Precision medicine within the humble CBC
Volume 10, Issue 21 | December 19, 2024
As we head into the twilight of 2024, we want to wish all of you a joyous holiday. All the best for 12 days of Christmas, eight days of Hanukkah, and seven days of Kwanzaa. We look forward to “seeing” you in 2025. May the new year bring you strength and success as well as happiness and health.
ALSO IN THIS ISSUE
Bird Flu Update
Is microRNA the key to diagnosis of neurodegenerative disease?
Precision medicine has been hidden in the CBC all along
If you’ve ever had a routine blood test, chances are it included a complete blood count (CBC). It’s the most basic of basic tests, literally a count of the number of each type of blood cell in a certain volume of blood. (Okay, fine, it’s actually an estimate based on how many cells you can see in a standard view under a microscope, but you get the idea.)
For each cell type, there is an established range of numbers that’s considered normal. For example, women are supposed to have between 4.2 and 5.4 million red blood cells per microliter (men have a bit more). If the number of red blood cells on Liz or Mara’s CBC falls within that range, it’s marked as normal for us. If it’s outside that range, it’s abnormal.
But it turns out that what's normal for each person is much more specific than that. Research just published in Nature (paywall for full article) showed that each individual has their own set of levels, called “setpoints,” to which their blood cell counts always return. “The typical healthy adult’s nine CBC setpoints [are] distinguishable as a group from those of 98% of other healthy adults, and setpoint differences persist for at least 20 years,” the paper states.
And those levels aren’t random. Setpoints for various blood cell types are associated with the risk of getting certain diseases. And if your current level of certain blood cells varies from what’s normal for you, that can be indicative of disease - even if that number falls within the historically “normal” range.
COMMENTARY: Ah, the humble CBC may be at the cutting edge of personalized medicine!
The rise of personalized or precision medicine over the last two decades has focused on cancer and test / drug combinations. (Those tests look for biomarkers that would indicate you’re more likely to respond well to a certain drug.) Advocates of personalized medicine (including Mara) have always said that it should not be restricted to one type of disease. That is why we are so excited about this data. Plus, they may actually explain the “everything was fine at my annual physical but then I got sick” phenomenon.
We understand that few diseases are accurately diagnosed with just one test or one biomarker, but given how universally CBCs are used, this research may mark the beginning of the next generation of personalized medicine. As usual, more data is needed. Assuming the data holds up, after that it will be all about physician education.
Bird Flu Update
First commercial H5N1 test available
Louisiana: US’s first severe human case and first backyard poultry outbreak
Bulk testing catches infected raw milk in CA; governor declares State of Emergency
Routine flu surveillance catches probable human case in Delaware
First probable human case in Wisconsin
California declares State of Emergency for Bird Flu
The first commercial test for H5 influenza is now available for clinicians to order. It’s a PCR test that was developed with support from the CDC.
This week, the state of Louisiana reported its first human cases of H5N1 flu and its first outbreak of the disease in poultry. The number of confirmed human cases in the US is now 61, and outbreaks in poultry have now been reported in all 50 states. The infected person is the first one in the US to be hospitalized with severe symptoms. The person is over 65, has underlying medical conditions, and is the first known person in the US to have been infected due to exposure from infected birds in a backyard flock.
Bulk tank testing caught a batch of infected raw milk in California, this one from Valley Milk Simply Bottled in Stanislaus County. The milk has been recalled. Several cats in the state have gotten infected by drinking raw milk, and most of them have died. Now that bird flu has spread to California dairies outside the Central Valley, the governor there has declared a State of Emergency in order to “provide state and local agencies with additional flexibility around staffing, contracting, and other rules” as they respond to the outbreak.
Routine flu surveillance caught a probable human case of H5N1 in Delaware, but the CDC was unable to confirm the diagnosis. Another probable human case was found in Wisconsin. This brings the number of probable but unconfirmed human cases in the US to seven.
California’s governor proclaimed a State of Emergency to streamline the state’s response to Bird Flu - allowing expanded monitoring and additional flexibility for state and local agencies to respond as needed.
Diagnosing neurodegenerative disease: MicroRNA FTW?
The 2024 Nobel Prize in Physiology or Medicine was awarded to Victor Ambros and Gary Ruvkun “for the discovery of microRNA and its role in post-transcriptional gene regulation,” turning these little nucleotide strings into one of the big stories of 2024. Why are they so important? MicroRNA exists throughout the animal kingdom - and it plays a critical role in determining which proteins cells make. Some recent papers explore ways in which microRNA could be used to diagnose neurodegenerative disease.
ALS
Amyotrophic lateral sclerosis (ALS) is hard to diagnose. The average primary care physician may see it only once or twice in a career, it has complex and non-specific symptoms (especially at the beginning), and time is short. Death typically results within three years of diagnosis.
As is the case with most neurological disorders, diagnosis is primarily a matter of recognizing telltale but non-obvious patterns within a wide array of clinical signs and test results. A previous review in the Journal of the Neurological Sciences concluded that a definitive ALS diagnosis is typically delayed one to two years after the first symptoms appear, including correcting the roughly 40% of cases initially misdiagnosed.
A definitive test for ALS would be a Big Deal, and a paper in Brain Communications presents one that researchers claim has quite extraordinary accuracy. Extracellular vesicles extracted from a blood plasma sample are evaluated for an eight-microRNA “diagnostic signature” that scores - wait for it - 100% both for sensitivity and for negative predictive value (the likelihood that a negative result is a true negative). Its specificity is nearly as good (96%), as is its positive predictive value (97%; the likelihood that a positive result is a true positive).
COMMENTARY: This paper shows clear correlation between its microRNA panel and ALS (accurately excluding Parkinson’s disease). While its sample size is not large, its results are consistent with work previously published (including by the same group). A definitive, less invasive biochemical/biomarker diagnostic like this one is desperately needed for both patient care and therapeutic development.
Alzheimer’s Disease
Two recent papers in Alzheimer’s & Dementia explore the “microRNAome” from different perspectives.
One explores correlations between microRNA and each of the three criteria used in an Alzheimer’s diagnosis: amyloid (one of the two proteins that form plaques and tangles in the Alzheimer’s brain), tau (the other protein), and neurodegeneration. Nineteen microRNA strings are identified as particularly interesting. However, the paper doesn’t make any claims beyond correlation, and for good reason - the interactions among microRNA, genes, and cellular processes are incredibly complicated. An excerpt from Figure 4A below from Alzheimer’s & Dementia, Journal of the Alzheimer’s Association, illustrates the issue for nine amyloid-related microRNA strings (blue and red ovals), showing which genes (in green) they interact with.
The second paper explores correlations between microRNA and degrees of cognitive impairment (early, late, and full-blown Alzheimer’s), with a special focus on what drives the 38% of mild cognitive-impairment cases to progress to full-blown disease.
COMMENTARY: Interestingly, there is no overlap between the microRNA strings identified in each of the two papers. It’s not clear whether this is good news or bad. It would be good news if each microRNA string is being used only at a specific stage of the disease. It would be bad if this disagreement ends up being noise, not signal. We believe that there is much work to be done before the technology is ready for clinical use.
One issue we have with the microRNA field overall is how the strings are named. Each string is labeled with a series of numbers (e.g., microRNA998.5p) that more or less reflects the order in which the strings are discovered. Good luck remembering one by name! It reminds us of street numbers in Tokyo, which are often assigned based on the order houses were built.
Appreciation: We would like to thank Sarah Igoe, MD for her work in cataloguing the COVID/Flu tests approved or authorized by the FDA. Another special shout out to Grace Gegenheimer for her tireless dedication week after week!
I love the weeks I remember to check Substack; I always find some really cool piece of science outside of my four respiratory virus epi walls those weeks because I read Precision Medicine!