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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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May 8, 2009

Altermune - Real Stuff or Not?

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Posted by Derek

Kary Mullis is an outlier among Nobel Prize winners. Attendees some of his invited talks in the years after his award will know what I’m talking about. These were famously random affairs, with the audience never knowing quite what to expect when the next slide came up on the screen. And his own book, Dancing Naked in the Mind Field, will give you about as much flakiness as you can stand.

But although he's been way off base about a lot of things, he may not be that way about everything. I notice (h/t Biotechniques) that he gave a lecture recently at San Jose State, and instead of hearing about the discovery of PCR, the students got an update on Mullis’s company Altermune, whose website website is intertwined with Mullis's own. The site is worth a look. Mullis has a vigorous writing style, and the rest of the front page is his pitch for his company’s approach to immunotherapy for infectious disease:

We have been slowly developing chemistry- the art of dealing, using instruments we devise, with things that are much too small for us to see. They have plus and minus charges on them that we can't feel; they have oily places on them much too tiny for us to notice oil and they have water-loving patches too small for us to see oil droplets beading up on the water. Microbes need all of these things, specific types of them, in fact, to survive, and none of them are beyond the scope of our instruments and our synthetic tools. That's our advantage. Just in this last century we have come to know these things the way we used to know javelins and swords.

How can we help our immune system? Altermune has a shot at it.

Give its antibodies - its workhorse molecules - bionic arms. That's right, little chemical extensions that allow an old antibody to do new tricks. Altermune, LLC, in collaboration with Biosearch in Novato, CA, this summer, fitted up some antibodies whose job used to be binding to something called galactose-alpha-1,3-galactosyl-beta-1,4-N-acetyl glucosamine, with new bionic arms, synthesized on an Applied Biosystems ABI 3900, arms that can tightly sieze an influenza virion, shake it a little bit for emphasis, and turn it over to a hungry human macrophage for further processing. The change was accomplished with a swallowed drug. No need to send the antibodies back to the factory. Viruses never saw the ABI 3900 coming.

It looks like he’s using DNA aptamers as recognition elements for specific pathogens, which are used to bring on a response from the ubiquitous antibodies that target 1,3-Gal-Gal antigens. Here's the patent on the technique. And I have to say, that’s not necessarily a crazy idea at all. That epitope has been suggested before as a way to boost immune response, and marrying that to an aptamer could work. (Other aptamer conjugates are under investigation). Of course, the problem (as with all nucleic-acid based things) is, how do you dose it (and how long does it hang around once you do?)

Mullis seems to be talking about oral delivery, which is a real challenge. But that makes me wonder about a report from a company called RXi, which claims to be having some success in delivering their RNAi therapy to macrophages through the gut. They're packaging things in beta-glucan particles and taking advantage of a transport system (and of the fact that there are macrophages in the gut wall waiting for whatever comes out of the food supply). Perhaps something like this would do the trick for a immunological approach like Altermune's?

The immune system scares me, to be honest. I think that evolutionarily we've always walked a narrow path between "strong enough to fight off threats" and "touchy enough to get you killed". Versions of the machinery that threw their hosts into anaphylactic shock too easily have been weeded out by strong selection pressure - you probably wouldn't live long enough to pass that blueprint on. But it's still a tricky thing to mess with (ask TeGenaro). Using existing antibodies might be the most sensible way to do it. . .

Comments (13) + TrackBacks (0) | Category: General Scientific News | Infectious Diseases


1. RB Woodweird on May 8, 2009 12:43 PM writes...

I happen to agree with what has been called the theory of multiple intelligences. We are all smart in some ways and profoundly stupid in others. Mullins always brings to mind the undergrads I knew who were world-class smart in their own way but didn't have enough sense to unscrew the light switch fixture before painging the wall with a roller. He got a Nobel for PCR, and that was commendable and good, but it doesn't mean he knows jack about anything else.

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2. kary mullis on May 8, 2009 12:44 PM writes...

There was a mistake in my website concerning the method by which our team made DNA aptamers. The
site (which should be changed soon--would be already if I couod do it myself) talks about an ABI synthesizer. I have always counted on Ron Cook at Biosearch for oligonucleotides and their derivatives. Ron has his own synthetic machinery and always has. He is probably the best oligonucleotide chemist in the world, and it is truly ironic that ABI was mentioned on my site.

The Altermune method has proven itself in vivo in the case of Anthrax in mice by J. Kiel and J. Vivekanada at Brooks Air Base in San Antonio using a molecule containing a derivatized DNA aptamer and an alpha-Gal epitope. The anthrax and the drug were administered nasally.

The influenza experiments have only been done in vitro, and with an aptamer that was not protected against metabolism (because we were uncertain as how to do this at the time.) They will be repeated now that we have learned how to stabilize them. I think they will work. It is
a little early to report this work as a flu cure. I mentioned at San Jose State that given the choice of dying from flu or trying our untested drug I (only administered to myself) would try the untested drug on myself. I was talking informally to a student and did not expect to see this end up on the net. It's true, but certainly not ready for publication. I should realize that in today's world everything you say ends up on the net.

For flu and anthrax pulmonary administration is reasonable. GI stability of our drugs has not been
tested. I would not be shocked, but wouldn't expect it. We will definitely work on it.

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3. jose on May 8, 2009 1:37 PM writes...

JJ, is that you? Did Xenobe Research Institute LLC finally close its door(s)?

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4. Lucifer on May 8, 2009 1:39 PM writes...

At least Mullis is involved in trying out a novel idea, rather than develop one stereoisomer of an old drug and patent it as a new drug.

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5. Chrispy on May 8, 2009 3:46 PM writes...

The idea is cute but I don't see how you get the aptamer on board quickly enough and at high enough levels to be effective. These models systems where you introduce both the agent and the aptamer at basically the same time are not really representative of an ongoing infection, which would include intracellular virus. And oral bioavailability -- really? Presumably you'll want to hook it to something like tetanus toxin or some other protein people already have antibodies to -- that'd have to be orally bioavailable, too. Well, good luck -- hope it works.

Thanks for PCR, by the way, KM. I read about PCR in graduate school in its early days (where I was studying synthetic chemistry) and it was one of the major reasons I switched to the biology side of drug discovery. It was such an elegant reaction, and the implications were so big, that I remember at the time being fairly dazzled. Now, of course, I run PCRs all the time.

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6. PIGL on May 8, 2009 9:56 PM writes...

Hi, all. I'm a lurker here, a mere ecologist who get's a kick out of reading things I barely understand. Mainly, I enjoy reading about horrible compounds F3Cl!

But if I understand correctly, I just read a blog comment by the man who invented PCR.

It's as if Darwin or Rutherford or Von Neuman or G\:odel were alive and posting.

Wow. Just wow.

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7. Sudouodo on May 9, 2009 3:43 PM writes...

Kary Mullis endeavor manifested a heightened interest and hope toward this alpha-Gal strategy since it was started a decade ago from a few labs in biotech and academia. e.g. US 6096725 and 6090381. Kiessling Laura's selective tumor targeting work reignited its hope. But as one of the earlier explorers, I would still be doubtful about some of the technicality on alpha Gal, like what Derek pointed out about the dosing. Mainly the important mutivalency requirement as well as the low half life on alpha-Gal due to alpha glycosidase. Maybe Clustered C-glycoside is needed.

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8. Charles Darwin on May 11, 2009 1:49 PM writes...

I thought I'd see if my post can equally impress PIGL. Upshot: I think it prudent to assume that all posters are not necessarily who they claim to be.

Returning to my crypt in Westminster Abby, Chas Robert

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9. Derek Lowe on May 11, 2009 2:05 PM writes...

Uh, "Chuck", if I can call you that, as far as I can tell, that really was Kary Mullis. . .

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10. trout on June 22, 2009 1:16 PM writes...

We need to remember to be thankful for people like Kary Mullis and rejoice in the fact that he thinks outside most boxes. Many intelligent people that read 'Dancing Naked in the Mind Field' (I loaned my copy out so many times it came back nicely stacked in a ziplock years ago) can't assimilate the broad scope of Kary's smarts. Just because he relates experiences that challenge many the open mind doesn't detract from the validity or reality of his experience.

PCR development is just one thing we have gleaned from his highly adaptive consciousness, and if you work in science, the odds are that you wouldn't be doing much important work without PCR, at least in some branch of your work.

You might stop to realize Dr. Mullis made the cognitive leap to defy 'in the box' thinking, dynamically alter several scientific paradigms, entertain many of us, and give the Nobel board apoplectic fits, in part due to his use of hallucinogens and the occasional wee bit too much nitrous oxide.

Judge him all you want. The whole of his life experience is what brought him to contribute to humankind as he has. He may not have comprehensive understanding of everything he discusses at lectures or writes, but many things he has stuffed in the scientific community's face, like the mythology surrounding global warming and AIDS research, cannot be entirely thrown out. Point of fact is, some of the most outlandish seeming things he has said do, in fact, speak the truth, if not point other minds to approach these topics from another angle.

I hope everyone remembers that the only advances that have been made that are significant in science have occurred by someone defying the existing accepted facts (paradigms) of their time that are taught and research is based on. Few physicists thought much of Einstein's relativity papers and we can all look back at the odd and often flawed character of the people that have pointed science and research back on track, now, as charming albeit eccentrically sweet, when at the time of their innovation they were widely attacked, scorned and defamed.

We all should be thankful Kary has lived his life exactly as he has and it ain't over yet.

I hope that you, Dr. Mullis, read this as well. I've tried to get in touch with you for years and consistently been thwarted. I'd truly enjoy the opportunity to share a note or two with you, if not sit down for a NOS tapped beer to see if your 'Pop' will come and discuss Life, The Universe, and Everything with us. I hope to read your post here with some contact info.

Keep it outside the box folks. I've been awarded 5 patents for things that smart people should have thought of years ago.

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11. joe on August 27, 2009 3:57 AM writes...

I recently saw Kary Mullis' talk on TED and was amazed. I'm not a scientist or chemist but merely a person suffering from MRSA. If what Kary says is true then I have great hope. These bacteria do not respond to most types of antibiotics. I've taken at least five types of antibiotics and none have completely cured the infection. I truly hope to one day be cured of Staph, it is truly tiring having to deal with it all the time.

Kary Mullis if you read this, thank you.

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12. James on March 28, 2010 9:41 AM writes...

Could this treatment work adainst lyme disease? Toxoplasmosis? If it could cure latent toxo we might start to live in a saner less violent world.

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13. eric on May 11, 2010 11:14 AM writes...

@Sudouodo After reading the patent I don't see why multivalency requirements would be a problem; couldn't you just add multiple alpha-gal epitopes to one side of the linker?

Also, what exactly is the concern about dosage? Is it that it would be difficult to keep the dosage high enough in the face of rapid degradation of the alpha gal epitopes, or what.

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