For more info about microRNAs, here is the review I wrote about microRNA Therapeutics:
http://www.nature.com/gt/journal/v18/n12/full/gt201150a.html

Hope it is helpful.

I try to be careful not to call non-replicative adeno gene therapies “viruses” (because they aren’t). In this case I was incorrectly overcareful. Or something.

Humanities? I’ll top you. I was a fine arts major. What’s a molecule?

You’re totally right, I had forgotten the part about the virus having expanded tropism. Yes, that would make it more dangerous. I guess inclusion of the miR122 targets is a theoretical risk too. My point was that in wt adenovirus E1A is expressed under a nonspecific promoter, so using a specific promoter + miRNA target to restrict that expression to a subset of cells is really just making an attenuated virus. So the virus isn’t engineered to be more lethal in cells with active CgA promoters, it’s engineered to be less lethal in cells that don’t have active CgA promoters.

Going back to the pointless nomenclature debate, you call this virus a “vector.” Do you really think of it this way? That’s fine if you do, but it’s just really different than how I think about it. To me, this is a modified pathogen. Some gene therapy vectors are modified pathogens too, but they’re modified to minimize pathogenicity. This is a pathogen modified to target and (as you correctly point out) enhance pathogenicity. It’s the opposite of gene therapy.

I disagree strongly that wild type adeno provides an upper bound on the potential toxicity. As was described by Dr. Gorski, this virus is engineered to be lethal to cells with an active CgA promoter, and it’s also engineered to improve its ability to infect cells that wild type adeno normally wouldn’t. Then there’s the inclusion of the miR122 targets. That’s a nice idea, but how well will it work in humans? I’d bet there’s still an awful lot we don’t know about how micro-RNAs normally work, much less what might happen in a case like this.

To be clear, I’m not suggesting that Essand’s vector is necessarily high risk. I’m just saying that we should not assume the risks are trivial (as Masters implied).

I fully concede that arguing whether oncolytic viruses should be considered gene therapy or not is like arguing whether Greenland should be a continent or not, i.e. kind of pointless. I respect your position, but to me there is still an important distinction there.

As far as Jesse Gelsinger goes, it’s true that it was a non-replicating virus, but what killed him was the immune response to virus administered through his bloodstream, i.e. to his whole body. So it wasn’t that the virus behaved unexpectedly, it was that his body reacted unexpectedly. Anyway, the only point I was trying to make was that your post implied that Essand’s virus might be more dangerous or unpredictable than other adenoviruses, but ultimately Essand’s virus is still a form of attenuated virus. If anything, wild-type adenovirus would place an upper bound on how dangerous Essand’s virus could be, so obviously safety testing is required, but it’s not like they would be starting from scratch.

I worked in gene therapy as well, for about 8 years. Non-viral rather than viral, FWIW. We suffered through some of the fallout when Gelsinger died, though not nearly as much as everyone who was working with adenoviral vectors.

I agree that Essand’s virus is distinct from ‘true’ gene therapy, but the fact remains that adenoviral vectors have been tried for a lot of applications in clinical trials, both as true gene therapies and as anti-cancer oncolytics, so the comparison is still apt IMO.

The vector Gelsinger received was a non-replicative, ‘true’ adenoviral gene therapy, BTW. I assume you know that, but others may not. Yet even though it was non-replicative, it still killed him, reinforcing the point that we cannot assume adenoviral vectors are innocuous. Most of the time they are, but I find Masters’ willingness to just ignore the risks either extremely naive or very disturbing. Even when we consider that potential patients might well be terminal, that doesn’t make it OK to hand-wave away real concerns about risk.

Also, as far as oncolytic viruses falling out of favor, I agree that Jesse Gelsinger had something to do with it, but I don’t think his death was the main factor. I think the ineffectiveness of the approach was the main factor. I remember there was huge excitement about Onyx-015, an oncolytic adenovirus, in the initial trials, but the whole thing fizzled because it ultimately didn’t lead to significant increases in survival. I’m not sure why, and I’m sure Dr. Gorski could provide a lot more insight into this, but my speculation is that it’s because most cancers are deadly only when they metastasize, and it’s probably impossible to fill a person’s body full of enough virus to infect every cell in their body without killing them. So oncolytic viruses would be most promising for primary tumors that are deadly even if they don’t spread (e.g. brain tumors), and even in those cases the virus isn’t going to infect every cell, so the tumor is likely to grow back.

As far as gene therapy goes in general, the European equivalent of the FDA is about to approve Glybera, an AAV-based treatment for lipoprotein lipase deficiency, so that will be the first gene therapy treatment to gain regulatory approval in the Western world. So while Dr. Gorski is probably right that “gene therapy” approaches for cancer have fallen in popularity, that’s not true in general.

The difficulty with Magnus’s virus is not that it is outre, but that it is not outre enough. It is a modified version of an adenovirus, which is known to be safe in humans.

Yes, plain old adenovirus is quite innocuous in humans. But this is a modified adenovirus, engineered to be a gene therapy vector that kills cancer cells. Cells that are almost identical to normal cells in almost every way. And as Dr. Gorski points out, we know from the Gelsinger case that adenoviral gene therapy vectors are NOT necessarily safe.

Moreover, Essand has engineered multiple new ‘tricks’ into this one. That makes it MUCH harder to predict how it will behave in humans – both whether it will be safe and whether it will be effective.

Masters really misses the boat on this. The difficulty with Essand’s virus is not that it’s too mundane and safe. The difficulties are that gene therapies have not shown much promise for cancer in the clinic, it involves several new approached that haven’t been tested in humans (so far as I know), it hasn’t been thoroughly studied in animals, and it’s one of hundreds (if not thousands) of promising ideas that are all competing for limited resources.

What costs the £1 million (less than two per cent of the price of Francis Bacon’s Triptych 1976) that Magnus needs to bring this medicine to patients is not the production, but the health-and-safety paperwork to get the trials started.

Here Masters makes it sound like a million pounds of nothing but paperwork. What he seems to be denigrating is a huge amount of essential effort to assure things like adequate safety of the virus in animals. And to ensure that the viral construct is really what it’s supposed to be And that it can be made reproducibly in a manner that’s consistent with clinical use. And yes, there’s a lot of paperwork involved, but it’s paperwork that’s essential to document all those assurance studies and ensure that IF this vector ever gets tested in patients, it has the best chance to work and we all have the best chance to learn from the results. Anything less is an insult to and an assault on the patients who might receive it.

Trivia, but this was too funny: “… I came across a blog about a quack in Mexico who had an idea about using sub-molecular particles – nanotechnology.” If you some of you folks are so good you can construct nanos straight from the fermions, let’s hear more, either now, or when you Nobel next year.
Maybe they are from bosons instead.

In another widely dispersed cancer story from mid-july, every little rag reported on a prostate treatment using radioactive gold, that homes to the cancer by virtue of “a compound from tea leaves”, that had just been tried in mice. (Woo, that’s sooo cooool. Well, not really.) The same week NCI cancer bulletin (and PNAS) reported on a trick that was way cooler, and in human trials already. It’s a new drug, G202, that homes to a protein called PSMA on the cell’s surface, by design, and PSMA itself then cleaves G202 (PSMA is a protease, and is being leveraged) to release a toxic compound (an analog of thapsigargin, originally from plants in genus Thapsia). Without being specifically cleaved, G202 isn’t toxic. Incredibly tricky. The radioactive gold is spraying decay products all over the place by comparison. One got tons of lay press, the more mature and fascinating research got none. The tea+gold stories in lay press did get some criticism: Derek Raghavan was sometimes quoted in the stories as saying the researchers were head-line hunting. Yup.

Personally i’m happy with the intricate details. Without intending to sound arrogant, the quote you display is pretty easily intelligible to anyone with a 1st year university-level grounding in molecular biology. It’s hardly unnecessary knowledge.

Additionally, I think the personal context Dr. Gorski adds is a good thing, given it provides evidence of relevant experience. And the knowledge that even the most educated among us can stake our hopes on theories and avenues of investigation that ultimately prove much less than hoped.

Note the title: “Is shameless self-promotion of your science a good idea?”

Note several citations of yourself and/or your own science to support your claims:

“a pesticide salesman named Jim Tassano sold DCA bought from chemical companies”
“Sometimes, as I recently discussed, these pitches are no more than overselling results in university and medical journal press releases.”
“what is reported in the news about science and the actual science itself are sometimes related solely by coincidence.”
“(I’ve even published a couple of papers on microRNAs.)” [No links provided—you are both Gorski D and Gorski DH in PubMed, yes?]
“(hopefully you will remember my deconstruction of this article)”
last paragraph: “In fact, my primary research interest for a long time was antiangiogenic therapy, and I had high hopes for it. Now, having come down to earth based on clinical studies done over the last 15 years, I’m a lot more skeptical of the sorts of treatments touted by someone like Masters.”

Also, is it because you are a scientist that you frequently offer intricate, yet perhaps unnecessary, details? I thought SBM.org was written mostly for lay readers, but you sound as though you are chatting with colleagues when you write things like:

Although his methods for adding the Tat-PTD to adenoviral vectors re described in this paper, in which Prof. Essand reports the construction of Ad5-PTD vectors, I haven’t been able to find a paper reporting the construction of Ad5[CgA-E1A-miR122]PTD or a paper showing its efficacy against xenograft models of neuroendocrine cancers, although I have found a paper in which Prof. Essand fiddled with his vector some more by adding somatostatin motifs that bind to somatostatin receptors expressed by neuroendocrine cancers, comparing his previous vector Ad5[CgA-E1A-miR122] to his new, improved, more somatostatin-y virus Ad5fkFWKT[CgA-E1A-miR122] in tissue culture for their ability to infect neuroendocrine cancer cells.

Granted, explanatory links are provided, but a 103-word sentence like that can be daunting to us mere mortals. You could eliminate this display of your knowledge and still have a fabulous post.

Anyway, I am certainly not telling you how you should write your posts—please continue with the awesomeness—I am merely wondering about the irony.

A minor point — Gerson never advised pancreatic enzymes for cancer as per the trophoblastic theory. That was the dentist, William Kelley, then Dr Nicholas Gonzales.

I suppose Big Pharm does look for easier profit than can be obtained from complicated, expensive and potentially risky treatments for rare cancers. The notion that anyone on earth would want to suppress an effective cancer treatment is ridiculous.

When I first read Masters’ article, I thought a bit like you. My first take was that perhaps Prof. Essand had been a bit too gullible and interested in helping Masters (and by helping Masters helping himself), but after I saw that Dr. Essand had let Masters talk him into selling the naming rights for his virus to the highest bidder my view became markedly less forgiving.

As for the article itself, it’s a cliche and a total mess. Masters shamelessly uses all the cliches about a lone genius fighting an uncaring medical establishment that’s too blinded to see the value in what he’s doing. He frames the story as being about a wondrous “hidden cancer cure” (so hidden that it even sits, unknown, unused, and apparently unloved by anyone except Prof. Essand and his team in a freezer outside of Prof. Essand’s office, “gathering frost”) that “eats cancer.” He massively oversells the potential of Prof. Essand’s virus and downplays the difficulties that would be encountered on the road to validating it as a treatment.

It was very recently that I wrote about investigator culpability in overhyping their research in press releases and news stories. Yes, sometimes a journalist with an agenda will latch onto a scientist’s research; it is up to the scientist to make sure that the journalist’s agenda does not overpower the science.

This story completely overwhelmed our national mediascape and it’s been propagated in almost every outlet. And a few days ago there was a “second wave” when some journalists realised that a 23-year old Croat is working in Essand’s team. Naturally he is dubbed a prodigy and a genius who fights to bring the hidden cancer cure to the public.
Anyhoo, I don’t think your headline is fair to Dr. Essand, who was “stalked” by the Telegraph reporter and then used as a scientific placeholder in the author personal quest to find a cancer cure for his friend. Actually I don’t even find the original article that egregious insofar that it is obviously a personal take on a difficult moral situation. However, the article has brought about dozens of anti-pharma articles in Croatia alone – which is damaging enough.
The bottom line is, I don’t think Dr. Essand carries much of the blame here.