Professor Emeritus Richard F. Ludueña discusses his novel theoretical framework for cancer chemotherapy, utilizing CRISPR-Cas9 to target specific tubulin isotypes. He also explores his current research into the historical intersection of science and religion in the ancient Mesopotamian centers of Harran and Edessa.
Part I: The Molecular Universe
Q: Your research highlights a fundamental challenge in oncology: that cancer cells are essentially ‘our own cells misbehaving.’ How does your proposed dual-target approach involving βIII-tubulin and CRISPR-Cas9 shift the paradigm away from traditional, often toxic, chemotherapy? The paradigm shift lies in moving away from blunt instruments. Traditional chemotherapy targets processes that both cancer and healthy cells need to survive. My proposal targets βIII-tubulin, a protein normally found in neurons and cancer cells. However, neurons in adults rarely divide, whereas cancer cells divide incessantly. My former graduate student, Dr. Consuelo Walss-Bass, discovered that dividing cells generate the α/βII tubulin dimer and localize it to the cell nucleus as they divide. My colleague Dr. I-Tien Yeh discovered that this process occurs in many types of cancer. My colleague Dr. Anna Portyanko showed that this occurs more frequently in cancers with poor prognosis. The idea is to first generate a complex between the α/βII tubulin dimer and a CRISPR-Cas9 targeting βIII. Thus, the α/βII tubulin dimer would act as a “homing mechanism” to deliver a CRISPR-Cas9 complex specifically into the nuclei of dividing cells. Once there, the CRISPR “wrecks” or silences the βIII gene. Without βIII-tubulin, the cancer cell is forced to rely on βII-tubulin. While the cancer cell “likes” βII, that isotype is far more susceptible to drugs like Taxol. We essentially trap the cancer cell in a state where it can no longer resist treatment.
Q: You’ve discussed the idea of removing N-terminal methionines to give the CRISPR complex an ‘expiration date’ via the ubiquitin system. From a clinical perspective, how critical is this temporal control? I view it as a vital “layer of protection” or a safeguard. Tubulin naturally has an N-terminal methionine that blocks its degradation. If we engineer the tubulin in our reagent to lack that methionine, the cell’s ubiquitin system will eventually recognize and degrade it if it lingers too long. In a slow-dividing normal cell, this gives the body time to clear the reagent before it can do any damage. In a fast-dividing cancer cell, the reagent does its work before the “expiration date” hits. It’s a way to ensure the therapy is self-limiting and doesn’t persist in the body indefinitely.
Q: βIII-tubulin seems to be a “double-edged sword,” providing cancer cells with both dynamic stability and protection from oxidative stress. Can you explain the chemistry behind that? Exactly. Microtubules must be dynamic for a cell to grow and move. We’ve found that βIII promotes that high level of dynamism. Furthermore, most tubulin has a cysteine at position 239 which is highly susceptible to being “shut down” by free radicals—the very oxidative stress that often causes cancer in the first place. βIII-tubulin is different; it has a serine at that position instead of a cysteine, making it immune to that oxidation. By stripping the cancer cell of βIII, we aren’t just making it more susceptible to Taxol; we are removing its shield against the harsh, oxidative environment it lives in.
Part II: From the Laboratory to the Library
Q: Moving from the laboratory to the library, you are currently writing a book on the history and religion of science in Harran and Edessa (modern-day Şanlıurfa). What drew you to these specific ancient centers? Ever since I was a little boy, I wanted to visit Nemrut Dağı in Turkey to see those colossal carved heads. In 2014, my daughter and I finally traveled there, and our tour included Harran and Edessa (modern-day Şanlıurfa). I was immediately struck by the absence of a detailed history of these regions, so I decided to write one. Harran served as an intellectual “bridge” and a major center for the worship of the moon-god, Sin. My hypothesis is that centuries spent meticulously tracking the moon and planets for spiritual purposes inevitably fostered sophisticated mathematics and physics. The people of Harran became the “tech experts” of antiquity. For instance, when a solar eclipse halted a battle between the Lydians and Medes, King Nebuchadnezzar turned to a courtier from Harran, Nabonidus, to explain the phenomenon. Archaeological evidence, such as a 7th-century BC table of reciprocals found in the region, confirms this advanced mathematical culture. Furthermore, these cities were geographical “hinges”; the Roman defeats at the Battle of Carrhae in 53 BC and near Edessa in 260 AD fundamentally altered the frontiers of the Roman Empire and the subsequent course of Western history.
Q: Does the history of these cities challenge the modern notion that science and religion must always be in conflict? I don’t believe they have to be in conflict. Science is based on the analysis of observations; religion is based on belief. Jacques Monod once said the one principle of science is that the universe is knowable. In Harran, the “religion” essentially funded the “science.” Their spiritual dedication to the heavens required them to become the best astronomers and mathematicians of their era. Conflict only arises when fundamentalism refuses to accept observed reality, but for much of history, the two were deeply intertwined.
Q: You mentioned that these cities sat on a geographical “hinge” that changed the course of world history. Could you elaborate on that? They sat on the border between the Roman/Byzantine West and the Persian East. Two specific battles near these cities changed everything. In 53 BC, the Roman general Crassus was defeated at the Battle of Carrhae (Harran). Had he won, Rome might have conquered all the way to India, creating a completely different global culture. Later, in 260 AD, the Emperor Valerian was captured near Edessa by the Persians. This forced Rome to pull back its frontiers from Germany and Romania to protect the Syrian border. That retreat ultimately weakened the empire’s defenses elsewhere, contributing to the eventual fall of Rome. These weren’t just local skirmishes; they were the turning points of Western civilization.
Q: Does your study of history provide any philosophical insights that inform your work in biochemistry? To be honest, I keep them separate! I call myself an “intellectual bigamist” because I love both areas—biochemistry and world history—deeply, but they occupy different parts of my mind. I’ve been reading world history since I was seven years old, and I practiced biochemistry for my entire career. However, there is a common thread: the “Open Access” exchange of ideas. In Edessa, you had Greek, Syriac, and Arabic scholars sharing knowledge. That same spirit of sharing ideas is why I published my current cancer research theory. I am retired; I have no lab. I am throwing these ideas out there in the hope that someone with the funding and the facilities will take the baton and test these hypotheses.
