interest is the demonstration that some disease-associated genes could be traced back to archaic human populations. For example, Japanese with a the low function variant of the NKX6-1 gene, which is traced back to the Denisovans, have an increased risk of type 2 diabetes. NKX6-1 is essential for the development and functioning of the pancreatic beta cells which produce insulin.    

The study also found a Neanderthal GLP1R  (glucagon-like peptide-1 receptor) variant that increased a person’s risk for developing type 2 diabetes. Knowing whether the person has a variant of GLP1R may be an important consideration in determining whether they are a candidate for Trulicity®, Ozempic® or the other GLP1R antagonists.

In total, the study identified two DNA variants that could be traced back to the Denisovans and 42 Neanderthal variants. These 44 variants also seemed to be restricted to people of East Asian origin. In addition, the study identified 371 pathogenic variants found in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar). These data came from full genome scans of 3,256 Biobank Japan participants located in 7 of the 8 regions in the country.   

The study, "Whole-Genome Sequencing Study Unravels Japanese Population History, Genetic Traits," published in Science Advances on April 19, 2024, by Andrea Anderson et al, (RIKEN Center for Integrative Medical Sciences) 45.6 million single nucleotide variants, over 9.1 million small insertions or deletions,  and more than 1,700 new loss-of-function variants, including gene knockouts.

Something to think about!

Best wishes,
Betsy