

Wednesday, November 21, 2007

Induced Pluripotent Stem Cells: The End of the Ethical Debate

Today, two truly momentous papers were published in Science and Cell, respectively. These papers were so important that even Yahoo! News recognized their importance, and news services prefer stories about giant bugs.

These “induced pluripotent stem cells” (or iPS, as opposed to embryonic stem cells, or ES) produced by these two labs are important for a variety of reasons.

First, these cells completely end the whole debate about whether or not obtaining stem cells from the destruction of a human embryo is ethical. That’s it. It’s over. Don’t want to hear any more about it.

Assuming these cells are indeed truly pluripotent, and there is every indication they are, and if none of the caveats below are a problem, then this is it. In the papers above, researchers used several different types of human cells, ones from an adult woman’s face (a 36-year-old Caucasian woman, in Takahashi, et al,) and foreskin fibroblasts (Yu, et al,), which are cells harvested during the circumcision of newborn boys.

(You didn’t think we just threw those cells away, did you? They’re essentially fetal cells, a veritable cell culture gold mine. They’re used for many kinds of research, especially growing viruses in culture. Plus, if you grow enough of them and sew them into a wallet, and then rub the wallet, it turns into a suitcase. Sorry, old joke.)

Second, there was an additional ethical problem with ES cells, though it was considered secondary to the destruction of human life issue. To obtain human ova to perform nuclear transfer and thus produce ES cells, a woman had to undergo hormone therapy and surgery. Granted, the procedures are pretty much the same as in IVF, but ovulation-inducing fertility drugs have been linked with later ovarian cancer.

Another concern is that human ova would be come very valuable as a cure for everything from spinal cord injuries to Parkinson’s to Alzheimer’s to genetic diseases, etc. Should you pay women for this valuable resource and to chance getting ovarian cancer at a later time?

Again, these debates are now ended. These iPS cells don’t need eggs.

Third, using cells from an adult woman’s face to produce iPS cells is truly a breakthrough. This provides the proof-of-concept that an adult’s cells can be reprogrammed to pluripotency. If only fetal cells or newborn cells were possible to reprogram, this technique would be useful to correct birth defects or inborn genetic diseases but could not help diseases like Parkinson’s or cure spinal cord injuries.

Fourth, this lentivirus technique is easy. Really easy. Many, many labs use the lentivirus vectors and selection techniques described in these papers to produce stably transfected cell lines. I’ve done it. When this technique is refined and, hopefully, declared safe, labs all over the country could begin using this protocol for patients.

Nuclear transfer (the “Dolly” technique) that uses ES cells, on the other hand, is much more difficult.

There are, as always, some caveats. This technique will probably produce stem cells suitable for many kinds of research. It’s going to be a huge boon to labs.

It may not safely work for people. The four genes used are transcription factors, and their upregulation (which means when more is produced) is associated with cancer cells. Cells produced using this technique may cause cancer instead of cures. Takahashi, et al, used Oct3/4, Sox2, Klf4, and c-Myc. (As a virologist, seeing Myc in there gives me the proverbial willies, even if it is the c-Myc gene and not v-Myc.) Yu, et al, used Oct4, Sox2, Nanog, and Lin28, though Lin28 may not be necessary.

“Lentiviruses” are retroviruses. The retroviruses used to insert the four genes into the cells may damage the cells’ DNA when they integrate into the chromosomes and thus cause cancer.

Yet, the possibility of a cure may outweigh the possibility of future cancer. Women choose the increased risk of future cancer to have children by ovulation induction, and they do it often.

Think of it this way: if you had a profoundly dehabilitating disease, such as Parkinson’s, or early-onset Alzheimer’s, or a spinal cord injury, you might be given the choice between a cure (or a profound reduction in symptoms,) but the risk might be a 10% chance of cancer in the next decade.

Wouldn’t you want the choice?

TK Kenyon, author of RABID: A Novel and CALLOUS: A Novel (Apr 2008)

RABID is “[A] philosophical battle between science and religion ... with four very subtle and intriguing central characters. This is a novel quite unlike most standard commercial fare, a genre-bending story--part thriller, part literary slapdown with dialogue as the weapon of choice.” –Booklist Starred Review

Read “Why Dante Became A Priest: Communion Is A Kiss,” the prequel to RABID! You can even read it on your Amazon Kindle!

Sunday, November 18, 2007

Recently, the Merck pharmaceutical company reported that its experimental HIV vaccine raised the rate of HIV infection among people who got the trial vaccine.

Yes, you read that right. It was worse than nothing. This vaccine was composed of a few HIV proteins strapped onto an adenovirus, which causes colds. Among people with good immunity to this common cold virus, about 80% of the population, it increased the chances of contracting HIV.

The saddest part is that this is not surprising.

Virologists have long been skeptical about the possibility of an effective HIV vaccine. HIV infects the very immune cells that you stimulate to defend your body against it. Stimulating these cells increases the rate at which HIV can infect those cells and the rate of HIV replication in these cells. Thus, an HIV vaccine can make it more likely that you’ll get AIDS, and you might get it sooner and worse than if you weren’t immunized.

So far, no one has found the Holy Grail of HIV vaccines: a broad, neutralizing antibody. A broad antibody is one that attaches to many variants of the virus. Protecting against a single strain of HIV is darn-near worthless because HIV mutates so fast that pretty much everyone has their own, personal strain. Neutralizing antibodies cause the virus or virally infected cells to be killed. Beyond the inability to find antibodies that broadly react with the many, many strains of fast-mutating HIV, many antibodies, including most of those produced in other HIV-vaccine studies, are not neutralizing.

Even in studies with monkeys challenged with simian immunodeficiency virus, we haven’t found a vaccine that produces neutralizing antibodies and protects well against a broad range of viral strains, and the few studies that do have promising results are confounded because the researchers often can’t explain why.

So why are we racing to human trials?

First, money. If a safe and efficacious HIV vaccine is produced, people will line up, set their names down on waiting lists, and pay beaucoup bucks to be immunized against this certain-death virus. To the pharmaceutical company, the patents will be a gold mine. Sure, they’ll throw a few vials of vaccine to the African or Thai prostitutes in the name of public heath and as thanks for dying during the testing of the really dangerous vaccines, but that won’t eat into their oil-company-like profit margins.

The pharmaceutical companies are so eager to find a vaccine that works, anything that works, that they’re willing to burn a few thousand African and Asian prostitutes to do it. Those populations are unlikely to sue for a variety of reasons, several of them being that they’re overseas, poor, and if the vaccine doesn’t works or backfires, dead.

I remember one vaccine that was up for review before going to human trials a few years ago, and the vaccine itself was expected to infect 30% of the trial participants with HIV and kill them. That’s not a failure rate, meaning that the vaccine didn’t protect them against getting HIV from someone else. That’s a side effect of the vaccine: slow death. Is it ethical? They were planning to test in and ultimately give this vaccine to destitute prostitutes, the kind who can’t afford condoms. Without the vaccine, the HIV infection rate is 100%. The other 70% may have been protected. However, the trial may have gone like the Merck trial above, and the other 70% may have been at greater risk, too.

Second, millions of lives. If anyone finds a vaccine that works, even partially, millions of lives can be saved, and the wildfire spread of infection can be slowed or stopped.

Third, the absence of a really, really good model system to study vaccines for proof of concept before going to human trials. Yes, monkeys get SIV (simian immunodeficiency virus,) but many monkeys like sooty mangabeys tolerate high titers of the virus without getting sick, and they do it with some unknown immune function. They don’t make neutralizing antibodies, either. (1) They defend some other way, and we’re not sure how.

Fourth, no better ideas. Scientists are working as hard as they can, as fast as they can, but HIV is still a highly evolved, diabolical pathogen. Its major antigens (virus bits that the immune system recognizes to figure out it’s a virus) mutate like mad, like internet viruses, to use a perfectly circular analogy.

So there you have it: Merck was trying to find a vaccine to save its bottom line and thousands of lives in the absence of good pre-phase-I model system. It backfired on them.

One other really sad thing: there are a lot of other trials out there using everything from naked DNA to canarypox vectors to the smallpox-vaccine virus. They might all have exactly the same problem: they make antibodies, but those antibodies don’t stop or slow the virus, and they might make the infection rate and disease course worse.

TK Kenyon, Author of RABID: A Novel

Saturday, November 10, 2007

The Hoax of Global Warming?


And what does your humble Non-Majors Science Instructor say?













Chart Source:


Average Year Highest Temperature Record: 1940
Average Year Lowest Temperature Record: 1954



So, what do we do about it?






TK Kenyon, Author of RABID: A Novel