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Is shameless self-promotion of your science a good idea?

As part of my ongoing effort to make sure that I never run out of blogging material, I subscribe to a number of quack e-mail newsletters. In fact, sometimes I think I’ve probably overdone it. Every day, I get several notices and pleas from various wretched hives of scum and quackery, such as NaturalNews.com, Mercola.com, and various antivaccine websites. I think of it as my way of keeping my finger on the pulse of the antiscience and pseudoscience wing of medicine, but I must admit that I don’t really read them all, but they do allow me to know what the quacks are selling and what new arguments they’re coming up with without actually going to each of their websites. I can then judge by the headlines and the blurbs included in the e-mails whether I think it’s worth it to go to the website itself and, of course, whether the topic might represent fodder for a good blog post. I will admit that not all the sites I monitor are as loony as the Health Ranger’s. In fact, I monitor the blogs and websites of the National Center for Complementary and Alternative Medicine (NCCAM), various naturopath organizations, and the like in order to learn of the “respectable” arguments being used to tout various nostrums.
Sometimes—albeit rarely—I even learn about some interesting new science.

One of the most common themes (besides antivaccine hysteria, claims that diet can prevent 95% of all cancers, etc.) tends to be one of a variety of pitches for various “cures” of serious diseases like cancer and heart disease that “they” don’t want you to know about; i.e., the Kevin Trudeau gambit. Who this “they” is can range from doctors to pharmaceutical companies to universities to the government, but the central message is that someone out there doesn’t want you to know The Truth. A variation of this sort of appeal is the claim that there is a promising new therapy, a cure even, usually natural, that is languishing somewhere because it can’t be patented, because pharmaceutical companies would lose money if it were ever validated and brought into clinical use, or because it goes against current medical dogma. It doesn’t even have to be natural. After all, dichloroacetate (DCA) is not exactly “natural.” After it was shown to have promise in animal models, a pesticide salesman named Jim Tassano sold DCA bought from chemical companies to desperate cancer patients from a website that claimed to be selling it only for pets with cancer, a ruse that fooled no one. Yet the “natural treatment” crowd embraced it whole-heartedly because it looked as though sellers of DCA were sticking it to The Man.

Unfortunately, it’s not just the quacks who use this method of selling their wares. I wish it were, but it’s not. Over the years, I’ve come across scientists who have used pitches that sound disturbingly like the pitches that I’ve just described. Sometimes, as I recently discussed, these pitches are no more than overselling results in university and medical journal press releases. Sometimes, they involve direct pitches to the public to fund their research. In many of these cases, I wonder whether the scientist involved is at the heart of it or whether he’s along for the ride, having been seduced by the blandishments of fundraisers, PR people, or others whose agenda might involve promoting his science but doesn’t necessarily involve safeguarding the scientist’s reputation. In fact, even Evangelos Michelakis, the University of Alberta researcher who discovered the antitumor effects of DCA, did some of that, albeit not in a manner that bothered me. It can be very tempting, I would imagine, if one has a therapy that’s been in the news and is frustrated by the inability to obtain funding to pursue what appears to be a promising line of research. This is particularly true these days, given the exceedingly tight paylines at the NIH and private foundations. Nevertheless, it makes me uncomfortable, and I was reminded of this discomfort when recently I came across a series of articles, in which a journalist was using a variant of the sales pitches above. While I’ll grant that what he’s trying to raise money for appears to be worthwhile research (more later), I also left feeling very uncomfortable at the sales pitch he had chosen, which resulted in his article “going viral” into other articles like this:

Interestingly, I haven’t seen anything yet in the skeptical blogosphere about this story (although it’s quite possible I might have missed it given that I’ve only gone down a few pages of Google searches); so I thought I’d dig in, even at the risk of bringing more attention to the issue. Also, to be fair, I must point out that this hype seems to be eminating mainly from a British writer, Alexander Masters, whose friend Dido Davies suffers from pancreatic neuroendocrine cancer, essentially the same cancer that claimed the life of Steve Jobs nearly a year ago, and not the scientist working on the project, Prof. Magnus Essand of the Uppsala University in Sweden. In fact, at several points he tries to throw out a note of caution. That doesn’t stop him from taking advantage of Masters’—shall we say?—enthusiasm, nor does it stop the usual suspects from using Prof. Essand’s work to attack big pharma, promote conspiracy theories about “natural” cancer cures “they” don’t want you to know about, and in general attack science. And no wonder. Let’s take a look at Master’s article:

On the snow-clotted plains of central Sweden where Wotan and Thor, the clamorous gods of magic and death, once held sway, a young, self-deprecating gene therapist has invented a virus that eliminates the type of cancer that killed Steve Jobs.

‘Not “eliminates”! Not “invented”, no!’ interrupts Professor Magnus Essand, panicked, when I Skype him to ask about this explosive achievement.

‘Our results are only in the lab so far, not in humans, and many treatments that work in the lab can turn out to be not so effective in humans. However, adenovirus serotype 5 is a common virus in which we have achieved transcriptional targeting by replacing an endogenous viral promoter sequence by…’

It sounds too kindly of the gods to be true: a virus that eats cancer.

‘I sometimes use the phrase “an assassin who kills all the bad guys”,’ Prof Essand agrees contentedly.

Yet, Masters tells us, this miraculous cancer cure virus (in actuality, a virus that might or might not represent a promising new treatment) is sitting in a little freezer near Prof. Essand’s office “gathering frost,” even though it is “exquisitely precise,” “only causes mild, flu-like side effects in humans,” and results in tumors in mice “melting away.” Those bastards! Why won’t they fund this science? Can’t they see that it’s so groundbreaking that it must be funded? Can’t they see that every month that this virus sits in Prof. Essand’s freezer is a month when millions of patients (OK, thousands of patients—well, maybe hundreds of patients) are dying unnecessarily?

I exaggerate a bit, of course, but that is basically the tone of Masters’ article, leavened occasionally with only the gentlest words of caution that this is all preliminary, that it might not work out. Indeed, Masters lays down an incredible piece of utter nonsense in describing how he finds potential new therapies in science that might have promise:

It was on one of those evenings that I came across a blog about a quack in Mexico who had an idea about using sub-molecular particles – nanotechnology. Quacks provide a very useful service to medical tyros such as myself, because they read all the best journals the day they appear and by the end of the week have turned the results into potions and tinctures. It’s like Tommy Lee Jones in Men in Black reading the National Enquirer to find out what aliens are up to, because that’s the only paper trashy enough to print the truth. Keep an eye on what the quacks are saying, and you have an idea of what might be promising at the Wild West frontier of medicine. This particular quack was in prison awaiting trial for the manslaughter (by quackery) of one of his patients, but his nanotechnology website led, via a chain of links, to a YouTube lecture about an astounding new therapy for neuroendocrine cancer based on pig microbes, which is currently being put through a variety of clinical trials in America.

I don’t know about you, but if I were Prof. Essand, I wouldn’t exactly be flattered that this is how Masters came across my work. In fact, I’ve actually had a couple of quacks cite my work before, and if I’m ever in the mood maybe I’ll blog about it sometime. In the meantime, all I can say about what Masters writes here is that it meets the criteria of being so wrong it’s not even wrong. What you’re more likely to find on quack cites are treatments based on prescientific understandings of cancer (in essence, humors and “imbalances”); wishful thinking like The Secret (the German New Medicine, for example); a complete misunderstanding of human physiology and science (such as Robert O. Young’s quackery claiming that all cancer is due to excess acid or, of course, homeopathy); or, if you’re lucky, maybe the sort of understanding of cancer we had 100 years ago, such as the trophoblastic hypothesis that underlies the quackery that is known as the Gerson therapy. Where you do see cutting edge science on quack websites, you will see its abuse, not its being put to use to develop promising therapies outside the mainstream. Deepak Chopra’s abuse of quantum theory comes to mind. What you are incredibly unlikely to find is any sort of cutting edge science applied to the problem of cancer or other diseases in a way that’s likely to do anything except to fleece the marks. How Masters could be so extravagantly clueless about how science works is truly astonishing.

Still, Masters’ article intrigued me enough that I did some PubMed searches for Essand’s work and any other work related to this particular viral construct, Ad5[CgA-E1A-miR122]PTD. You probably all know me well enough by now to realize that, whenever I see a story about science or medicine that piques my interest, I try to “go to the tape,” so to speak; i.e., find the original research articles in the peer-reviewed literature describing the work. The reason, of course, is obvious; what is reported in the news about science and the actual science itself are sometimes related solely by coincidence.

In any case, this article from 2011 in Gene Therapy, this article from 2010 in PLoS ONE, and this article from 2007 in Clinical Cancer Research appear to be the main articles describing this particular virus. In brief Prof. Essand appears to have done a fairly clever thing. He’s taken an adenovirus and altered it to target it to neuroendocrine tumors while at the same time decreasing its ability to replicate in other cell types. He’s done this using two strategies. First, he took a promoter that is highly active in cells of neuroendocrine origin, the chromogranin-A (CgA) promoter. A promoter is a stretch of DNA that controls the expression of a gene. Depending upon what transcription factors (proteins that control gene expression) bind to its sequences, it can turn genes off or on based on intracellular signals, cell type, and any number of factors. CgA is a protein in secretory granules of neuroendoocrine cells that serves as a precursor of several biologically active peptides made by the cells. For purposes of targeting the adenovirus, the CgA gene is highly expressed in neuroendocrine tumors and CgA is known to be a sensitive and specific tumor maker for neuroendocrine tumors. So the basic idea is to use the CgA promoter to drive the adenovirus (dubbed Ad[CgA-E1A]) infecting the neuroendocrine cancer cells to make the E1A protein, which results in replication of the virus only in cells that normally make CgA; i.e., neuroendocrine cells. The final act of the adenovirus life cycle is to lyse the cells and release all the replicated viral particles, hence the term “oncolytic” virus. These new viral particles then disperse and infect nearby cells, repeating the cycle.

This isn’t the clever part of what Prof. Essand has done. Thus far, all he’s done is to make a pretty straightforward choice of a promoter that is as tissue- or cell-specific as he can think of, stick it into an adenoviral vector, and use it to drive the adenovirus to make the genes that promote its replication. It’s a nice trick but nothing we haven’t been doing at least since the 1990s to make an oncolytic adenovirus more cell-specific. What was clever was what he did to address a major problem that adenoviral gene therapy can have, namely liver toxicity. The CgA promoter isn’t perfectly specific (no promoter is). It has some activity in liver cells (hepatocytes), which means that, especially for liver metastases (which is where neuroendocrine cancers tend to metastasize first, there is the potential for even this specific virus to replicate in hepatocytes and lyse them just as it’s lysing tumor cells, just at a lower level. The result would be liver injury, hepatitis in essence. Enough hepatocyte death, and it could mean patient death.

To lessen the chance of that, Prof. Essand took advantage of microRNAs. MicroRNAs are small RNA sequences (usually around 20-22 nucleotides long) that are complementary to (and therefore bind to) specific sequences in the messenger RNAs (mRNA) for various genes, preventing the mRNA from being turned into protein by either preventing translation or by inducing the degradation of the mRNA. In other words, microRNAs (miRs) block protein synthesis at the mRNA level. Indeed, microRNAs have become increasingly appreciated as a major mechanism regulating gene expression. (I’ve even published a couple of papers on microRNAs.) What Prof. Essand did was to take target sequences for a microRNA, miR-122, and tack six copies of this target sequence on to the 3′-untranslated region of the E1A gene. It turns out that hepatocytes make a lot of miR-122, so much miR-122 that this single microRNA makes up around 70% of the total microRNAs that hepatocytes make. What that means is that in hepatocytes miR-122 will silence (shut down) E1A before it can even be made into protein. That’s the even neater trick.

Finally, apparently Prof. Essand has made one other modification, namely adding the protein transduction domain (PTD) of the HIV-1 Tat protein (Tat-PTD) inserted into the viral fiber, hence the name Ad5[CgA-E1A-miR122]PTD. The reason to do this is to increase the ability of the virus to bind to cell types not making the coxsackievirus-adenovirus receptor (CAR), which adenovirus requires for entry into the cell. 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.

Perusing Prof. Essand’s papers, I note that Ad[CgA-E1A] does a pretty good job of suppressing neuroendocrine tumor growth in mice and prolonging their survival in xenograft models. I also note that Ad5[CgA-E1A-miR122] does appear to demonstrate better targeting in that it causes less liver toxicity in mice associated with more specific silencing of E1A expression in hepatocytes in mice. What I did not see was an experiment demonstrating that either Ad[CgA-E1A], Ad5[CgA-E1A-miR122], or Ad5[CgA-E1A-miR122]PTD “melting tumors away.” What I do see are some interesting results in preclinical models. Do these results warrant following up, perhaps even in clinical trials? Sure. I’d like to see them followed up. Are they so amazing that it is a crime that the clinical trial hasn’t been funded yet? No. Funding is very, very tight right now, and there are a lot of great projects out there (mine among them, I would say at the risk of being too boastful) going unfunded because, in the US at least, the NIH is only funding at about the 7% level through the NCI. Yet that is exactly the impression that Masters gives in his article. It’s full of colorful language, such as describing the virus as surging “through the bloodstreams of test animals, rupturing cancerous cells with Viking rapacity”; a “virus that eats cancer”; and similar overblown language. Even Prof. Essand gets in on the act, calling his virus “an assassin who kills all the bad guys.” This virus, even if it works exactly as advertised in Masters’ article does not “eat cancer.” It kills cancer cells with a high degree of specificity. That’s a good thing, but far from a cure. Even though Masters does occasionally tamp down the rhetoric below 11, it doesn’t sound convincing:

The closer you get to manipulating the cellular forces of human existence, the more you sound like a schoolboy babbling about his model aeroplane. Everything in the modern genetics lab is done with kits. There are no fizzing computer lights or fractionating columns dribbling out coagulations of genetic soup in Magnus’s lab; not a single Bunsen burner. Each narrow laboratory room has pale, uncluttered melamine worktops running down both sides, wall units above and small blue cardboard cartons dotted everywhere. Even in their genetics labs, Swedes enjoy an air of flatpack-ness. The most advanced medical lab in the world, and it looks like a half-fitted kitchen.

Nothing at all against Prof. Essand. He seems like a nice enough guy and a good scientist, but I highly doubt that he has the most advanced medical lab in the world, particularly in light of his funding difficulties moving his virus to the next stage.

Besides the tone of Masters’ article, which is at its core not that far removed from a lot of articles I saw on DCA and some e-mails I get about various cancer “cures,” particularly the part where he cites that infamous Amgen study at face value claiming to find that most basic science research can’t be reproduced (hopefully you will remember my deconstruction of this article), there’s another thing that bothers me:

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. Trials come in three phases. What Magnus was suggesting for his trifling £1 million (two Mont Blanc diamond-encrusted pens) was not just a phase I trial, but also a phase II, which, all being well, would bring the virus right to the point where a big pharmaceuticals company would pay 10 or 100 times as much to take it over and organise the phase III trial required by law to presage full-scale drug development.

‘So, if Calvin Klein or Elton John or… Paris Hilton stumped up a million, could they have the virus named after them?’

‘Why not?’ Magnus nodded, showing me the bacteria incubator, which looks like an industrial clothes washer, only less complicated. ‘We can make an even better one for two million.’

I don’t know about you, but I’m not sure I like the idea of wealthy donors getting to name potential cures after themselves if they fork over enough money. It’s one thing to put their name on a building (and even that can cause problems, as the Robert Wood Johnson University Hospital found out when it sold the naming rights to its new children’s hospital to Bristol Myers-Squibb. Of course, if a pharmaceutical company were to buy the rights to Prof. Essand’s adenovirus, it would be able to call it anything it wants if it turned it into a product. Be that as it may, imagine the Calvin Klein adenovirus or the Elton John cure for cancer or maybe the Lady Gaga cancer tenderizer. The possibilities are endless.

Regular readers know that I’m not someone who is somehow anti-capitalist or against pharmaceutical companies making profits on general principle. Nor am I opposed to universities doing some fundraising to try to start clinical trials on promising therapies that they don’t have funding for. In fact, I’ll even direct you to Prof. Essand’s oncolytic virus fundraising page. If you’re so inclined, donate. It looks like worthwhile research, and as a fellow biomedical researcher I’d like to see it advanced.

But remember this. Despite what Masters implies in his article and what others citing his article are saying explicitly about Prof. Essand’s virus, it is not because “they” don’t want you to know about Essand’s research that it is not being funded. It’s probably not even because pharmaceutical companies can’t profit from it. They certainly could. They could take Essand’s viruses and modify them more to make them even more specific and more oncolytic, patent the new viruses, and potentially make boatloads of money.

I’ll tell you the most likely real reason for Prof. Essand’s difficulties securing funding for his trial as someone who used to do gene therapy research himself back in the late 1990s and early 2000s: Gene therapy for cancer (which, let’s face it, is what oncolytic viral therapy in essence is) has fallen out of favor in the cancer research world. The primary reason is the highly publicized death of Jesse Gelsinger in a clinical trial of adenoviral-delivered gene therapy, a death that also reminds us that adenoviral gene therapy is not necessarily as safe as it is being advertised. True, much progress has been made in the last 13 years, and it’s virtually certain that adenoviral therapies are likely safer than they were when an idealistic 18-year-old paid the ultimate price for his altruism. But we don’t know, and scientists have become considerably more gun shy when it comes to adenovirus-mediated gene therapy. There’s just not much interest in it anymore, and I’ve noticed a marked fall-off in the number of abstracts describing gene therapy being presented at the big cancer conferences over the last decade or so.

Look at it this way. There are hundreds, if not thousands, of promising therapies out there. Gene therapy is hard. Heck, Prof. Essand shows us that. Look at all the manipulations of his adenovirus backbone he had to do to try to get it to infect the cells he wants it to infect, replicate in the cells he wants it to, and, just as importantly, keep it from replicating in the cells in which he doesn’t want it to replicate. Then remember that, to eliminate cancer, this virus has to destroy virtually every cancer cell. That is the magnitude of the challenge. Add to that the various other difficulties that any sort of virus-based therapy faces in terms of manufacturing clinical grade material and assuring its safety, and it’s not too surprising that pharmaceutical companies are taking a “wait and see” attitude. This is especially true given that life-threatening neuroendocrine cancers are not that common, limiting the number of patients who would benefit from this form of gene therapy that would require a high cost to develop. Worse, there’s no a priori way to know that Prof. Essand’s treatment would be any more likely to succeed than any of the other promising experimental treatments currently in the pipeline for various cancers. From the published information, which doesn’t appear to include Ad5[CgA-E1A-miR122]PTD, I can’t even hazard a guess.

Yet the assumption is that it is. It’s human nature, after all. People who develop a new treatment always assume that it is more worthy than other people’s new treatments, and people who know someone with the disease will tend to agree because they want their loved one to live. Unfortunately, those of us in the biz have seen these “miracle cures” before that eliminate tumors in mice but don’t to nearly as much in humans. It was immunotherapy in the 1980s. Then in the 1990s it was antiangiogenic therapy and, yes, gene therapy, including therapy with oncolytic viruses. 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. I only wish that Prof. Essand hadn’t let himself be sucked into being part of the hype.

Posted in: Basic Science, Cancer, Clinical Trials

Leave a Comment (19) ↓

19 thoughts on “Is shameless self-promotion of your science a good idea?

  1. cervantes says:

    That is of course the great challenge of medical research funding: you have to somehow pick the winners based on speculation. NIH reviewers are tasked with somehow reconciling innovation with significance, i.e. the money should go to real discoveries, but those discoveries also have to matter for producing better human health. We don’t have a crystal ball, so there’s no way to always get it right, or even perhaps to be right most of the time. Naturally we’re all frustrated when our proposals don’t get funded, and we know it’s because the reviewers just aren’t as brilliant as we are, but what can you do?

  2. Nikola says:

    I wrote about this story yesterday on my blog (Croatian):
    http://laikaskeptik.wordpress.com/2012/09/09/farmaceutske-kompanije-ignoriraju-novootkriveni-lijek-za-rak/

    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.

  3. David Gorski says:

    I beg to differ.

    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.

  4. Nikola says:

    Yes, you are very probably right. I simply decided to forgive Masters when I realized his motives, and of course the stark contrast between all things pseudo in his article versus the ones in Croatian press.
    Why exactly are you against selling the naming rights to a potential donor? Is it the scientist in you which recognizes that a name may be one of the rare satisfactions a typical scientist may get from his hard work? I don’t see how that’s somehow a “pimping out” of your discovery, and selling it to a company is not. One might call it selfless, giving your future name-recognition away just for a *chance* of a cure.
    As one who values rationality over the influence of such propaganda I am opposed to shameless marketing by default, yet I don’t see a significant difference.
    Do you perhaps think it’s just another way for a quack to circumvent the usual process and attract gullible lone investors? I can see how that would be dangerous as a rule. And yes, I may be less than objective in this case, having read the criminal Croatian coverage first, which may have blunted my outrage at the Telegraph article and Essand.

  5. pmoran says:

    – trophoblastic hypothesis that underlies the quackery that is known as the Gerson therapy.

    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.

  6. Xplodyncow says:

    Dr. Gorski, I think you are brilliant, and I love reading your posts. I hope you’re not offended when I ask—are you intentionally being ironic with this post?

    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.

  7. Locky says:

    -Xplodyncow:

    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.

  8. rork says:

    Agree with Locky – I probably will not go run out and read the papers (sometimes I will, but not today), so a brief sketch of the tricks engineered into the vector helps allot, and some of those ideas were interesting and new to me cause I don’t work on those kinds of tricks.
    Agree with Gorski that using DNA, and a rare cancer type, both don’t help the funding chances. Just try obtaining a big data set for those tumors from published papers.

    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.

  9. qetzal says:

    Some of the things I found most annoying about Masters’ article:

    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.

  10. evilrobotxoxo says:

    This is a pretty small point, but as someone who works on gene therapy, I don’t think that oncolytic virus therapy should be considered a form of gene therapy. There are some technical similarities, and I know lots of people lump those together, but conceptually they’re totally different. Gene therapy (or what they now frequently call gene-based therapy) involves putting genes (or maybe RNA) into some part of the body so that a protein gets made. Usually it’s done with replication-deficient viruses, or it can be done through non-viral means. Oncolytic viruses involve modifying a replication-competent virus so that it only kills tumor cells. It’s true that the oncolytic viruses have genes inside, but in gene therapy the goal is to deliver the genes (hence the name), but in oncolytic viruses, the goal has nothing to do with gene delivery.

    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.

  11. evilrobotxoxo says:

    @qetzal: the only reason why wild-type adenovirus is benign in humans is because of dose and typical mode of exposure. If someone grew up a huge batch of wild-type adenovirus and injected it into someone’s brain, they’d be screwed. Oncolytic adenoviruses, generally speaking, are not more dangerous than the wild-type viruses are. They’re usually weaker versions of normal viruses that retain their native level of pathogenicity exclusively in tumor cells. There are viral strategies for cancer that are more like gene therapy, where there is a toxic transgene the virus carries into the tumor, but I don’t think that’s the case here.

  12. qetzal says:

    evilrobotxoxo,

    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.

  13. evilrobotxoxo says:

    @qetzal,

    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.

  14. Xplodyncow says:

    Locky, you said, “[T]he quote you display is pretty easily intelligible to anyone with a 1st year university-level grounding in molecular biology.” Ay, there’s the rub. Some of us readers are merely wannabe scientists with useless degrees in the humanities—no molecular biology for me. :-D

  15. qetzal says:

    evilrobotxoxo,

    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).

  16. evilrobotxoxo says:

    @qetzal:

    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.

  17. mousethatroared says:

    Xplodync
    “Locky, you said, “[T]he quote you display is pretty easily intelligible to anyone with a 1st year university-level grounding in molecular biology.” Ay, there’s the rub. Some of us readers are merely wannabe scientists with useless degrees in the humanities—no molecular biology for me. ”

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

  18. qetzal says:

    You’re right. It’s not a vector, it’s a virus.

    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. :-)

  19. jen_angela says:

    In reply to # qetzalon 12 Sep 2012 at 12:16 pm
    “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.”

    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.

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