Linkage 7/22: Smarter Dosing and Fossil Diaries
A large portion of medical research is dedicated to designing and testing new and better drugs for treating disease. But what if we could improve treatments with the drugs we already have - and potentially cut costs at the same time? That’s the proposal made in an editorial this week in the Journal of the American Medical Association written by the Medical Center’s M. Eileen Dolan and Vanderbilt University’s Russell Wilke. Their article, “Genetics and Variable Drug Response,” is an optimistic snapshot of the current state of pharmacogenetics, the use of genetic information to improve the use of pharmaceuticals.
Though individualized or personalized medicine has been a goal of physicians and researchers for several years, the science (as it tends to do) is moving slowly. But as Dolan and Wilke write, promising pharmacogenetics examples are beginning to accumulate, from genes for enzymes found to influence the metabolism of chemotherapy and anti-clotting drugs to genetic variants that predict severe side effects from various agents. Some of these discoveries have already made it to the clinic, such as the genetic test (developed at the University of Chicago by Mark Ratain) for a variant that affects the response to the cancer drug irinotecan. Physicians can use the test to lower the dose in patients found to carry the variant associated with severe side effects at the normal dose.
Dolan and Wilke dream even bigger about pharmacogenetics. Currently, the standard drug dose is set by the average response of a large population, hoping to capture a level where people get the most benefit at the least risk. But as more information about the genetics of drug response are revealed, those doses can be better shaped to each patient according to their own personal risk-benefit. This could bring some drugs deemed “too dangerous” back to common use, if some patients have a genetic profile that enables them to endure the treatment safely.
“For drugs with a narrow therapeutic index, pharmacogenetic studies may hold the potential to resurrect treatments previously withdrawn from the market, particularly for agents designed to fill underserved clinical niches,” they write.
If smarter dosing can truly bring effectiveness up and toxicity down, it would be a benefit to both patients and the health care system in general. One suggestion by the authors is to start building gene-based drug dosing into electronic medical records, creating alerts for doctors about “drug-gene interactions” similar to current alarms for potentially dangerous drug-drug interactions. The future of medication may be more complicated than “take two of these,” but smart implementation may save dollars and lives.
Cohen Video
The American Society of Clinical Oncology recently filmed a short video with Medical Center associate professor of medicine Ezra Cohen, where he talks about how he decided to treat cancer patients while working as a small-town family physician. It’s a nice piece about how doctors are inspired to do their work and the connection between laboratory research and clinical care. If you want to see more videos with Dr. Cohen, he discussed head-and-neck cancer with ScienceLife almost exactly one year ago.
Elsewhere…
Right after his very cool study on the genetic origins of limb development was published, evolutionary biologist Neil Shubin departed for his annual expedition to the Canadian Arctic in search of fossils from the earliest limbed creatures. If you want to follow along with the hunt, Shubin’s teammate (and Tiktaalik co-discoverer) Ted Daeschler is blogging from the dig for the Philadelphia Inquirer! Read about how their remote site on Devon Island is “almost like Mars,” and how the expedition is already finding interesting fossils two days into the trip.
It’s one of the most significant events in Earth’s history: the moment when a sea creature first stepped - or more likely wriggled - onto land. The momentous occasion 400 million years ago opened up a whole new habitat where life on Earth could evolve and spread out, and made that first bold pioneer and its peers the ancestor to everything from dinosaurs to birds to humans. Obviously, scientists would love to know more about what that brave explorer looked like, and have long hunted for their fossils. But genetics offers another way to journey back in time and look at the biology of the first fish to leave the water, and a study published today by University of Chicago scientists suggests that the genetic tools to make those first historic steps were present long before they actually occurred.
Just looking at the sequences revealed many similarities between the CsB switches of fish species and tetrapods. But the real test was to determine whether the switches performed similar functions despite 400 million years of divergent evolution. To test this required a little bit of mad science: swapping gene sequences across species. First, the CsB switch from a mouse was put into a zebrafish embryo, where it was shown to activate gene expression in the distal fin. The reverse experiment - zebrafish CsB into mouse embryo - was even more exciting, as the primitive fish switch successfully activated gene expression in the developing mouse paw (seen at right).
Teaching with Treadmills
More Honors for Shubin
The unsung heroes of scientific research are the graduate students*. Graduate students provide the enthusiasm to run experiments 7 days a week and all hours of the day and night to generate data for publications and their own thesis projects. The fresh perspective a graduate student brings to an area of research can also provide new ideas to their mentors and collaborators, spotting connections or opportunities that might have been missed by those with more experience. In even the biggest discoveries, graduate students play a critical role.
Six months ago, some of the world’s brightest evolutionary biologists and scholars gathered on the University of Chicago campus for a three-day birthday party celebrating Charlie Darwin’s 200th. At the time, the blog featured 


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