Massive Project to Study the Link between Genetics and Health

 

Spit kit: Genetic data from a diverse group of 100,000 California patients will be gleaned from samples of saliva, captured in kits like this one.
Credit: Kaiser Permanente

 

 

 

Kaiser Permanente has compiled the genetic and medical data of 100,000 of its members

 

 

MIT Technology Review, July 27, 2011, by Emily Singer  —  Most health insurers are wary of genetics because, in most cases, it’s not yet clear how a particular genetic variation influences an individual’s health, or whether it should affect their care.

Now Kaiser Permanente, the nation’s largest nonprofit health plan, has announced that it’s finished the first phase of a massive project to compile genetic, medical, and environmental information for 100,000 of its members. Researchers also analyzed the length of participants’ telomeres—a molecule structure at the tip of the chromosome that has been linked to aging. This represents the largest telomere study to date.

The resulting data, gathered in collaboration with the University of California, San Francisco, will soon be available to outside researchers who study how different genetic and environmental factors influence disease. It took about 15 months for the team to collect and analyze the genomes of 100,000 people ranging in age from 18 to 107. The team used gene microarrays—small chips designed to quickly detect hundreds of thousands of genetic variations across the genome.

While genetic studies have been done on this scale before, they focused on one or a few diseases, such as diabetes and heart disease. The Kaiser project is unusual in that it includes years of comprehensive medical information—including blood-test results, medications, and other conditions—in the form of electronic health records. (Kaiser was one of the earliest adopters of electronic medical records in the United States.)

“The computerized data goes back 15 years,” says Neil Risch, a statistical geneticist at UCSF who co-led the study.  “It’s not like we have 100,000 blood-pressure measurements—it’s closer to a million.” By combining that information with prescriptions, for example, researchers could examine how genetics influence blood pressure and the effectiveness of medication.

Researchers will also incorporate environmental data, such as air-quality and water-quality records, based on knowledge of where participants lived and when.

Because the average age of the participants in the study is 65, “we think some of the most interesting initial questions will relate to aging,” says Cathy Schaefer, executive director of the Kaiser Permanente Program on Genes, Environment, and Health, and a co-leader on the project. “Specifically, are there genetic and environmental influences that lead to people living to a ripe old age without serious problems?”

Researchers will continue to follow participants as long as they continue to receive health care from Kaiser. They can examine, for example, how accurately telomere length can predict longevity or healthy aging.

Genetic studies such as these have often raised privacy issues—the concern is that individual participants could be identified and their data misused. In this case, because the health-plan provider is involved in the research, the fear is that Kaiser could use genetic information to alter rates or drop some members. But this type of discrimination is outlawed by the Genetic Information Non-Discrimination Act, passed in 2008. In addition, research participants’ information has special protection under the Health Insurance Portability and Accountability Act.

Patrick Taylor, a fellow at Harvard Law School’s Center for Health Law Policy, Biotechnology, and Bioethics, says he is not concerned about privacy issues in this case, in part because the project has oversight from the National Institutes of Health. (The project was funded by a two-year $24.8 million grant from the NIH.)  In addition, Kaiser has a long history of commitment to its members, says Taylor, who has studied the organization.

Bacteria blues: Bacteria collected in the bottom of the tube on the right have been labeled with a blue imaging agent.   Credit: Niren Murthy

 

 

 

A new contrast agent could detect bacteria on medical implants, and help doctors decide how to treat infection

 

 

 

MIT Technology Review, July 27, 2011, by Katherine Bourzac  —  A new contrast agent that targets microbes can be used to illuminate bacterial infections in living animals. It could ultimately enable doctors to safely spare more of a limb during amputations.

It’s usually clear when a patient has a bacterial infection and needs to be treated with antibiotics, says Jason Bowling, director of epidemiology at the University of Texas Health Science Center at San Antonio, who was not involved with developing the imaging agent. But sometimes an infection is more difficult to diagnose. For example, it can be difficult to tell when a patient who has pain at the site of a hip or knee replacement has an infection. This sometimes leads doctors to prescribe antibiotics when they aren’t necessary.

An imaging scan capable of detecting bacteria would quickly answer the question, sparing uninfected patients from unnecessary antibiotics or even from surgery to remove the implant. Where there is an infection and the implant is removed, imaging could help ensure that no new hardware is implanted until the infection has been completely cleared.

It’s challenging to image infections because many of the molecules used to target bacteria can accumulate in tissue that is merely inflamed rather than infected, says Niren Murthy, professor of biomedical engineering at Georgia Tech, who was involved with developing the new agent. The new imaging agent is taken up by bacteria in large quantities, but it won’t stick around in other tissue. “We had to find something very specific to bacteria,” he says.

Murthy’s group stole a trick from a group of viruses that gets its genome inside bacteria by attaching it to a bacterial food source, a carbohydrate called maltohexaose. Bacteria have proteins on their cell walls whose job is to bring maltohexaose inside the cell, and this happens even if that maltohexaose is attached to an imaging agent. Animal cells don’t have these proteins, so they don’t take up the contrast agent.

 

There are already two bacterial imaging agents on the market for use in preclinical research. But these are not as sensitive or as versatile as the Georgia Tech probe, says W. Matthew Leevy, professor of chemistry and director of biological imaging research at the University of Notre Dame. Those earlier imaging agents work by a different mechanism—they stick to bacterial cell walls rather than accumulate inside the cell. The Georgia Tech probe is two orders of magnitude more sensitive than any made in the past, which means it can detect much smaller populations of bacteria. Leevy says it should be compatible with a wide array of imaging technologies, including MRI, PET, and fluorescence imaging.

In a paper published online in the journal Nature Materials this week, Murthy describes imaging bacterial infections in living mice using the new contrast agent—maltohexaose attached to a fluorescent protein. Fluorescent imaging is useful for animal studies, but the method can’t be used to visualize the deep tissues of the body because the light simply cannot get out. Murthy is now coupling maltohexaose with imaging agents suitable for imaging with PET.

It will be critical to make the new contrast agent compatible with imaging technologies commonly found in hospitals, says Bowling, who runs a clinic where he monitors patients with bone infections. He says it’s often difficult to decide whether a patient has recovered and can be taken off the drugs. “There’s not a lot of data on when to stop treatment, and you can’t tell if you’ve truly cleared an infection or not,” he says. Other uses for the imaging agent might include helping doctors determine whether a diabetic’s foot problems are due to infection, and visualizing the extent of an infection in patients who need an amputation.

Leevy says he expects the agent to be available to researchers soon, but he says it could be difficult to bring the imaging technology into the clinic. While it could make a big difference for some patients, he says, the narrow potential market could discourage a company from making the large investment necessary to bring the agent through clinical trials.

New Type of Drug Kills Antibiotic-Resistant Bacteria

 

Nano killer: This drug-resistant staph bacterium has been split open and destroyed by an antimicrobial nanoparticle.   Credit: IBM

 

 

 

Scientists hope bacteria won’t develop resistance to nanoparticles that poke them open

 

 

MIT Technology Review, Spring/Summer 2011, by Katherine Bourzac  —  Researchers at IBM are designing nanoparticles that kill bacteria by poking holes in them. The scientists hope that the microbes are less likely to develop resistance to this type of drug, which means it could be used to combat the emerging problem of antibiotic resistance. This type of drug has not had much success in clinical trials in the past, but initial tests of the nanoparticles in animals are promising.

Drug-resistant bacteria have become a major problem. In 2005, nearly 95,000 people in the United States developed a life-threatening staph infection resistant to multiple antibiotics, according to the U.S. Centers for Disease Control and Prevention. It takes just one to two decades for microbes to develop resistance to traditional antibiotics that target a particular metabolic pathway inside the cell, says Mary B. Chan-Park, professor of chemical and biological engineering at Nanyang Technological University in Singapore, who was not involved with the research. In contrast, drugs that compromise microbes’ cell membranes are believed to be less likely, or slower, to evoke resistance, she says.

“We’re trying to generate polymers that interact with microbes in a very different way than traditional antibiotics,” says James Hedrick, a materials scientist at IBM’s Almaden Lab in San Jose, California. To do this, Hedrick’s research group took advantage of past work on a library of polymer building blocks that can be mixed and matched to make complex nanoparticles. To make a nanoparticle that would selectively attack bacterial membranes and then break down harmlessly inside the body, the IBM group put together three types of building blocks. At the center of the polymer sequence is a backbone element that’s water-soluble and tailored to interact with bacterial membranes. At either end of the backbone is a hydrophobic sequence. When a small amount of these polymer chains are added to water, the differences between the ends and the middle of the sequence drive the polymers to self-assemble into spherical nanoparticles whose shell is entirely made up of the part that will interact with bacterial cells. This work is described this week in the journal Nature Chemistry.

IBM’s labs aren’t equipped for biological tests, so the researchers collaborated with Yi Yan Yang at the Singapore Institute of Bioengineering and Nanotechnology to test the nanoparticles. They found that the nanoparticles could burst open and kill gram-positive bacteria, a large class of microbes that includes drug-resistant staph. The nanoparticles also killed fungi. Other types of deadly bacteria that have different types of cell membranes would not be vulnerable to these nanoparticles, but the IBM researchers say they are developing nanoparticles that can target these bacteria, too, though it is more difficult. “Through molecular tailoring,” says Robert Allen, senior manager of materials chemistry at IBM Almaden, “we can do all sorts of things”—designing particles with a particular shape, charge, water solubility, or other property.

The IBM researchers believe the drug could be injected intravenously to treat people with life-threatening infections. Or it could be made into a gel that could be applied to wounds to treat or prevent infection.

However, Chan-Park cautions, other drugs that work by this membrane-piercing mechanism have not been very successful so far. Those that have shown early promise on the lab bench either were toxic to animal cells or simply didn’t work in the complex environment of the human body.

More tests will be needed to say definitively whether the nanoparticles are safe and will work in people. Initial tests of the IBM particles with human blood cells and in live mice have been promising. Allen says the nanoparticles didn’t interact with human blood cells because their electrical charge is significantly greater than that of bacterial cells. There were no signs of toxicity in mice injected with the particles, and none of them died.

In addition to developing nanoparticles that can attack other types of bacteria, the IBM group is working on making larger quantities of the designer polymers, scaling up from the current two-gram capacity to the kilogram quantities needed for larger clinical tests. IBM won’t be getting into the pharmaceutical business, says Allen, but the company plans to partner with a healthcare company to license the polymer drugs.