There is a recent medical advance that you may not have heard about unless you are a healthcare professional or encountered it from the patient side – CAR-T cell therapy. A recent study shows the potential for continued incremental advance of this technology, but already it is a powerful treatment.

Like all technologies, the roots go back pretty far. It was first discovered that immune cells protect against cancer in 1960. In 1986 tumor-infiltrating lymphocytes were used to attack cancer cells. In 1993 the first generation of genetically modified T-cells using the chimeric antigen receptor (CAR) technique was developed. This technique fuses the business end of an antibody to a receptor on a T-cell (hence a chimera) which potentially targets that T-cell against whatever antigen the antibody targets. So you can make antibodies against a protein unique to a specific type of cancer, then fuse part of that antibody to T-cell receptors, put those T-cells back into the patient and they will potentially attack the cancer cells. This first generation CAR-T cells were not effective clinically because they did not survive long enough in the body to work.

In 1998 it was discovered that adding a costimulatory domain (CD28) to the CAR allowed it to persist longer in the body, creating the potential for clinical treatment. In 2002 this technique was used to develop second generation CAR-T cells that were shown for the first time to fight cancer in mice (the first study was of prostate cancer). Then in 2003 CAR-T cells using CD19 instead of CD28 were developed, and found to be more effective. In 2013 the first clinical trial in humans showing efficacy of CAR-T therapy in cancer (leukemia) was published, starting the era of using CAR-T therapy in treating blood cancers. The first CAR-T base treatment was approved by the FDA in 2017.

Over the last 8 years CAR-T therapy has become standard treatment for blood-born cancers (lymphoma and acute lymphoblastic leukemia). T-cells are taken from patients with cancer, they are then genetically modified into CAR-T cells, reproduced to make lots of them, and then given back to the patient to fight their cancer. In the last decade scientific advance has continued, with research targeting other proteins to potentially fight solid tumors. In 2017 scientists starting using CRISPR technology to make their CAR-T cells allowing greater control and improved function.

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Japan is planning on releasing treated radioactive water from the Fukushima nuclear accident into the ocean. They claim this will be completely safe, but there are protests going on in both Japan and South Korea, and China has just placed a ban on seafood from Japan. In a perfect world we would just have a calm and transparent discussion about the relevant scientific facts, make a reasonable decision, and go forward without any drama. But of course that is not the world we live in. But let’s pretend it is – what are the relevant facts?

In 2011 a tsunami (and poor safety decisions) caused several reactors at the Fukushima Daichi nuclear power plant to melt down. These reactors were flooded with water to cool them, but heat from continued radioactive decay means they need to be continuously cooled. The water used has become contaminated with 64 different radioactive isotopes. In the past 12 years 350 million gallons of contaminated water has been stored in over 1,000 tanks on site, but they are simply running out of room, which is why there is urgency to do something with the stored contaminated water. How unsafe is this water?

Over the last 12 years the short half-life isotopes have lost most of their radioactivity, but there are still some long half-life isotopes. This is good because the shorter the half-life the more intense the radioactivity per mass, by definition. Really long half-life isotopes, like carbon-14 (half-life 5,000 years), have much lower intensity. Also, the contaminated water as been treated with several processes, such as filtration and sedimentation. Most of the remaining radioactive isotopes have been removed (to levels below acceptable limits) by this process, although carbon-14 and tritium remain.  How much radioactivity is left in this contaminated but treated water? That is the key question.

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Decades of complex research and persevering through repeated disappointment appears to be finally paying off for the diagnosis and treatment of Alzheimer’s  disease (AD). In 2021 Aduhelm was the first drug approved by the FDA (granted contingent accelerated approval) that is potentially disease-modifying in AD. This year two additional drugs received FDA approval. All three drugs are monoclonal antibodies that target amyloid protein. They each seem to have overall modest clinical effect, but they are the first drugs to actually slow down progression of AD, which represents important confirmation of the amyloid hypothesis. Until now attempts at slowing down the disease by targeting amyloid have failed.

Three drugs in as many years is no coincidence – this is the result of decades of research into a very complex disease, combined with monoclonal antibody technology coming into its own as a therapeutic option. AD is a form of dementia, a chronic degenerative disease of the brain that causes the slow loss of cognitive function and memory over years. There are over 6 million people in the US alone with AD, and it represents a massive health care burden. More than 10% of the population over 65 have AD.

The probable reason we have rapidly crossed over the threshold to detectable clinical effect is attributed by experts to two main factors – treating people earlier in the disease, and giving a more aggressive treatment (essentially pushing dosing to a higher level). The higher dosing comes with a downside of significant side effects, including brain swelling and bleeding. But that it what it took to show even a modest clinical benefit. But the fact that three drugs, which target different aspects of amyloid protein, show promising or demonstrated clinical benefit helps confirm that the amyloid protein and the plaques they form in the brain are, to some extend driving AD. They are not just a marker for brain cell damage, they are at least partly responsible for that damage. Until now, this was not clear.

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Despite robust efforts to fight it, malaria remains one of the most significant infectious diseases affecting humans. According to UNICEF – ” In 2021, there were 247 million malaria cases globally that led to 619,000 deaths in total. Of these deaths, 77 per cent were children under 5 years of age.” Efforts to minimize malaria cost about $7 billion per year, through vaccination, drug therapy, and spraying pesticides to kill the mosquitos that carry the disease. Mosquito populations are developing resistance to the pesticides, however, which could raise the costs of control, while available funds can fluctuate.

One potential solution is using genetic engineering to fight malaria, and there are several approaches being developed that are close to being ready for deployment. They all use an approach known as a gene drive, which causes a desired trait to spread more quickly through a population than regular Mendelian genetics would allow. This idea is actually 60 years old, but newer techniques, such as CRISPR, are making it much easier and more powerful.

With sexual reproduction, each offspring has two sets of chromosomes, one from each parent. So organisms have two copies of each gene (each copy is called an allele). They then pass one of their two copies onto each offspring. Mendelian genetics assumes that there is a 50% chance for each allele to be inherited, and this is mostly true. The gene drive phenomenon refers to situations in which one allele has an advantage over the other, so it is more likely to be inherited. There are naturally occurring gene drives, but we’re going to focus on the latest synthetic gene drive, which involves CRISPR.

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RFK Jr., who is now running for the Democratic presidential nomination, is anti-vaccine. He will vehemently deny this, but I don’t buy it for a second. He is simply playing the, “I’m not anti-vaccine, I am pro-safe vaccine” gambit, which is disingenuous and always has been. We have been covering this topic for years, and David Gorski did a recent excellent review of this at SBM. You can’t claim not to be anti-vaccine, and then defend a long list of anti-vaccine tropes.

RFK has apparently been avoiding his views on vaccines on the campaign trail, but it always seems to come up. On the Joe Rogan podcast RFK found what he must have thought was a friendly environment, and felt free to repeat is claim that vaccine cause autism. This is a topic I have been covering for two decades – vaccines do not cause autism. But let’s do a quick review of this harmful claim.

This first appeared in the 1990, when the anti-vaccine movement hit upon the increase in autism diagnoses as a new tactic. They start with the assumption that all bad things that happen to children are caused by vaccines, so obviously they must also be causing the rise in autism. When Andrew Wakefield came out with his fraudulent and now retracted study claiming an association between the MMR vaccine and autism, he became an instant celebrity of the anti-vaccine movement. Trouble is – the MMR vaccine does not cause autism. Wakefield, it turns out, had a patent on an alternative vaccine and was trying to torpedo the competition. But the anti-vaccine movement does not let science, evidence, or basic logic get in their way. So they simply moved over to a vaccine ingredient, thimerosal, which is a mercury-based preservative.

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In my last post I noted that even mentioning general vague support for the LGBTQ community was enough to trigger very specific feedback, often making erroneous scientific claims. Each claim requires a deep dive and article-length discussion. Even though the discussion that followed in the comments was better than I thought it would be, it still filled with additional dubious claims. I suspect there are two main reasons for this. The first is that the topic of gender identity is complex and not intuitive. It may feel intuitive, as if your immediate gut reaction is all that is necessary to deal adequately with the topic, but it really isn’t. Ultimate this topic deals with how our brains construct our own sense of self, identity, and reality. These are always tricky concepts to deal with – and as I have pointed out before in other contexts, our brain constructs are counterintuitive by their very nature. In other words, our brains evolved for these constructs to feel real and automatic, and for the subconscious processes that create them to be invisible to us.

Second, the issue of gender identity has been highly politicized. This has resulted in any discussion of the topic being flooded with biased and deliberate misinformation. The usual FUD (fear, uncertainty doubt) strategies apply. And of course – science is hard. Even seemingly straightforward questions are actually quite complex. This makes it easy to create confusion by “just asking questions” or selectively applying skepticism.

One question at the heart of the trans issue is this – what is the rate of regret or even detransitioning after medical transition? One narrative is that adolescents (often conflated with “children”) are being prematurely herded down a road to transition, which they later regret. The other narrative is that, generally speaking, making the decision to transition is taken very seriously, with very low levels of later regret. Which is true?

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Yesterday’s post was the first in an exchange about the effects of climate change on public health. Today’s post is my response.

Part II

Climate change is a critically important topic for society today, and it’s important that the public have a working knowledge of the facts, causes, effects, and potential interventions regarding climate change, so I am always happy to discuss the topic. Unfortunately, it’s a very complex topic that has been highly politicized and polarized. The science often becomes wrapped up in ideology – the best indication of this is that one’s political affiliation is the strongest predictor of the public’s opinions regarding climate change. The media, as they do in general, is happy to sensationalize the topic and often does not provide good context or background. Scientists have gotten better communicating about climate change, but not enough to override political affiliation.

My sense is the core issue is that the complexity of climate change allows everyone to cherry pick those details that fit their narrative. You can find examples to support whatever narrative you want to believe. You don’t even have to be factually incorrect (although many people certainly are), you just have to be selective in your details and interpretation. Climate change is a Rorschach test of subjective validation and confirmation bias.

I say this all because I think Scott’s narrative comes through very clearly. He contacted me asking fervently for a debate on this specific topic, the health effects of climate change. I thought this was a little odd since I have never written or expressed an opinion about this topic before. It seems he assumed what my position was based on other things I have written about climate change – that I think it’s real, it is primarily being caused by humans, and the effects are likely to be bad for the environment and human civilization. This brings up another aspect of the climate change debate, that people generally take sides and think that everyone fits relatively cleanly into the “for or against” side. Once someone thinks they have detected what side you are on, they then ascribe the entire package of views to you.

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This is the first entry in an exchange between me and Scott Hastings, who requested the exchange. This is his opening arguments. My response will be tomorrow’s post.

Part I:

Hi Steven, first of all, I am tremendously grateful to you for taking time to engage with me on this very important topic. Thank you.

I’d like to start by sharing just a few media articles I found that are now over 3 years old:

New York Times: November 13, 2019 “Climate Change Poses Threats to Children’s Health Worldwide”

ABC News Australia: November 5, 2019 “11,000 scientists declare climate emergency warning world faces catastrophic threat”

CNN: November 12, 2019 “The climate crisis will profoundly affect the health of every child alive today,”

Wired: November 13, 2019 “How the Climate Crisis Is Killing Us, in 9 Alarming Charts, A new report from over 100 experts paints a devastating picture of how climate change is already imperiling human health.”

We are both physicians, so I don’t want to leave out the American Medical Association statement on climate change.

I think you get the point…We are daily inundated with a “climate emergency” just around the corner.  It also seems that all the experts (at least 97% anyway) are in some general agreement about the “devastating catastrophe” lurking somewhere out there. However, the official IPCC-5 report seems to be a whole lot less confident than the headlines mentioned above.

My aim is to take exact verbiage from IPCC-5, then apply the most up to date scientific literature available to cross-check their stated claims. Since I’m a physician, I am specifically interested in health outcomes as a result of climate change. I am looking at global health trends (since this is a global phenomena), as well as trends in global natural events like floods, fires, and hurricanes as these obviously contribute to health outcomes.  It’s simple really, in our world of experts, nobody needs to be an expert at opening the newspaper the morning after the superbowl to see who won the game. In this case, the “newspaper” is going to be scientific research literature based on global observational trends from generally that was published in the past 6 years. What I will not include is modeling studies. That’s like trying to predict who is going to win the superbowl. I’m not interested in that.  Just real-world objective observations found on google scholar or pubmed. I’m only interested in who won the superbowl, not in some supposed “superbowl prediction expert”.

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Some ideas never seem to die. There is something compelling about the narrative, perhaps because it fills some explanatory need. One of those narratives is that “they” have “the cure” to cancer but are keeping it hidden from the public in order to protect the profits that result from cancer treatment. I recently received the following e-mail (partly redacted):

“I read many articles by physicians like yourself that claim secrets cannot be kept about cancer cures.  I beg to differ.

Pharmaceutical firms require their associates to sign confidentiality agreements as a condition of employment.  If they breach it, it’s safe to assume that they risk grave consequences for doing so.

These companies could care less about sick people.  They only care about the health of their bottom line.  They make far more profit on lifetime treatments rather than one-shot cures.  After the patent expiration on a cure, the steady stream of revenue comes to a halt.

A cure eliminates the need for any new drug development unless the side effects are unpalatable.  I was even told as much by a retired employee of a pharmaceutical company.  She saw the private memos from their lobbyists.

In any case, the confidentiality contracts are why secrets are kept in the pharmaceutical industry.  It’s also why cancer cures can be kept hidden as it would be treated as a trade secret.  No one wants to be brought up on a felony charge of industrial espionage.  Nor do they wish to be sued for it by their former employer.

Ask yourself the following question: would you risk your family’s future under those circumstances?  No way!  If you signed one of those legal instruments, you would never divulge such information if you came across it.”

The notion that a pharmaceutical company could hide a cancer cure is, in my opinion, and from the perspective of an academic physician who has participated in clinical research for pharmaceutical companies, hopelessly naive. The belief comes partly from looking into a complex system from the outside, without any real idea how it actually works.  First let’s talk about the science and then we’ll turn to the logistics of the conspiracy itself.

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As many experts predicted, the COVID-19 pandemic is slowly sliding into an endemic infection. A pandemic is essentially when an epidemic goes worldwide. Endemic means that an infection is here to stay. It is no longer considered an “outbreak” but is constantly spreading around a population without having to be introduced. The flu, for example, is endemic, although it is also seasonal. Measles was endemic in the US, but then was eliminated through vaccination and was reduced to isolated outbreaks. However, it is transitioning to being endemic again because of vaccine hesitancy.

While we are all anxious for the COVID-19 pandemic to be over, I don’t remember any expert claiming that the virus would go away, or be eliminated to any significant degree. Rather, it would simply become like the flu, an endemic simmering infection that becomes part of the background. The only question has been – what is the best path to transition from pandemic to endemic? Some argued that perhaps the best path was to simply let the pandemic run its course, and create immunity through natural infection. This has always been an unscientific and dangerous suggestion, because that path leads through a maximum of disease and death.

The evidence clearly shows that the best path to minimizing COVID while ending its pandemic status was through a combination of vaccination and infection. We have no choice about the infection part because there is no plausible way to reduce it to zero (as China discovered). But we do want to reduce the spread of COVID, especially to vulnerable populations, while reducing the risk of serious illness, hospitalization and death through vaccination. Pandemics always eventually burn themselves out, even in the pre-vaccination era, but we don’t want that to happen from a plague-level decimation.

Evidence has been building that the best immunity from COVID is through hybrid immunity – a combination of vaccination and breakthrough infection. I managed to go two years without getting COVID, for example, but eventually succumbed once mask-wearing no longer became commonplace. However, by that time I had been fully vaccinated and boosted, so when I did get COVID it was indistinguishable from a fairly mild cold. If there weren’t a pandemic (and I didn’t test positive) I would have just thought I had a summer cold. Hybrid immunity works either way, whether you were infected then vaccinated, or vaccinated and then contracted COVID (the preferred order).  Continue Reading »