Serendipity in science shows need for global disease - and basic - research

One gets the impressions that scientists are fighting tooth and nail for research grants and that – in this atmosphere – more funding for research on global problems like malaria is a hard sell. Right now, the NIH spends $170 million of its $30 billion budget on malaria research. That’s $170 million for a disease at which half the world is at risk.

Map of malaria risk (in red). Licensed under Public Domain via Wikimedia Commons

Somewhere between a half to 1 million people die from malaria every year and most of these deaths are in children. I am well acquainted with these statistics as I wrote them in the introduction of three first-author papers, several grants, and countless presentations. The numbers served as a plea for the audience to care about my research and a justification for the federal money spent on a disease that doesn’t really affect Westerners.

Apparently the fact that the malaria parasite is really freakin cool is not justification enough. I mean Ebola – c’mon – it only has seven proteins! But the malaria parasite encodes over 5,000 proteins, many of which have no similarity to any known protein in other organisms and many of which are highly specialized for invading cells inside your body and hiding from your immune system.

Malaria parasites (stained dark purple) inside red blood cells. By Department of Pathology, Calicut Medical College, via Wikimedia Commons.

But researchers at the University of Copenhagen (UC) and University of British Columbia (UBC) published exciting new findings last month in Cancer Cell that will hopefully bolster the argument for why global disease research can pay off!

When the malaria parasite invades red blood cells inside the human body, it secretes hundreds of its own proteins, leading to drastic remodeling of the red blood cell: picture a saggy water balloon transforming into a rubber ball with protrusions, or knobs. These knobs stick to molecules on the host’s endothelial wall, sequestering the infected red blood cells and making it easier to acquire nutrients while also avoiding clearance in the spleen.

One of the malaria proteins in the knob, VAR2CSA, binds to highly complex chains of sugars on the placenta of pregnant women, latching the infected red blood cells onto the placenta and endangering both the mother and unborn child. It was while trying to develop a vaccine against malaria for pregnant women, that Dr. Ali Salanti of UC had an idea.

"For decades, scientists have been searching for similarities between the growth of a placenta and a tumor. The placenta is an organ, which within a few months grows from only few cells into an organ weighing approx. two pounds, and it provides the embryo with oxygen and nourishment in a relatively foreign environment. In a manner of speaking, tumors do much the same, they grow aggressively in a relatively foreign environment," Salanti said in a statement to the university last month.

It turned out the complex sugar chain, chondroitin sulfate A (CSA), which the parasite binds to, is found only on the placenta and many types of tumors but not on other healthy cells. Salanti tested whether the malaria protein could be exploited as a way to selectively deliver cancer drugs to tumors.

Working with Dr. Mads Dausgaard at UBC, a prostate cancer researcher, he found that fluorescently labeled VAR2CSA protein, produced in the lab, not only bound tumor cells but was also internalized by the cancerous cells. The researchers attached the protein to a toxin and found that the fusion killed many types of tumor cells but not healthy cells, which lacked the receptor for the VAR2CSA protein.

They next tested the toxin-VAR2 fusion on mice with different types of tumors transplanted. Treatment with the fusion drug essentially halted tumor growth in mice with non-Hodgkin’s lymphoma, while tumors in mice treated with the toxin not fused to the malaria protein grew four times the size. In mice transplanted with prostate cancer cells, treatment reduced tumor size by over 50% compared to the control and two of the six mice were even in remission 32 days after treatment. Finally, all mice with highly aggressive metastatic breast cancer died when untreated or receiving the toxin alone. In contrast five of the six mice that received the fusion drug survived with no spreading of the cancer more than 50 days after drug treatment. Other organs in the mice appeared normal and even high concentrations of toxin-VAR2 didn’t affect healthy mice.

The University of Copenhagen, in collaboration with Salanti and Dausgaard, has launched a biotech company to pursue their work further, with hopes to test it in humans in the next four years. “The biggest questions are whether it'll work in the human body, and if the human body can tolerate the doses needed without developing side effects. But we're optimistic because the protein appears to only attach itself to a carbohydrate that is only found in the placenta and in cancer tumors in humans," Salanti concluded in his statement.

Reference:

Salanti, A. et al. Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein. Cancer Cell, 2015; 28 (4): 500-514. DOI: 10.1016/j.ccell.2015.09.003.