WALTHAM, Mass. In a busy lab nestled in Middlesex County, a team of researchers peers into a microscope. In the glow of a cryo-electron microscope, they look at blurry images and start to see a protein take shape. Using Cryo-EM, a method that flash freezes proteins to image them at extreme resolutions, the lab uncovers the secrets behind ALP, the first of a new class of drugs that could revolutionize cancer treatment.
At this lab, chemists and biologists are learning how to design proteins, small biomolecules produced everywhere in the body, into self-assembling protein machines. Current research focuses on alkaline phosphatase (ALP), a protein present in abundant concentrations in cancer cells and stem cells. With the help of an L-phosphopentapeptide synthesized in the lab, ALP could destroy cancer cells by transforming into sharp ribbons that shut the cancer cell down from within while keeping healthy cells alive. The goal is to design “self-assembling” materials, which, like Lego pieces, snap together on their own in very specific shapes as a way to fight cancer.
To understand why these therapies are so promising, it helps to know why cancers are so hard to cure. Most cells in our bodies serve highly specialized roles: neurons transmit signals, muscle cells contract, and skin cells protect. These cells are only able to divide a limited number of times before dying. Stem cells are the exception. Unlike the trillions of other cells in our bodies, they have the potential to morph into many different cell types, and they can divide and multiply infinitely under the right conditions. Stem cells in the body are highly regulated, while cancers represent a dark mirror of this biology. Cancer cells “go rogue,” dividing uncontrollably, destroying tissue, and often undergoing dedifferentiation, reverting to a more primitive, stem cell-like state.
The similarity between cancer cells and healthy cells makes treatment extraordinarily difficult. Traditional therapies like chemotherapy and radiation are essentially scorched-earth approaches. One of the biggest goals of modern cancer therapies is to find treatments that hurt cancer cells without hurting healthy ones by exploiting molecular differences.
The Self-Assembling Solution
The human body is filled with proteins, which are complex molecules that carry out nearly every function of life. They build tissue, move nutrients, and send signals. Their precise folded structures determine their role. Some proteins can even cause cells to self-destruct, a function at the center of this research.
One foundation of the lab’s work is the discovery that stem cells produce large amounts of ALP, or alkaline phosphatase. Researchers later observed that a simple protein, L-phosphopentapeptide, kills stem cells but not healthy cells. When ALP interacts with a specially engineered L-phosphopentapeptide, it triggers an astonishing transformation: the peptide self-assembles into nanofibers or nanoribbons inside the target cells’ nuclei. ALP is also overproduced in many cancer cells, making them vulnerable.
This connection revealed that since both stem cells and certain cancers share high ALP activity, a therapy targeting ALP might selectively eliminate dangerous cells while sparing healthy ones. While cancer cells were destroyed, healthy cells broke down their extra ALP without sustaining damage. The treatment works like a Trojan horse: the cancer cells invite it in and cause their own demise.
While the exact mechanisms remain mysterious, early results against bone cancer are promising. The treatment appears to exploit cancer's greatest weakness—its attempt to regain stem cell-like properties. In trying to become more resilient, these cancer cells accidentally make themselves vulnerable to a completely new kind of attack.
Researchers are now investigating the precise mechanisms by which ALP assembles L-phosphopentapeptide into cancer-killing nanofibers. Recent experiments reveal the specific dosages and time spans needed for ALP to most effectively kill cancer. The next challenge is explaining exactly how these nanoribbons kill cancer cells, which could lead to smarter, more effective therapies.
Beyond this, work has expanded to include a previously ignored protein component, called intrinsically disordered domains. Most protein segments fold into common shapes, or "domains,” which help predict a protein’s function. Intrinsically disordered peptides, however, remain flexible and dynamic. This flexibility allows them to interact with multiple partners and adapt to different environments. With just a few modifications, these disordered peptides can turn into fixed, self-assembling structures. The lab is leveraging this flexibility to design entirely new protein architectures that could trigger different reactions in different cells.
The significance of this work goes far beyond just one potential treatment. These new models are helping build an entirely new scientific infrastructure for protein design. A better understanding of these overlooked proteins could reveal new secrets of the biological machinery in current organisms.
This philosophy echoes across the lab, which draws on physics, materials science, and molecular biology to imagine what medicine could look like if built molecule by molecule.
Scientific discovery here is framed not as the achievement of individuals, but as the product of collaboration and accumulated knowledge. Just as current studies on reaction speeds and intranuclear accumulation build on predecessors’ findings about ALP in stem cells and cancers, they provide the foundation needed to turn these insights into real treatments. These breakthroughs also rely on partnerships with scientific suppliers, such as Biomatik, which provided the alkaline phosphatase (ALP) central to the experiments. But these partnerships come with challenges as well: due to changes in the ways ALP is manufactured and a wide variety of protein forms, researchers must ensure that what is used is applicable across different labs.
While treatments developed using self-assembling proteins are still not publicly available, if successful, they could represent a new class of drugs: biologically responsive, highly selective, and activated only in the presence of disease. Rather than flooding the body with chemicals, future medicines might build themselves inside us, guided by the disease itself.