#13 - Here comes the sun (2024)

The Two-Headed CalfTomorrow when the farm boys find thisfreak of nature, they will wrap his bodyin newspaper and carry him to the museum.But tonight he is alive and in the northfield with his mother. It is a perfectsummer evening: the moon rising overthe orchard, the wind in the grass. Andas he stares into the sky, there aretwice as many stars as usual. - Laura Gilpin

The living exist because of our sun. Its energy, fueled by the star’s brilliant fusion of hydrogen atoms into helium, provides undulating warmth and diurnal light to Earth. Life harvests energy to stave off entropic disorder, create activity and store it as chemical bonds.

One would think that over billions of years of evolution that selective pressure might give life a pro-sun adaptation. My friend Peter, a psychiatrist practicing in upstate Minnesota (latitude: 46 degrees N), feels like the best therapist ever each April, when many of his patients seemingly “feel better.” He then goes through his perennial realization, that of course, the sun is out and Seasonal Affective Disorder is a real thing. Yet we as contemporary humans, especially in Western societies, are a particularly sun-phobic culture, especially when it comes to ultraviolet (UV) radiation.

I rarely wear sunscreen, which blocks UV light from penetrating skin. I do when I am on vacation at the beach or on an open sunny hike. I know that by not using sunscreen I subject myself to some potential health risks including photoaging of skin, sunburn (erythema) and increased risk of skin cancer. These effects are mostly catalyzed by exposure to ultraviolet light.

The sunscreen market is robust, over $10B in 2020, with new brands, formulations and technologies being marketed constantly. My friend Justin’s company Junk Theory is developing some new SPF products. My friend Nina does a great overview of sunscreen in her newsletter, including the development of some living sunscreens, containing bacteriophage or microbes. Mary Schmich opens her viral commencement speech with “wear sunscreen.” Overall sunscreen is probably a good thing.

But there is growing evidence that decreased exposure to UV energy is increasing preventable health conditions including cardiovascular disease, autoimmune diseases (psoriasis and multiple sclerosis), myopia and cancer. A large 20 year prospective study on 25,000 Swedish women demonstrated a decrease in all-cause mortality that correlated with total sun exposure. A retrospective analysis of UK Biobank data showed a reduction in all-cause mortality with decreasing latitude, a proxy for UV intensity, across the UK.

It is rare to find anyone to decry the physician’s stance of “wear sunscreen when outdoors.” Have we taken it too far? Outside Magazine has published a slightly conspiratorial and inflammatory article, titled, “Is Sunscreen the New Margarine?” Despite common wisdom, does sun exposure, and more specifically UV exposure, possibly improve health outcomes? Can the immunosuppressive properties of UV be leveraged to improve health, despite the risk of developing skin cancer?

Ultraviolet Radiation

Emission spectrum from the sun, as it reaches the earth. Humans can see between 400 nm and 700 nm with infrared at greater wavelengths and ultraviolet at shorter wavelengths.

The earth receives roughly 1000 W/m21 of solar radiation. This is incredibly powerful; thermodynamically, at this rate, all of the US energy needs in one year (2023) can be fulfilled with just 3 hours of the sun’s full power. Solar radiation is broken up into different spectra, with around half of the total energy existing as long wavelength infrared radiation. Only 4% of the sun’s energy comprises UV, which is split into 95% UVA (320-400 nm), 4% UVB (280-320 nm) and almost no UVC (100-280 nm) reaches the earth’s surface.

The short wavelength radiation, such as UV, has higher energy, and accordingly more reactive potency and danger. Generally, UVA causes sunburns, UVB causes DNA damage and UVC can kill viruses. Higher energy X-rays have wavelengths of around 0.1-10 nm.

History of Therapeutic Uses of Ultraviolet Radiation (UVR)

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Mechanisms and system immunosuppressive effects of solar UVR mediated through skin

Skin based infections

One of the first documented uses of UVR in modern medicine was the high altitude sanatoriums that peppered 19th century Europe for what physicians at the time called heliotherapy, described by Thomas Mann in his novel, Magic Mountain. Niels Finsen was awarded the 1903 Nobel Prize in Medicine for the highly successful treatment of lupus vulgaris, a form of tuberculosis afflicting the skin.

Ultraviolet Blood Irradiation (UBI)

Shortly thereafter Emmett Knott discovered that after drawing blood from sick dogs with staph or strep infections, directly irradiating blood with UV2 and subsequently reinfusing the blood back to the dogs, he was able to completely eliminate the infections and cure the dogs3. In 1928, the first human patient was treated with UBI. A woman developed sepsis during an abortion procedure and made, after treatment, a miraculous recovery. UBI remained a frontline anti-infective treatment in the first half of the twentieth century, before the advent of penicillin made it soon obsolete. With the rise of drug resistant microbes some advocates have clamored for a return to the use of UBI to treat infections in modern times.

UV-B catalyzed formation of Vitamin D

Vitamin D is the most well known health consequence of exposure to UV light. It is a secosteroid, that is required for a variety of different health needs, most notably for proper bone health. Vitamin D insufficiency (VDI) was first linked to Rickets disease but now is a substantial health concern for other conditions. UV-B catalyzes 7-dehydroxycholesterol, stored in the skin, to form cholecaliciferol, which is further converted in the liver and kidney, to become the biologically active form of Vitamin D3 (calcitriol). UV-B seasonality, latitude, use of sunscreen and skin color4, can all have an impact on Vitamin D production in the skin. As a result government health agencies recommend dietary Vitamin D. Strangely, oral supplementation of Vitamin D in prospective placebo-controlled randomized clinical trails5, have failed to yield statistically significant health benefits in all-cause mortality, or in specific conditions. Still data exist demonstrating sufficient serum levels of 25(OH)D6 do correlate with positive health outcomes, begging the question:

Outside of bone health, is Vitamin D status more of a biomarker for sun, or UV-B, exposure, rather than an active molecule that promotes health benefits?

The answer is a resounding, I’m not sure. Dr. Bill Rigby7, a rheumatologist at Dartmouth, was a pioneer in understanding the immunological impact of Vitamin D8. His mechanistic work on Vitamin D, showed that calcitriol suppressed white blood cell activity9, but only once immune cells were activated and expressed Vitamin D Receptor (VDR). Their work has major implications in how Vitamin D may play a role in mitigating excessive inflammation in autoimmune disease.

UV-B impact on the immune response

There are other anti-inflammatory and immune suppressive effects that occur when skin is exposed to UV-B, both locally and systemically. It is presumed that immune modulation is mediated by an array of molecules other than Vitamin D, including nitric oxide10, urocanic acid and others. This forms the mechanistic basis for using phototherapy to treat skin autoimmune disease such as psoriasis and atopic dermatitis. Phototherapy for these indications are deployed at major research institutions including the Mayo Clinic and Cleveland Clinic. But the idea that UV light can induce a systemic immune change is harder for people to fathom.

COVID-19 and Cytokind

After COVID-19 ballooned into a pandemic and the world slowed to a grinding halt, many of us who worked in the life sciences wanted to help. Gus built and ran his own PCR test setup so we could rapidly and sensitively detect for COVID positivity, when drive through tests were scarce. Chris, at Augmenta, reached out to patients who were asymptomatically COVID positive, and profiled their immune responses to discover a therapeutic broadly neutralizing antibody to SARS-CoV-2 in eleven days.

Similarly my friend John MacMahon, a fellow Stanford ultimate player and BSIM runner, had sent me compelling data from COVID-19 patients in Wuhan. We noted the concordance between elevated cytokine levels in patients with severe COVID-19 illness with cytokine levels reduced by UV-B to ameliorate graft vs host disease. If UV-B could re-establish immune balance, as certain epidemiological studies posited, we hypothesized UV-B would be beneficial in treating severe COVID-19 illness11.

Elevated cytokine levels that correlated to ICU care in Wuhan 2020, alongside reduction in same cytokines after exposure to UV-B in GvHD models

To test this we formed a project called Cytokind. John is a serial medical device entrepreneur with expertise in cardiovascular disease and sat on the board of Luma Therapeutics, a psoriasis phototherapy company. John was and continues to be the heart of this project, uniting phototherapy experts, clinicians and OMICS specialists with the goal of running clinical studies to validate the promise of phototherapy.

In 2022, with Cytokind’s support, Co-PIs, Dr. Carmen Castilla and Dr. Frank Lau, ran a small randomized pilot study with 30 hospitalized COVID-19 positive patients, at Louisiana State University. Patients were exposed to UV-B for roughly five minutes per day for eight days and monitored for follow up over the next twenty eight days. Although the enrollment was too low to achieve statistical significance, the data were seductively suggestive of efficacy, with no adverse events, as 28-day mortality in the UV-B arm was reduced by 60%, compared with placebo. Furthermore, serum samples taken from patients at various time points, demonstrated a statistically significant, rapid decrease in cytokine levels associated with disease severity. More follow up is required to prove and uncover the mechanism of efficacy of UV-B in COVID-19.

Unfortunately, while Cytokind’s results were promising, the developments of COVID-19 mRNA vaccines, paxlovid and better medical protocols obviated the need for UV-B in the context of COVID-19, much like penicillin elbowing out UBI.

Multiple Sclerosis

Cytokind changed course towards applying what we learned in COVID to multiple sclerosis (MS). MS is a progressive, neurodegenerative disease, where the “insulation” of neurons (myelin) is destroyed by autoimmunity. Untreated, patients experience fatigue, reduced mobility and terrible flares of numbness, pain and blindness. The etiology of MS has been proven to be correlated to Epstein-Barr virus infections, though there are other alternative hypotheses as well. MS affects roughly 1,000,000 in the United States with women affected more than men by almost four to one.

MS also exhibits a strong latitudinal effect, where incidence rates are highest in the northeast of the US. Based on this observation, in a first of its kind, small phototherapy trial for MS in Australia, Dr. Prue Hart demonstrated a provocative result that progression of MS can be slowed with exposure to low levels of UV-B, and that the effect of UV-B was long lasting, enduring months after cessation of phototherapy. Based on these data, Cytokind is now seeking to run a highly powered, at home study of phototherapy for MS patients.

Treatment of other conditions

Excavating a mechanistic condition understanding of light therapy has the potential to unlock, low cost, highly scalable treatments. I mean the sun is free!12 Like the field of immuno-oncology, we harbor solutions for our own immune maladies, skin deep, with a tan. The literature, while sparse, is suggestive, that immune modulation through phototherapy could be beneficial for those suffering from infertility, Alzheimer’s Disease, chronic regional pain syndrome, myalgic encephalomyelitis chronic fatigues syndrome, and more. Further laboratory and clinical studies will be needed.

Immunity, society and women

One last point: I am frustrated by the anti-women bias, among other biases, that is pervasive in medical systems. Women, by far, suffer more from autoimmune and rheumatological conditions13, compared with men. Pregnancy is one of the coolest and most significantly immune modulating events that a human being can experience, but it brings with it harrowing, immune mediated challenges of preeclampsia, polycystic ovarian syndrome, endometriosis and more. We must honor our mothers more.

Yet most of our clinical work and science has been done on men and by men. Our healthcare system is consistently oblivious to the plight of women writ large, with limited solutions for MS, systemic lupus erythmatosus and other conditions that primarily affect women. What if there were women conducting and designing these experiments instead?

The story of the sun and phototherapy is a story of women. It’s Athena over Apollo. The modern pioneers of the science of UV, its role in carcinogenesis, immunosuppression and phototherapy are the following amazing women and others:

• Dr. Prue Hart, professor at Telethon Kids, whom I have already mentioned above. She is such a badass and a close collaborator with Cytokind.

• Dr. Mary Norval14, emeritus professor at University of Edinburgh; cool presentation

• Dr. Margaret Kripke, emeritus professor and first chair of immunology at MD Anderson; she presents a cool talk about environmental drivers of cancer

As we continue to uncover the science, the history, the athletic femininity and the possibilities of phototherapy, I hope we can unchain their gift of the sun. The free and abundant life giving resource, that they offer to all of us to edify our human lives.

Here comes the sun…