A Genetic Test for Organ Rejection


Rejection hurts: A tissue biopsy from a heart transplant patient shows that the donor heart (pink) is being attacked by the patient’s immune cells (purple), indicating that the organ is being rejected.   Credit: Hannah Valantine



Rising levels of donor DNA in recipients’ blood could mean the organ is in danger



MIT Technology Review, March 30, 2011, by Emily Singer  —  A new test could provide a noninvasive way of monitoring heart transplant patients for organ rejection. The test, which relies on DNA sequencing to detect fragments of the donor’s DNA in the recipient’s blood, still needs to be validated in clinical trials. But physicians hope it will ultimately offer an easy way to detect the signs of organ rejection in all types of transplant patients, perhaps earlier than other approaches.

Organ rejection is still a common problem after a heart transplant—only 50 percent of patients are alive 10 years after the procedure—and transplant recipients must undergo constant monitoring for signs of organ rejection. For people with donor hearts, this typically means an invasive cardiac biopsy weekly for the first few months, then two to three times a year after that. The procedure is uncomfortable, costly, and somewhat risky.

Biopsies detect rejection by analyzing a small piece of tissue from the donor heart for signs that the patient’s immune system is attacking the organ. But in response to an immune attack, some of the cells in the transplanted organ die, releasing DNA into the bloodstream. The new test, published today in the Proceedings of the National Academy of Sciences, detects this DNA in a sample of the patient’s blood.

In the new study, researchers first compared donor and recipient DNA, searching for single letter differences that would distinguish DNA fragments from the two sources. They then designed a sequencing-based test that could detect a genetic profile unique to the donor. Analyzing blood samples collected from 39 transplant patients over several months, they found that rising levels of donor DNA correlated with the biopsy results. “It’s a very sensitive marker,” says Hannah Valantine, a cardiologist at Stanford and one of the researchers on the study. “The ratio of donor DNA remains stable in absence of rejection. But when there is rejection, we see a rise in donor DNA.”

Valantine says she got the idea after reading a paper published by Stanford engineer Stephen Quake in 2008 that described detection of fetal DNA in maternal blood. Quake’s team then did proof-of-concept tests in female patients with male donor hearts to confirm that it was possible to find this DNA.

“The test holds a lot of promise,” says Elaine Reed, director of Transplant and Immunogenetics Testing at the University of California, Los Angeles. Reed was not involved in the study. Because the results are specific to organ rejection, the test might be applicable to other organs as well, she says. For example, liver and kidney transplant patients are monitored using a blood test for an enzyme called creatinine. But rising levels of that enzyme can be linked to different kinds of damage, not just organ rejection, and it indicates that extensive damage has already occurred.



A Search Engine for the Human Body



Inside out: A close up of a CT processed by new software from Microsoft.
Credit: Microsoft Research




Microsoft software recognizes organs and other structures in medical images.

MIT Technology Review, March 30, 2011, by Tom Simonite  —  A new search tool developed by researchers at Microsoft indexes medical images of the human body, rather than the Web. On CT scans, it automatically finds organs and other structures, to help doctors navigate in and work with 3-D medical imagery.

CT scans use X-rays to capture many slices through the body that can be combined to create a 3-D representation. This is a powerful tool for diagnosis, but it’s far from easy to navigate, says Antonio Criminisi, who leads a group at Microsoft Research Cambridge, U.K., that is attempting to change that. “It is very difficult even for someone very trained to get to the place they need to be to examine the source of a problem,” he says.

When a scan is loaded into Criminisi’s software, the program indexes the data and lists the organs it finds at the side of the screen, creating a table of hyperlinks for the body. A user can click on, say, the word “heart” and be presented with a clear view of the organ without having to navigate through the imagery manually.

Once an organ of interest has been found, a 2-D and an enhanced 3-D view of structures in the area are shown to the user, who can navigate by touching the screen on which the images are shown. A new scan can also be automatically and precisely matched up alongside a past one from the same patient, making it easy to see how a condition has progressed or regressed.

Criminisi’s software uses the pattern of light and dark in the scan to identify particular structures; it was developed by training machine-learning algorithms to recognize features in hundreds of scans in which experts had marked the major organs. Indexing a new scan takes only a couple of seconds, says Criminisi. The system was developed in collaboration with doctors at Addenbrookes Hospital in Cambridge, U.K.

The Microsoft research group is exploring the use of gestures and voice to control the system. They can plug in the Kinect controller, ordinarily used by gamers to control an Xbox with body movements, so that surgeons can refer to imagery in mid-surgery without compromising their sterile gloves by touching a keyboard, mouse, or screen.

Kenji Suzuki an assistant professor at the University of Chicago, whose research group works on similar tools, says the Microsoft software has the potential to improve patient care, providing it really does make scans easier to navigate. “As medical imaging has advanced, so many images are produced that there is a kind of information overload,” he explains. “The workload has grown a lot.”

Suzuki says Microsoft’s approach is a good one, but that medical professionals might be more receptive to the design if it indexed signs of disease, not just organs. His own research group has developed software capable of recognizing potentially cancerous lung nodules; in trials, it made half as many mistakes as a human expert.

Criminisi sticks by the notion of using organs as a kind of navigation system but says that disease-spotting capability is also under development. He says, “We are working to train it to detect differences between different grades of glioma tumor”—a type of brain tumor.

The Microsoft group also intends the tool to be used at large scales. It could automatically index a collection of 3-D scans or other images, making possible new ways of tracking medical records, says Criminisi. Today, records are kept as text that describes scans and other information. A search tool that finds the word “heart”, for example, would not know if that meant it appeared in a scan or was mentioned in another context. If a hospital’s computer system indexed new scans, the Microsoft software could automatically record what was imaged in a person’s records and when.