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The insulin producers of the islets are called beta cells. (Cell types alpha, gamma, delta, and epsilon perform other functions.) They are the only physiological sources of that hormone. So, if their numbers decline, trouble looms. And it declines in a condition called type-1 diabetes. This happens when, in a phenomenon called autoimmunity, the body’s own immune system attacks complement beta cells, destroying up to 80%.
Without an alternative supply of insulin, a person with type 1 diabetes will die. (In type-2 diabetes, insulin continues to be produced but the body’s cells acquire resistance.) Supplemental insulin may be administered by injection or through a device called an insulin pump. But a better approach might be to replace the missing beta cells and somehow protect them from immune attack.
Some lucky patients actually have their beta cells replaced – by transplant from human donors. And Vertex Pharmaceuticals, a Boston firm, is testing beta cells grown from stem cells for the same purpose. But neither approach includes immune protection. This means that both require the administration of immunosuppressive drugs to prevent rejection following any transplant, let alone one where autoimmunity is at play. A session at this year’s meeting of the American Association for the Advancement of Science in Denver looked at how transplanted beta cells could be made hypoimmunogenic — in other words, invisible to the patient’s immune system.
Sonja Schreffer, who works at the University of California, San Francisco (UCSF) and Seattle-based Sana Biotechnology, proposes a dual approach to deal with the fact that the immune system has two arms. One, the adaptive arm, is the basis of tissue rejection. This adaptive arm can recognize the signature of “self” provided by a person’s HLA proteins. These molecules contain so-called hypervariable regions, which vary from individual to individual. If the immune system comes in contact with non-self HLA proteins, it recognizes the cells using shock troops called killer T-cells and antibodies, labeling them as interferents and attacks.
So the first part of Dr. Schreffer’s approach is to block the production of HLA proteins in lab-grown beta cells for transplant. This could be done by editing two genes involved in their production, theoretically rendering the cells invisible to the adaptive arm.
However, the lack of HLA proteins brings the cell to the attention of the other arm of immunity, the innate system. Its soldiers are called NK (natural killer) cells and macrophages, and one of the red flags it reacts to is the absence of any type of HLA. However, this can be prevented by over-expression of a protein called CD47, which Dr. Schreifer’s team also achieved by genetic manipulation of their beta cells.
It seems to be working. In an experiment whose results were announced just before the meeting, the team first induced diabetes in a laboratory monkey and then injected their modified beta cells into one of its muscles. The diabetes went away, and stayed away for more than six months. Now they have moved towards the people. In a trial starting at Uppsala University Hospital in Sweden, the human version of the modified cells will be implanted into a patient’s forearm.
Disrupting HLA expression of beta cells is not the only possible way to subvert the adaptive immune system. Hasna Machi of the Technical University of Munich in Germany told the meeting how she and her mentor Matthias Hebrock are trying to develop an alternative. To protect against this, a third party is introduced, which is called a suppressor cell.
Suppressor cells “talk” to killer T-cells, silencing them. So Dr. Hebrock’s group is working with Wendell Lim of UCSF, who is engineering suppressor cells specifically activated by a protein on the surface of beta cells to create some betas. -Cell Security. In this case there is no need to build up a level of protection against the innate immune system, as it will not see anything wrong.
Dr. Machi said that Hebroek’s group is also working on a way to turbocharge beta cells. It involves a protein called MAFA, which regulates insulin gene expression. Suppressed levels of MAFA are a hallmark of type 1 diabetes, so increasing its presence appears to be a promising approach. So far, researchers have shown that increasing MAFA levels in beta cells derived from stem cells increases the amount of insulin produced.
Data presented by Lori Sussel of the University of Colorado show that type 1 diabetes affects one in 500 Americans. The global average may be closer to one in 1,000. It is also a huge source of human suffering and a lucrative market for anyone who can come up with something resembling a cure rather than a cure. Although there is still a way to go, hypoimmunogenic beta cells could, potentially, bring it closer.
© 2024, The Economist Newspaper Limited. All rights reserved. From The Economist, published under license. Original content can be found at www.economist.com
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