Interesting new vaccine production method

There’s a lot of innovative work being done to develop new ways to jumpstart our immune systems, both in the “immune system trigger” part, and the packaging. For instance, there are efforts focused on virus-like particles (VLPs), liposomes, and various nano-structures (a couple of examples). This week in Science, a team including Eckard Wimmer, famous for de novo synthesis of poliovirus, reports its work in exploiting “codon pair bias” to create weakened poliovirus strains with great vaccine potential. Science mentions two teams currently exploring this method—Wimmer’s at Stony Brook University, and a team led by Olen Kew at the CDC.

We currently have a live poliovirus vaccine that is not without risk of causing the illness it is supposed to prevent. The thinking on this new strategy is that the genetically crippled virus could never mutate in such a way to overcome all of its flaws; further, the methodology could possibly be applied to any virus to create new vaccines.

Here’s the abstract:

Virus Attenuation by Genome-Scale Changes in Codon Pair Bias

J. Robert Coleman,1 Dimitris Papamichail,2* Steven Skiena,2 Bruce Futcher,1 Eckard Wimmer,1† Steffen Mueller1

As a result of the redundancy of the genetic code, adjacent pairs of amino acids can be encoded by as many as 36 different pairs of synonymous codons. A species-specific “codon pair bias” provides that some synonymous codon pairs are used more or less frequently than statistically predicted. We synthesized de novo large DNA molecules using hundreds of over- or underrepresented synonymous codon pairs to encode the poliovirus capsid protein. Underrepresented codon pairs caused decreased rates of protein translation, and polioviruses containing such amino acid–independent changes were attenuated in mice. Polioviruses thus customized were used to immunize mice and provided protective immunity after challenge. This “death by a thousand cuts” strategy could be generally applicable to attenuating many
kinds of viruses.

Because everyone wants to coin a catchy phrase I guess, they call the method “synthetically attenuated virus engineering” or SAVE. The paper sums the potential benefits:

…these results suggest that synthetic attenuated virus engineering (SAVE) could play a role in creating new vaccines for various types of viruses. By deoptimizing codon pair bias, one could systematically attenuate a virus to variable but controllable and predictable extents. This approach has four key features: (i) It produces a virus encoding precisely the same amino acid sequences as the wild-type virus, and therefore eliciting the same immune response. (ii) It is a systematic method apparently applicable to many viruses, and possibly not requiring detailed, virusspecific research. (iii) The attenuation is not subject to reversion, simply because of the sheer number of mutations. (iv) It can be combined with other attenuating changes (such as amino acid changes from adaptation of the virus to low temperatures or alternative species) or with other synthetic biology approaches to attenuation (18, 19), thus taking advantage of additional modes of attenuation while providing the unique advantage of limited reversion.

Codon pair bias is a little more complicated twist on codon usage bias (or just codon bias) which is a principle that has been applied in codon optimization for synthetic genes. Greatly simplified, in the genome there are multiple three-letter codons that can result in single amino acids, but some just seem to translate better than others. This preference can be used to promote high levels of gene expression in a selected organism, for instance. If you do the opposite, though, you can produce an organism that the body recognizes as a threat, but it really isn’t because it just can’t quite get the job done. It’s like an instruction manual written in Engrish. You know it’s an instruction manual but damned if you can understand it.

Here’s another writeup at ArsTechnica.

DNA testing is risky business for all concerned

I’ve been reading a flurry of posts and news stories over the past several days (see the latest at Wired Science) about California’s attacks on DNA testing businesses like Navigenics and 23AndMe. In what could be the opening salvo of a long and expensive battle, California’s health officials have issued cease-and-desist letters to up to 25 biotech companies that offer direct to consumer genetic testing. California says only a doctor can order a genetic test—under no other circumstances should this be available to consumers. Health Dept. official Karen Nickles made the spurious justification for this action,

“The public demand around access [to genetic information]… has created the worried well,” Nickles declared, noting that the results could be difficult for consumers to understand or act upon. “Once they get the results, they don’t know what to do about it.”

As always, the excuse is that the public is stupid and must be protected from itself. Or could it be that certain erstwhile links in the DNA chain of custody are a bit miffed about missing out on the money/data/privacy of consumers? Such as, oh, I don’t know, doctors, labs, and insurance companies who desperately want to have your genome on file? Not that they would ever use it against you—perish the thought! If you can just pay cash directly to some biotech company and get the results delivered to you, that’s a threat.

Indeed, an individual representing one of the targeted companies noted that although the health department feebly claims that its action was spurred by “multiple consumer complaints,” it’s more likely to have been spurred from within the (profit-motivated) health industry, to which I would add let’s not forget the insurance industry.

“If we could find out who put the bee in their bonnet, my guess it’s the medical community,” Greenspan [partner at DNATraits] said. “I think that the medical community doesn’t want to lose control of who orders the test.”

A couple of comments from Wired readers I thought worth repeating here….

“One (this one) wonders if insurance companies put this ‘Bee’ in the bonnet. If the individual orders the test, it does not go into the medical record, and insurance companies can not use said data to provide or deny their services. Mandating testing through medical professionals could be the first window to genetic discrimination by insurance companies…” – Matt

“Given the privacy-hostile nature of the US corporatocracy, you’d have to be crazy or incredibly stupid to hand over your genetic data to companies not bound to abide by even the token protections of HIPAA.” – realitydose

Yes, I think until a whole lot of things get figured out, I’ll stick to my policy of not handing out my DNA to anyone. Period. You’d be well advised to do the same, unless you have a very good reason to seek genetic testing at this time. If you’re just curious and have $1000 to blow, quite frankly, at this time no one can foresee what kind of risks you may be taking by enabling the collection of this data.

That’s nice, but you still can’t have my DNA

Wired Science reports that our Dear Leader signed the Genetic Information Nondiscrimination Act (GINA) law today. Theoretically, you now can’t be denied a job or insurance based on the titillating secrets hiding within your DNA. I’m sure there will be plenty of creative ways around that within 10 years or so. Further,

“GINA’s not perfect: The law doesn’t specifically keep genetic information out of third-party hands. It also doesn’t apply to the military. (So actually, you still might be denied entrance to Gattaca based on a genetic test.) And some people say health insurance won’t ever be fair without a pricing structure that makes discrimination impossible.”

The GINA law is a good thing. A great thing, even. It’s good that they can’t say, “Hmmm, looks like you’ve got a 28% chance of having clogged arteries by the age of 45, so we’re not going to insure (or hire) you.” But there is no way in hell I’m ever going to have my genome sequenced and entered into some medical record that frankly, I have zero control over. Laws change, and corruption happens. Government and businesses work out ways to do and get what they want, not to mention the fact that data of all kinds is stolen and sold on a regular basis.

I’m not trying to sell tin foil hats here, folks, but in the case of genetic data we simply do not know what the world is going to be like within 20-50 years. No, I don’t think individuals are going to be secretly “targeted” in some way but I do think genetic information will just be another way that people will be grouped and categorized, probably right out in the open, and to some end that a lot of them will be unhappy about. Since we do not yet know what we will be able to learn from or do with the genome in the future, how could we possibly know how releasing or even (supposedly) securely storing your genetic data might come back to you in the future? There could even be some sort of disadvantage to your kids who aren’t even born yet. Just a thought.

On the “open genome” side of the aisle, there are a few adventurous people so far, like Craig Venter and George Church, who are happy to have their genomes published in the name of science. Better them than me, but I guess only time will tell whether my paranoia was a waste of neurotransmitters or not.

I, for one, welcome our performance-enhanced overlords

Bioethicist John Harris writes a short op-ed here against the backdrop of the Human Fertilisation and Embryology Bill currently under debate in the UK. The bill deals with embryonic stem cell research and chimeric embryos, among other things, and apparently has people thinking we’ll be growing half-animal, half-human babies, or some such. (I’ll take the little red-headed frog baby with the six legs and the beaver tail, please.)

Harris says that eventually, enhancement technologies will bring on the replacement for the human race. And why not? If we can fix mutations that cause disease, shouldn’t we? If we can grow new eyes for a blind person or new kidneys for someone dying of kidney disease, shouldn’t we?

But people tend to start getting upset when we consider “optional” things (a purely subjective term). This is because we have a long-ingrained and useless cultural fear of playing god. The fact is, we already manipulate our bodies and our behavior every day with all manner of substances that we eat, drink, or breathe. We will soon reach a point where average people will have access to technologies—whether drugs, genes, or physical modifications of various types—that will make us question whether some of us are still human. Harris believes that our ability to modify ourselves signals the end of our familiar brand of human, at least.

While he discusses lots of benefits of our new-found technological powers, he also notes that modifications may spawn injustices (think Gattaca, or X-Men). I agree, that will definitely happen to some degree. Unless we can modify out of ourselves some of our most basic behaviors. Regardless, they can plug me in whenever they’re ready. I’m first in line for an upgrade! I’m thinking maybe wings, and definitely a neural interface for the Internets.

If this topic interests you, maybe you’ll be lucky enough to attend this session at the World Science Festival in NYC.

Update: Here’s another angle from the New Scientist editor’s blog: A human hybrid speaks out

Venter: people should not be afraid of their genome

Tech Review has a short interview with Craig Venter, first person to fully sequence and then publicly release his diploid genome.

TR: You’ve had sections of your genome in the public domain for several years now. Any second thoughts about putting the entire high-quality sequence out there?

CV: No. And I applaud Watson for doing this as well. A key part of the message here is that people should not be afraid of their genetic codes or afraid to have other people see them. That’s in contrast to the notion that this is dangerous information that should be kept under lock and key. We’re not just our genetic code. There is very little from the code that will be 100 percent interpretable or applied.

We understand that we’re not just our genetic code; however, would insurance companies, employers, and others be as understanding? Could something like the world of Gattaca come about? Here’s what the U.S. government has to say on the subject. The majority of states have already enacted laws offering protection from genetic discrimination, but the Federal government has not passed the Genetic Information Nondiscrimination Act (GINA).

The paranoid side of me insists that even with nondiscrimination laws in place, people will be discriminated against on the basis of some statistical probability gleaned from their genomes. Personally, I would never willingly release data about my genome. Unfortunately, in the future I may have to choose between that and functioning in society.

PLoS Biology links:

A New Human Genome Sequence Paves the Way for Individualized Genomics
The Diploid Genome Sequence of an Individual Human

Bill to ban ownership of genes found in nature

Some time ago when there was a small uproar about Indonesia being reticent to share its strain(s) of H5N1 with the global scientific community, I wondered, if I got H5N1 would any samples taken from me be under my control? Could I get a lawyer and stop my samples or sequences from being shared? Probably not, but I’m still not sure why, as it appears governments or private corporations can go much farther than that and own the patent rights to your genes and your pathogens’ genes. This is a case of ignorance on the part of the government when this whole practice started.

Michael Crichton explained yesterday in this article how private companies own about a fifth of your genes, as well as the genes of other species including pathogens. The discoverers of genes patent them and then charge large royalties to every researcher or doctor, etc., who wants to study or test for the gene, often to include mutations as well. So patenting genes greatly increases the cost to you of benefiting from the research, even though the gene is obviously an integral part of your own body. They also charge royalties for the study and testing of diseases. The owner of the Hepatitis C genome gets millions of dollars from researchers who must pay in order to study.

Why should people or companies own a disease in the first place? They didn’t invent it. Yet today, more than 20 human pathogens are privately owned, including haemophilus influenza and Hepatitis C. And we’ve already mentioned that tests for the BRCA genes for breast cancer cost $3,000. Oh, one more thing: If you undergo the test, the company that owns the patent on the gene can keep your tissue and do research on it without asking your permission.

I find this outrageous. If you don’t want them to take your diseased tissue and find new ways to profit from it, then you can just die because your doctor’s not going to treat you, and your insurance company is not going to pay, unless you have the test. The cure, according to Crichton:

Fortunately, two U.S. congressmen want to make the full benefit of the decoded genome available to all Americans. Last Friday, Xavier Becerra, a Democrat of California, and Dave Weldon, a Republican of Florida, sponsored the Genomic Research and Accessibility Act, to ban the practice of patenting genes found in nature. Becerra has been careful to say the bill does not hamper invention, but rather promotes it. He’s right. This bill will fuel innovation, and return our common genetic heritage to us. It deserves our support.

Will this stifle research? Well, there could be some problems regardless of Crichton’s statement. There will still be plenty of $billions to be made in developing methods to test for, and treat these diseases, and the expectation of profit that is inherent in any other medical and pharmaceutical research would apply. The main problem as far as I can see is that the discoverer of a gene, no longer being able to sell the results to companies that develop applications, would also have to come up with end user products associated with it in order to profit from the research.

I think the bill is an excellent idea in some respects, since those USPTO clerks likely had no idea what they were doing when they started granting patents to our own genes. But to encourage basic research there must be a way for those research institutions to recoup investment.


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