AI, mRNA, Cancer Vaccines and "Stargate"

Reality check. Curb your enthusiasm, and beware of grifters.

Yes, I know that is actually Grok drawing an assembled DNA strand and a “Stargate”. I tried and tried, but Grok just could not understand what mRNA structure looks like, and does not know the difference between DNA and mRNA. Which tells you something about “Artificial Intelligence.”

The image below is closer to the structure of messenger RNA (mRNA) - in water, without being bound to positively charged fats (cationic lipids):

Visualization of two example UFold RNA secondary structure predictions. From top to bottom: ground truth, UFold prediction, and E2Efold prediction. Two RNA sequences are (A) Aspergillus fumigatus species, the RNA ID is GSP-41122, as recorded in SRPDB database. and (B) Alphaproteobacteria subfamily 16S rRNA sequence whose database ID is U13162, as recorded in RNAStralign database. Citation link here.

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“Stargate” program for mRNA cancer vaccines.

Here they go again. Really? Is this the narrative you would want to push two days into your second term as President of the USA?

Calling Susie Wiles, press room, STAT, we have an emergency narrative control problem ….

I can’t believe that we are being spoon-fed this hype from the likes of Oracle’s Larry Ellison so soon after the inauguration. Having this guy lecture us on mRNA vaccines for cancer is over the top. And apparently the prior propaganda reference to “Star Trek” (operation warp speed) is no longer effective, and we need something bigger, more potent. Something else out of science fiction television that evokes yet another trendy topic -“unidentified aerial phenomena” (UAP). “Stargate”. Perfect. What could possibly go wrong? Marketing genius.

This all makes me throw up a bit in my throat.

This is so amazingly (and dangerously) naive that I can hardly believe I am hearing it. I do not even know where to start. I am dumbfounded. The simplest summary is that this is clear-cut grifting. Precisely what I was afraid of when Bill Gates triumphantly announced his having met with President Trump.

We thought, we hoped, that President Trump had learned from the past, but this is not looking good.

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Regarding AI-driven rapid development of universal genetic vaccines

I could write a long essay on the complex molecular immunology of antigen processing and presentation via Class I and Class II Major Histocompatibility Complex proteins, and the diversity of MHC in the (outbred) human species, but most readers would clock out, and those that could really understand it already know all about this. I am quite confident that Larry Ellison does not, and also confident that Larry Ellison is yet another tech bro who does not let his ignorance get in the way of promoting his opinions. Why is it that so many successful Silicon Valley leaders think that their success in the IT space translates directly into broad expertise in other areas? And why do politicians and “public health officials” keep allowing themselves to be influenced by these poseurs? Is it just about the money?

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Regarding Cancer Immunology and universal cancer vaccine development

Not only is antigen processing and presentation complicated, but cancer immunology is even more so. Where to begin?

Here is a highly abbreviated and simplified introduction, which Wikipedia thinks is too complicated for most to understand!

Bottom line- to a significant extent, cancer is a disease of failure of an individual’s immune system to recognize and stop the growth of cells from your own body that have evolved, under the pressure of your immune system, to escape immune surveillance. Cancer is a multi-step process. One way to think about this is that many cancers represent the consequence of a series of mutations which confer various properties like unrestricted growth, ability to migrate to other places in the body, and most importantly abilities to develop immune tolerance - to escape the ability of the immune system to recognize and eliminate them.

As if that was not complicated enough, humans (unlike inbred mice) are highly diverse in the fundamental genetics of immune response - they have a lot of diversity in their major histocompatibility molecules, among others. So, if you were able to develop a cancer vaccine for one person, it is highly unlikely to work for another person, because their ability to process and recognize tumor antigens would be different.

The most gentle thing I can say about all of this is that the idea that one could sequence the genome of a cancer cell and based on that (within 48 hours!) develop a universal cancer vaccine for that type of tumor is profoundly naive. This pitch would not survive five minutes of scrutiny by any Torrey Pines, Boston, or Silicon Valley venture capital firm that I have ever presented a business plan to. Researchers have been investigating and pitching the idea of tumor sequencing leading to cancer genetic vaccine development ever since the idea of gene therapy first arose in the 1970s. This type of simplistic thinking was outdated decades ago! The problem is not how to manufacture an mRNA or DNA (or viral vectored) vaccine. It is not something that we can apply Artificial Intelligence to in order to more rapidly design a genetic vaccine. The problem is that we do not really understand how to circumvent fundamental problems associated with cancer immunology.

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Regarding Government “Big Science Programs” choosing Winners and Losers

Beyond the cancer biology and immunology, and putting aside the current problems with mRNA vaccine technology, there is a deeper issue here. This involves corporatism - in other words “public-private partnerships”, and the government essentially choosing scientific winners and losers. What is being proposed is not pro-innovation. It is not pro-science. This is pro- big business. This is an example of precisely what we do not need to do if we are to promote innovation and “Make America Great Again”. The role of limited government in a situation like this should be to act to insure the purity (lack of adulteration), identity (is the product what it claims to be), safety and effectiveness of any medical products that emerge from private entrepreneurship. The role of government should not be to specifically sponsor and partner with big business (or NGO) to push one solution over another - no matter how “sexy” or “trendy” the name, concept or buzzwords. Unlike biodefense, the cancer market is huge. It does not require government subsidy.

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Regarding “Business Development” and “Capture” involving the US Government

I have been formally trained (by some of the best beltway bandit types) in Federal “Business Development” and “Capture Management”. The key that unlocks the door to big funding is to figure out the pain point of the government official that controls the funding, and then develop and offer them a solution that will resolve their pain. This can be done in a sincere way, seeking to craft and offer the best possible solution to the customer, or it can be done in an unscrupulous way, by offering the solution the customer wants to hear but which may not actually work or otherwise solve the problem. I have been very successful as a “Capture Manager” because of my scientific credibility, history of innovation, and personal integrity. I would not pitch solutions that I did not believe in. However, if the customer is naive, the easy sell is to pitch what they want to hear as a sort of partnership. That way, the customer “owns” and has to take responsibility for the outcome, and if things don’t work out they have an incentive to sweep the failure under the rug.

Just the way things are inside the beltway.

In contrast, if you sell a solution to General Motors that does not work, they lose car sales, and you lose a customer. Very different dynamic.

In my opinion, what we seem to have here is a salesman - Larry Ellison - having successfully pitched a naive government customer - President Trump - outdated ideas and technology wrapped in sexy new words and concepts - “Artificial Intelligence”, and “mRNA vaccine”. Trump wants the USA to be #1 in Artificial Intelligence - that is his “pain point”. And he has a sense of personal achievement and investment in the mRNA platform consequent to Operation Warp Speed. And then you have the failed Biden cancer “moonshot” initiative. Which I am confident President Trump would love to best. Put those three elements together and you have a winning pitch for a multi-billion dollar federal program.

Which I predict will be an abysmal failure. Hopefully I will be proven wrong, because who doesn’t want universal cancer vaccines. Just like who doesn’t want a universal influenza vaccine. But wanting something does not necessarily make it a good use of taxpayer dollars, or make for good stewardship of government resources. There are many unmet needs that those resources might be applied towards. The question is, in what we hope will be an era of fiscal restraint, is this program the best use of these billions of dollars?

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Regarding innovation in mRNA or other vaccine technologies

I am occasionally asked if the current generation mRNA vaccination technology could be made safe. My standard response is that pigs might be able to fly if they only had wings. My point is that anything is theoretically possible. It might be possible to come up with an mRNA delivery platform that lacks the problems and disadvantages of the cationic lipid nanoparticle-based system currently being used. And to address the issues of the side effects of pseudouridine. And.. and .. and.

Scientific innovation is good. But it generally requires hard work, is time consuming, and generally is high risk. Occasionally some young buck comes up with a simple revolutionary game changer. But those are few, far between, and hard to predict. Black swans.

The risks associated with infectious diseases are generally overstated. The human immune system has been dealing with infectious diseases during the entire course of human evolution, basically fighting off the threat to a standoff. Much of the neanderthal DNA that persists in the general population involves those very major histocompatibility complex molecules that are so critical to managing antigen presentation and immune responses.

Many of the risks associated with cancer can be traced back to environmental toxins, lifestyle, obesity, and dietary factors. In my opinion, we are highly unlikely to discover some universal magic bullet vaccine or therapeutic for treating or preventing cancer. What we can do, with a high probability of success and measurable improvements in public health, is to do “The Science” (tm) necessary to better understand these things, and to accurately and succinctly convey that information to the public.

That is how we should be spending public funds. Not on bankrolling some new “cancer moonshot” program named after a science fiction TV program, and based on outdated ideas that have been on the table and (largely unsuccessfully) explored for decades.

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