Posts Tagged ‘DNA


the path to a new health paradigm takes one big step

Two or three years ago as the first direct-to-consumer DNA kits were being offered by companies like 23andMe and Navigenecs a big kerfuffle erupted when the California and New York departments of public health threatened to shut them down. The authorities claimed it was their duty to block the tests because the tests were offered online rather than through a licensed physician and because they were worried to death that the test results might be misinterpreted and cause unnecessary anxiety among recipients.

I was working with CA State Health Department people back at the time through my job in cancer public health. Nevertheless, I always suspected that the legal moves by the states were more to protect their statutory prerogatives and the medical profession than to protect the public. After all, I had been running into similar excuses to control cancer information among physicians for 30 years. Back in the ’70s some doctors would not tell their patients that they had been diagnosed with cancer for the ostensible reason that it would cause a lot of anxiety, and, besides, often there wasn’t much physicians could do about many cancers at the time. The situation improved after informed consent laws were passed forcing medical practitioners to explain diagnoses to patients before treating them. Also the organization I worked for would not give cancer patients professional-level pamphlets or journal reprints for fear of “confusing” patients and for fear of the docs who’d clobber us.

A lot of debate about the hypothesized impact of genetic information has been similar to the argument about the advisability of cancer information in years past. Fortunately some studies have been conducted to try to measure the emotional impact of genetic test information, especially genetic indicators for diseases like Alzheimer’s for which there is no treatment. The NY Times reported a couple of days ago about a study published recently in the News England Journal of Medicine that found essentially that news from the genetic tests didn’t cause a lot of anxiety in a study group of 2000. Many people didn’t take advantage of free genetic counseling offered or even discuss it with their doctors. Nor did the test affect behavior much in a positive way, such as changing lifestyle toward better eating habits. The surprising finding was how little impact the information had on people.

An author of one of the study stated:

“The medical field has been paternalistic about these tests,” says Peter J. Neumann, the lead author of the study, who is director of the Center for the Evaluation of Value and Risk in Health at Tufts Medical Center. “We’ve been saying that we shouldn’t give people this information because it might be wrong or we might worry them or we can’t do anything about it. But people tell us they want the information enough to pay for it.”

The author of the article, John Tierney, offers:

The traditional structure of American medicine gives control to doctors and to centralized regulators who make treatment decisions for everyone. These genetic tests represent a different philosophy, and point toward a possible future with people taking more charge of their own care and seeking treatments customized to their bodies. “What we have today is population medicine at the 30,000-foot level,” says Dr. Topol. “These tests are the beginning of a new way to individualize medicine. One of the most immediate benefits is being able to use the genetic knowledge to tweak the kind of drugs people take, like choosing among statins and beta blockers to minimize side effects.”

I agree with Tierney. This is a step toward a new way of medicine. As I write this the conflict over health care reform is on again. The health care model in the US is a mess and isn’t financially sustainable with about 8,000 baby boomers being added to Medicare each day. I think we need to shift a great deal of health responsibility to people, but it must be real, empowered responsibility with knowledge tools, decision making, and a support infrusturcture that’s available to all citizens. Conservatives use the term “responsibility” as a code word for blame. You know, “You’re  responsible (i.e., to blame) if you’re sick, not me. Don’t ask me for taxes to fix you up.”

If people are to take meaninful responsibility they need a system that provides them with meaninful information about their genetics, real time data about how they’re doing through, perhaps, mobile health monitoring, and a worldwide communication system that makes the latest scientific evidence about disease freely available in comprehensible, personalizable form. Putting up barriers to information like the results of DNA test through spurious fears of damaging effects is not the way to go about it. In the last century and a half we’ve created a huge, expensive scientific and medical system that restricts information and authority to an elite few gatekeepers. That’s got to change.


is synthetic life approaching?

By Richard Wheeler (Zephyris) 2007. Lambda rep...
Image via Wikipedia

There has always been a metaphysical aura about life. In addition to the material in a cell or other living thing, most people seem to think that when we say “life” we’re talking about a spark or energy that transcends the material constituents of that living thing.

But suppose that organisms that show all the properties of life can be created by off-the-shelf raw materials of our world and made to function as living through human-designed processes? At no point would some spark or energy be added to jump-start life processes although complex chemical reactions are central to synthesizing the constituent parts. (Is the term Frankenmolecules already taken?)

Researchers are working on just such approaches in an effort to understand the details of how living things get organized, and just recently another step was  taken. Princeton chemist Howard Hecht and his team built proteins from scratch, put them in bacteria, and the bacteria used them to grow and carry on just like the proteins they naturally generate. They demonstrated that there’s nothing mystical or magical about molecules generated in vivo. Actually, there were two artificial steps: they designed artificial DNA that then generated the synthetic proteins.

“What we have here are molecular machines that function quite well within a living organism even though they were designed from scratch and expressed from artificial genes,” said Michael Hecht, a professor of chemistry at Princeton, who led the research. “This tells us that the molecular parts kit for life need not be limited to parts — genes and proteins — that already exist in nature.”

“What I believe is most intriguing about our work is that the information encoded in these artificial genes is completely novel — it does not come from, nor is it significantly related to, information encoded by natural genes, and yet the end result is a living, functional microbe,” said Michael Fisher, a co-author of the paper who earned his Ph.D. at Princeton in 2010 and is now a postdoctoral fellow at the University of California-Berkeley. “It is perhaps analogous to taking a sentence, coming up with brand new words, testing if any of our new words can take the place of any of the original words in the sentence, and finding that in some cases, the sentence retains virtually the same meaning while incorporating brand new words.”

Although millions of proteins from evolved DNA already exist, the ones Nature has produced is only a small fraction of the proteins that could be produced by heretofore unseen DNA and protein combinations. The potential design space is vast. Some people think living things were produced by intelligent design from the beginning, but I think these experiments are getting us closer to the truth. Evolution of the world’s material into living things over a hell of a long time gave us what has gone before, but we’re getting closer and closer to true design of life forms from a huge set of possibilities that will become part of our world in the not-too-distant future.


the paradigm for the genetics of complex diseases is changing

The structure of part of a DNA double helix

Image via Wikipedia

One of the themes of this blog is that living things are complex and making clinical gains from areas of research such as genetics is just plain hard. There’s been a lot of questioning of genetic research lately, but, as I’ve tried to point out, there are many factors other than plain ol’ DNA involved in finding the way genes manifest in disease. That basic situation got a better expectation this past week when two highly respected genetics researchers at the University of Washington, Mary-Claire King and John McClellan, published an essay in Cell titled, “Genetic Heterogeneity in Human Disease.”

For decades the basic genetics paradigm held that common diseases are caused by common variants (CDCV). That is, to look for genetic causes for cancers the reasonable thing would be to identify genetic variations (mutations) found most often in cancer cases. That makes sense, but it turns out that finding these common genetic variations is not enough to explain all the disease. King and McClellan say:

…from the perspective of genetics, we suggest that complex human disease is in fact a large collection of individually rare, even private, conditions…In molecular terms, we suggest that human disease is characterized by marked genetic heterogeneity, far greater than previously appreciated. Converging evidence for a wide range of common diseases indicates that heterogeneity is important at multiple levels of causation: (1) individually rare mutations collectively play a substantial role in causing complex illnesses; (2) the same gene may harbor many (hundreds or even thousands) different rare severe mutations in unrelated affected individuals; (3) the same mutation may lead to different clinical manifestations (phenotypes) in different individuals; and (4) mutations in different genes in the same or related pathways may lead to the same disorder.

There’s a huge idea here: Complex human diseases involve sets of complex genetic variations, so many, in fact, that each person’s case of a disease may have individual characteristics. We accept the idea that each individual is unique, but it’s perhaps surprising to think that your case of cancer, for instance, may bear individual characteristics.

The overall magnitude of human genetic variation, the high rate of de novo mutation, the range of mutational mechanisms that disrupt gene function, and the complexity of biological processes underlying pathophysiology all predict a substantial role for rare severe mutations in complex human disease. Furthermore, these factors explain why efforts to identify meaningful common risk variants are vexed by irreproducible and biologically ambiguous results.

Next-generation sequencing provides its own challenges. Whole-genome sequencing strategies detect hundreds of thousands of rare variants per individual (McKernan et al., 2009). Biological relevance must be established before a mutation can be causally linked to a disorder. The critical question is not whether cases as a group have more rare events than controls; but rather which mutation(s) disrupting a gene is responsible for the illness in the affected person harboring the variant. Variable penetrance, epistasis, epigenetic changes, and gene-environment interactions will complicate these efforts. It will be fun to sort out. [Emphasis mine.]
So, as I’ve remarked before, life is complicated. Living systems are the most complex things we know of in the universe, and we’re only now beginning to explore them in detail. We want results to save us now! But it’s going to be some time before we fully understand diseases like cancer and then a long time ’till effective therapies are widely available. Moreover, we have no idea what it’s all going to cost, and, as our recent rancorous debate on health care demonstrates, cost is no trivial matter.

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