Genetic Modification as Medicine

On ERV, Abbie Smith provides an update on a pioneering treatment for hemophilia that uses viruses to insert missing genes in a patient’s DNA. Hemophilia results from from the mutation or deletion of a gene that makes a blood clotting agent called Factor IX; without it, hemophiliacs are at risk for uncontrolled bleeding. While Factor IX can be delivered pharmaceutically, utilizing viruses to modify patients’ DNA yields long-term improvements in natural Factor IX production. Abbie writes, “the amount of therapeutic Factor IX these patients needed (on average) dropped from 2613 IU/kg to 206. The people who got the ‘high’ dose of virus dropped that down to 92 IU/kg. They went from 15-16 ‘bleeding episodes’ a year, to one.” They also saved $2.5 million.

Next, Abbie revisits research on treating HIV by removing CCR5 receptors that the virus uses to enter white blood cells. Much excitement was generated in 2008 when the “Berlin Patient” was declared to be functionally cured of HIV after receiving bone marrow from a donor with a mutation that preludes manufacture of the CCR5 protein. Now scientists are considering using gene therapy to disable CCR5 production in HIV patients, but there’s a catch: some HIV quasispecies utilize other receptor proteins, and even a small population of such viruses can take over when a patient is not producing CCR5. For this reason, Abbie writes that this therapy may hold more promise as a vaccine for HIV than as a cure.

Meanwhile, HIV itself has been genetically modified to help some sufferers of acute lymphoblastic leukemia by training cytotoxic T cells to target cancerous B cells. Abbie writes, “for all the time HIV has stolen from people, from families, its nice to see it giving some time back.”

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Chance Cancer Mutations

This new year, researchers concluded that 2/3 of the difference in cancer risk between different parts of the body can be attributed to the number of stem cell divisions those parts undergo. More cell divisions reflect a higher risk as errors that occur naturally during the DNA replication process can contribute to the development of cancer. In other words, the same genetic mutability that enables evolution also ensures that many people will be afflicted by a terrible disease. On Pharyngula, PZ Myers suggests this is one reason our cells naturally get old and stop dividing: because if they continued forever, too many mutations would accumulate in the individual.

Of course, mutations are rare and unpredictably distributed, and not all of them are dangerous, making who gets cancer largely a matter of chance. The new study shows which cancers are most influenced by lifestyle factors such as using tobacco. PZ writes,”colorectal and lung cancers do have a significant risk beyond what can be accounted for by stochastic errors, so pursuing a reduction in exposure to risk factors, like diet and smoking, can have a useful role in reducing the incidence of these cancers.” On the flip side, the incidence of pancreatic cancer (for example) can be totally accounted for by random mutation.

Life, Death, and ERVs

In a phenomenon known as Peto’s paradox, large mammals do not develop cancer more often than small mammals, despite having more cells that could go haywire. On Life Lines, Dr. Dolittle writes “Some researchers suggested that perhaps smaller animals developed more oxidative stress as a result of having higher metabolisms. Others proposed that perhaps larger animals have more genes that suppress tumors.” But a new hypothesis argues that large mammals have evolved to minimize the activity of ERVs, which are ancient viral elements integrated into our DNA. Active ERVs can cause cancer and possibly other diseases; mice exhibit about 3300 active ERVs, while humans exhibit about 350. On the blog known as ERV, Abbie Smith writes “some of the young ERVs in humans, the ones that can still code for a protein here and there, are reactivated in HIV+ patients.” Researchers are considering targeting these ERVs in order to combat HIV; as Abbie writes, “You could train the HIV+ individuals immune system to ‘see’ the ERV components in an HIV infected CD4+ T-cell, and BAM! Kill the HIV infected cell!” But she warns that other ERV components are expressed in many normal human cells, and teaching our immune system to target them might be a very bad idea.

Recalculating Round Numbers

The price of human genome sequencing has fallen spectacularly since the turn of the century; what then cost $100,000,000 is now promised for only $1000. This race toward zero makes even Moore’s Law look like a snail’s pace, but the $1000 price tag does come with a couple asterisks. For one, providers will need high demand to pay off the multi-million dollar sequencing array that makes it possible, and low demand should result in higher prices.  For two, $1000 will only buy you a rough draft of your genome. On Discovering Biology in a Digital World, Todd Smith writes “While some sequencing technologies claim they can produce data with errors as low at one in 10 million bases, a six billion genome sequence will still contain thousands of false positive variants.” To separate the sequencing errors from the actual DNA mutations, you’ll need to double-check (at least).  Meanwhile, Chad Orzel cautions America about getting its billion back. Advertisements for a tax prep service claim Americans overpaid the IRS by $1,000,000,000 last year.  That’s about $3 per citizen, but after cutting out the young, the old, and Mitt Romney’s “47% percent,” Chad estimates about $48 per two-income household. So while the promise of a billion dollars may lure in new customers, the vast majority of them will not come out ahead.

Making Cancer, and Making It Worse

On Pharyngula, PZ Myers says that cancer, unlike an infectious bacterium or virus, is not the product of millions of years of evolution. Instead, PZ writes, “Cancer misuses and perverts existing processes in your cells to send them out of control.” But what causes cancer? Well, it happens about 20,000 times a day in your body. Luckily, it is almost always repaired. It is the mutation of DNA during cell division. Just one base out of place, and suddenly the gene that made a protein to tightly regulate cell division is making a protein that encourages the cell to divide continually. Depending on what other mutations this cell line, by chance or carcinogen, accumulates, it can grow to destroy the body. PZ also explains the role of tumor suppressor genes, which generally stop uncontrolled cell division.  Sexual beings have two copies of every gene in their bodies, and for some cancers to be successful, both copies of a tumor suppressor gene must be knocked out.  On the other hand, new research at the Weizmann Institute suggests that for leukemia cells to proliferate, one copy of a cancer-causing gene must remain healthy even though the other must be mutated.  And on Respectful Insolence, Orac takes another look at the endless parade of cancer quackery in the media, in this case a talk-show host praising a doctor whose treatment regimen (including 150 pills per day and a coffee enema) appeared in a clinical trial to make pancreatic cancer patients die sooner.

Posted to the homepage on September 23, 2013.