This bioluminescence image of an anesthetized mouse injected with anti-cancer T cells shows that they gather preferentially in two spots: the spleen, where T cells hang out until mobilized, and the tumor. The red areas have the highest T-cell concentrations. Since this particular cancer, a melanoma, was derived from melanocyte-containing skin cells that display similar antigens, the hairless tail and legs also light up. Losing your melanocytes will cause skin depigmentation; losing a battle to melanoma is fatal.

Engineering Immunity

Caltech scientists are designing living tools that immune-system cells can use to fight disease, thanks to a $750,000 grant from the Skirball Foundation. The gift will expand the Engineering Immunity program founded by David Baltimore, the Millikan Professor of Biology, and Pamela Bjorkman, the Delbrück Professor of Biology and an investigator with the Howard Hughes Medical Institute.

For nearly 40 years, Baltimore has studied how genetic information gets from viruses into host cells. He codiscovered an enzyme that enables the RNA of certain viruses to make a DNA copy of its hereditary information—genetically engineering its host. DNA’s transcription of information to RNA was well known, but no one knew that RNA could write back. That discovery so altered science that Baltimore and two other researchers won a Nobel Prize.

Engineering Immunity puts viral genetic-engineering capabilities to good use. Researchers in Baltimore’s lab are designing highly customized, stripped-down viral molecules containing genetic components that inhibit real viruses and tumors. These molecules can sneak into your body’s cells, inserting their protective cargo into the cells’ DNA. Engineering Immunity project manager and lead scientist Lili Yang (PhD ’04); then-staff member Pin Wang (MS ’00, PhD ’04), now at USC; and Baltimore recently published a method for designing injectable versions of these molecules that are capable of selecting a specific cell type, such as the cells that kick off immune responses. This vastly reduces the risk, time, and cost involved in previous methods for genetically modifying human cells, which involved removing them, working with them in a laboratory, and then reintroducing them into the body.

Four years ago, the Skirball Foundation provided the project’s seed funding. Since then, the program has grown into a massive HIV- and cancer-research effort that extends far beyond Baltimore and Bjorkman’s collaboration to include teams at UCLA, USC, and Children’s Hospital Los Angeles.

The new grant is intended to do just what the first one did—encourage research seen as too exploratory for most organizations to support. This new money will underwrite three immune-system studies, a breakthrough in any of which could lead to substantial improvements in an array of medical applications.

Yang plans to learn more about T cells—white blood cells central to cellular immunity—by actually watching them in action. She has developed a method for labeling the T cells of interest with a bioluminescent imaging gene, allowing them to be tracked in a live animal in real time. Biologists can now watch how T cells behave when they encounter the friend-or-foe tags known as antigens, when they kill tumor cells, and when they recede after the battle is complete. A wide range of experiments being done in concert with medical imaging under way at UCLA could significantly improve cancer treatments by identifying the critical conditions needed for immunotherapy to work.

Visiting Associate in Biology Daniel Kahn, an obstetrician affiliated with the David Geffen School of Medicine at UCLA, will study some newly recognized types of immune cells that may hold the key to a longstanding mystery: Why don’t pregnant women reject their own fetuses, which are packed with antigens from the father that are foreign to the mother? Could pregnancy-specific diseases like preeclampsia result from the immune system going awry? Finding the answers may not only strengthen treatments for pregnancy-specific conditions, but perhaps may improve the long-term success of organ transplants.

Finally, postdoc Ryan O’Connell will tackle RNA molecules called microRNAs or miRs. Discovered just a few years ago, miRs turn out to be powerful players in the development (or inhibition) of cancer. Three of them, called miR-155, miR-146, and miR-34, have been linked to cancers of the immune system but are also involved in immune-cell development and healthy responses to inflammation. These microRNAs may be able to trigger cells to proliferate, kill themselves, or stop replicating—properties that might be exploited to deal with cells that have run amok and begun growing abnormally.

Engineering Immunity—started by one funder’s leap of faith in a speculative line of research—is paying huge dividends. Says Baltimore, “The Skirball grant was the most important grant I ever received. . . . The foundation took a chance in supporting an unproven notion.” With that “unproven notion” now going full steam in labs across Southern California, the Skirball Foundation is once again out in front in supporting science in its earliest, most basic stages. —AW