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Virus-Only Gene Editing, Or Not?

I wrote here about a new company (Homology Medicine) that claimed to have a viral method for gene editing that did not involve any sort of double-strand DNA breaking enzyme (as you need during the CRISPR, TALENs, or zinc-finger nuclease methods). That’s a pretty interesting claim, because double-strand breaks (DSBs) are powerful but can be hard to control. But as is always the case, interesting claims need interesting evidence to back them up. As I said at the time:

This is a testable hypothesis, of course. The company will be working very hard to produce convincing results, and if they do, they can expect to see a lot more than $127 million. I’d be a little jumpy about investing at this point, though, because it’s certainly true that a lot of neat stuff doesn’t quite pan out. (The current research boom, looked at from that perspective, is due to a slightly higher-than-normal run of neat stuff actually working).

Even at the time (as a link in that post shows) there were skeptics in the field, and now a new manuscript on bioRxiv will give those skeptics more support. It’s from Paula Cannon’s lab at USC, and it makes for pretty grim reading (if you’re an investor in Homology, anyway). The earlier work from City of Hope (the stuff that kicked off Homology’s founding, PNAS or PubMed Central) seemed to involve homology-directed repair (HDR), although the details hadn’t been fully worked out. But this new paper reports that they just cannot make the viral vectors do what they are advertised to do.

Not at all. The original paper reported that AAV genomes packaged into capsids from Clade F viruses (AAV9, for example, and apparently only the capsids from that group) could do the gene-editing trick. Cannon’s lab has been trying to reproduce that, using good old green fluorescent protein (GFP) as a marker. They’ve packaged that into the AAV9 vectors as well as the more traditional AAV6, which has been reported many times to insert such genomic material into human stem cells, and tried editing both a stem-cell line and three others. It didn’t go well. The AAVg experiments altered between 20% and 80% of the stem cells, depending on the viral vector load, but even at the highest load the AAV9 experiment only seemed to transduce about 3% of the cells. Which is basically the opposite of what was reported.

The same went for the other three non-stem cell lines, including one (K562) that the original paper had reported as being efficiently transduced in the absence of any DSB nuclease enzymes. They went on to try these experiments at more than one gene locus, but in every case they couldn’t show that the viral payload had been incorporated into the targeted cell genomes. In general, if you tried the gene editing with AAVs alone, no matter what clade they were from, the amount of GFP seen in the cells dropped off rapidly, consistent with it just being expressed from some exosomes at first and not really getting edited in. No matter what experiment they tried, they could not find anything that contradicted the previous conventional wisdom (that unless you can target some double-strand breaks, that AAVs by themselves can only do less than 1% transduction). And they were able to reproduce none of the earlier findings that caused such interest at the time.

At present we are unable to explain our inability to reproduce the findings of Smith et al. Perhaps there are unidentified features in their AAV constructs, or some aspect of their vector production, purification, or titration methods that contributed to this phenomenon. Nevertheless, the reported ability of clade F AAVs to perform highly efficient nuclease-independent genome editing by homologous recombination is clearly not a universal phenomenon.

Nope, sure doesn’t look like it. This news came out yesterday, highlighted by Anthony Regalado’s Twitter feed at Technology Review, and it’s not hard to see just when that happened. We’ll see what response the company has – this is one of those times where it’s both a scientific question and a business one. . .

 

13 comments on “Virus-Only Gene Editing, Or Not?”

  1. Barry says:

    Since the fidelity of Homology Directed Repair is less than the fidelity of modern CRISPR/Cas DNA cleavage, this approach baffles me.(or would baffle me, even if it worked)

  2. John Wayne says:

    If you are a person who knows this data that suggests this company platform may be less than advertised, if the company was public you could short their stock.

    (1) Is it legal to do so?
    (2) Is it ethical to do so?
    (3) Could Paula herself short this stock and then publish?
    (4) How about her friends, family, research group or anybody who could learn this data?

    I think the answer are: yes, no, yes with caveats, yes. This doesn’t seem like ‘insider trading.’

    Anybody have any knowledge here? To what extent are you allowed to use your knowledge of science to make bets on the market?

    1. Peter S. Shenkin says:

      My understanding is that insider trading only applies to insiders, that being a stockholder does not make you an insider, and that even insiders who learn pertinent facts from outside sources may do as they please. (It may get dicier if such an insider tells another insider….)

      I am not a lawyer, etc..

      1. Not a lawyer says:

        I am not a lawyer.

        The way it’s been explained to me is that if you operate on non-public information, you’re at risk for insider trading.

        If you do research on AAVs, hold stock in companies that use AAVs, discover that it won’t work through unpublished research, then dump all your stock – the SEC is going to come knocking once your paper is published. Even if you have no ties to the company. You’ll have to argue that your stock sale wasn’t due to the unpublished results and this is going to be tough. A lawyer would probably advise you to hold your stock until the paper is published before making any sales.

        It’s not about where you get the info but more about whether or not everyone else has access to that info.

      2. Walther White says:

        No, my friend. Insider trading means you take a position (e.g. buy or sell a stock) based on internal AND non-public company information that you obtain.

        If, however, you are using scientific rationale and intelligence to analyze a company and realize they are bonkers, then you can short them confidently. It’s not insider trading–no one in the company divulged this to you.

    2. J Rosenblum says:

      Not only is it legal and ethical, it’s downright American to short a stock if you have figured out the company is BS-ing the market.

    3. StumpedByTheCaptchaMath says:

      Agree with the others, as long as you’re not legally tied to the company it’s not insider trading. Obviously, you can’t be an employee of the company. But I think it’d also be considered insider trading if your lab was contracted to do work with the company and you found out their science was BS.

      1. StumpedByTheCaptchaMath says:

        One caveat to my agreement with the others: I’m not sure about Peter’s comment that, “even insiders who learn pertinent facts from outside sources may do as they please.” As an insider, it would be tough to prove that pertinent facts you learn are from outside sources and not inside sources. And you likely would not be given benefit of the doubt in such a case.

    4. Hap says:

      I would assume it’s okay (legal and ethical) to short based on an analysis of the data. It seems iffy to short before publishing, though, particularly depending on where the research in the paper was funded (if someone else paid for it, they could constrain what you do with it and may restrict your ability to profit from it). If you did the research on your own, with no intent to publish and no funders, then it would be seem reasonable to short them if you wished. (As usual, IANAL).

      Buying a stock is equivalent to holding the position that a company is likely to make money and putting your money on that opinion, and shorting is holding that the position that they won’t, and putting money on that opinion. Nothing is wrong with either stance – it’s just that that’s not enough for lots of people.

    5. Anonymous says:

      I do not see any Conflict of Interest or similar disclaimer in the Cannon preprint. That, I think, would be REQUIRED if she was taking any financial interest in the FIXX stock, directly or indirectly (e.g., advising others to short the stock).

      If I was suspicious of a company’s claims, I could mix some stuff together in the kitchen or garage and try to figure something out and use what I learned to take a position on their stock. It’s the wet lab equivalent of the finance guys downloading all of the financial statements, published papers, public info (interest rates, a monsoon affecting delivery of a key component, etc.) and using their insights to take a position. In Cannon’s case, her experiments were paid for by the NIH and a Taiwan USC Scholarship.

      I think that it would be (1) legal (2) ethical to short the stock but (3) and (4) are trickier for me. If you do not intend to publish on your own, (3) is OK but (4) might not be. If you intend to publish after shorting the stock, that sounds like a borderline “pump and dump” tactic, which is illegal. (In pump and dump, you buy low, you actively spread false stories (“about to be acquired by Big Company!”) to encourage others to buy the stock thus pumping up the price, then you sell = dump at a profit, leaving others stuck with overpriced stocks that they can’t sell.) I don’t like it.

      Here are some numbers on FIXX from their stock quote:
      Shares Short (Jul 14, 2019) 4 2.37M
      Short Ratio (Jul 14, 2019) 4 9.2
      Short % of Float (Jul 14, 2019) 4 9.81%
      Short % of Shares Outstanding (Jul 14, 2019) 4 5.32%
      Shares Short (prior month Jun 13, 2019) 4 1.79M

      Are those numbers reasonable for comparable companies in this sector? Anything suspicious? Is it too late for me to get in and make a quick buck?

  3. Okemist says:

    In 2012 I was working on a compound for a Biotech company when some analyst wrote an analysis starting off with why I shorted company… And his thoughts on why the drug would not be approved. The stock price crashed, the drug did not show efficacy, and I went on to another project after 4 years of making that drug. It sucked, but there was nothing illegal, just an investor doing due diligence. In fact if you bet against drugs being approved, you will win 90+% of the time.

  4. Anon says:

    Don’t you all think that we need to hear from other labs regarding its reproducibility? At the least we should wait for rebuttal from Homology Medicines.

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