Published On Nov 24, 2015
The Bleeding Edge
A Boston lab looks to the plucky and omnipresent red blood cell for a new generation of therapies.
Harvey Lodish saw his first red blood cells as a high school student, during summer research in a lab. Lodish, a professor of biology and bioengineering at MIT, went on to become a pioneer in the study of those useful couriers, which deliver oxygen throughout the body. His academic work came to focus on the genes that control the production of these cells, governing how they grow from progenitor cells to the characteristic disks that assume concave sides as they reach maturity.
Lodish now believes that researchers can usefully reengineer red blood cells. A company he helped start, Rubius Therapeutics, is looking at ways to turn them into delivery vehicles that can carry medicine throughout the body.
Q: What makes red blood cells useful to tinker with?
A: Medicines that are ingested as pills or injected into the bloodstream are active in the body for a few days at most. But red blood cells circulate in the body for about 120 days before they’re degraded. So if you could somehow make these cells carry medications, they could stay in the blood for a much longer period.
There’s also something unique and useful in how red blood cells are formed. When an immature red blood cell is made in the bone marrow, its nucleus gets ejected before the cell is released to the bloodstream. So a mature red blood cell lacks a nucleus and lacks DNA.
Q: And why is ejecting the DNA important?
A: It means we can genetically modify the DNA in progenitor cells—the marrow cells that become red blood cells. But the modified DNA itself will be ejected before the cell is released.
This means there’s no danger that the altered DNA will stick around and cause trouble. That’s ordinarily a concern in stem cell gene therapy. Stem cells can mature into several types of cell, and like all cells with a nucleus, they can divide and multiply through the process of mitosis. You don’t want to introduce the one cell in a million that will cause a tumor. But red blood cells don’t have a nucleus or DNA, so they can’t divide and multiply. That’s an advantage over any other cell therapy.
Q: Where did this research idea start?
A: The Defense Advanced Research Projects Agency, otherwise known as DARPA, was interested in making large numbers of red blood cells that could be transfused into patients, and particularly into soldiers. DARPA’s contractors were trying to take progenitor cells and turn them into red blood cells in culture, but they couldn’t do the crucial last stage. We figured it out, but Dan Wattendorf, DARPA program manager of the Biological Technologies Office, emphasized it wasn’t economical to produce blood for transfusions that way. Then Dan said, “Can we make high-value red blood cells?” I said, “What do you mean by that?” And he said, “I don’t know, think about it.” So we started looking at what made these cells unique, and how that might be turned to our advantage.
Q: What are other ways you could use genetically modified red blood cells?
A: We can make a cell express a protein that would cure a genetic disease. In many genetic diseases people are missing a particular protein—their bodies don’t make it. So we could use red blood cells to make it instead. There are several proteins that look very promising.
We could also use red blood cells prophylactically. We’re going to be working with the Department of Defense on this. If you’re sending soldiers into a zone that’s contaminated with you-name-it nasty substance, you could give them red blood cells that protect them. For example, you could make red blood cells that express enzymes that destroy nerve gases, which are organic chemicals that interfere with the nerves’ signals to the organs. If you could prophylactically give soldiers the ability to destroy the chemical, you could save lives.
There are lots of applications. We can equip red blood cells with antibodies to neutralize all sorts of nasty pathogens: bacterial toxins, viruses, you name it.