The Story of SMO
Smooth(ened) operator helps control growth during development but promotes common form of cancer when left unchecked.
The story of SMO starts with the humblest of beginnings as just one of hundreds of random genes scientists have painstakingly identified in the fruit fly. Within just a few of decades of its discovery, however, SMO has been revealed to be a prime time player in one of the most ubiquitous cellular developmental pathways, one shared by nearly every species on earth. Along the way, this gene has accrued such importance that a Nobel Prize has been granted for the discoveries around it, and it is now the target of a multibillion-dollar effort to wipe out the most common form of cancer known to man.
In 1910, the first set of experiments to identify genes in Drosophila melanogaster, the common fruit fly, took place in Columbia University’s infamous “Fly Room.”Flies with observable natural mutations were crossbred in order to interrogate the mechanisms of genetic inheritance. In the decades since, Drosophila has become a highly popular model organism for genetic studies due to its small size, quick generation time, large brood and transparent embryos.
Developmental biologists, in particular, sought to exploit the larval fruit fly’s regularly segmented body plan. The thinking was that systematically mutating genes that code for proteins within developmental pathways could reveal the secrets of how embryos developed from an amorphous blob of cells into a precisely structured organism, and how this process might go wrong.
In the late r97os and early r98os, a small cadre of researchers led by developmental biologists Eric Wieschaus and Christiane Ni.isslein-Volhard at the European Molecular Biology Laboratory in Heidelberg, Germany, had been using the carcinogen ethyl methanesulfonate to randomly mutate individual Drosophila genes to figure out their function. Mutate one gene and maybe nothing observable happens. Mutate another and the fly is born with fewer than normal body segments. Mutate yet another and the segments’ spatial patterning becomes disrupted. The process was kind of like moving into an old house, realizing none of the switches on the fuse box are labeled, and flipping each one on and off in turn to figure out how everything was wired up.
Over the course of a few years, Wieschaus and Nusslein-Volhard identified a handful of genes that played critical roles in determining Drosophila’s body segmentation and patterning. Following fly biology protocol, the names they gave these genes were based on physical characteristics of the developing embryos in which the genes had been shut off. Mutating the gene hedgehog, or SI-IH, made the embryo look stumpy and covered in bristles. Mutating patched, or PTCH, caused a patchy appearance. Not surprisingly, mutating smoothened, or SMO, gave rise to a smooth, cue ball-like embryo.
How smoothened works on the molecular level
Wieschaus and Nusslein-Volhard and others worked out how each of the proteins synthesized from information stored within the chemical structure of SHH, PTCH, and SMO fit together into an interconnected pathway. The hedgehog protein is a signaling molecule that migrates between nearby cells. It fits like a key into the patched protein receptor, which sits on the outside surface of the cell membrane. Adjacent to patched is smoothened, a protein that straddles the membrane, one end sticking out of the cell and the other poking into the interior of the cell.
The hedgehog pathway works like a series of check and balances. Patched tamps down the activity of smoothened. When hedgehog lands on patched, the patched receptor turns off, thereby releasing the inhibition applied to smoothened. Uninhibited, the portion of smoothened jutting into the inside of the cell sets off a chain of molecular events, triggering the expression of genes involved in growth.
The key realization by Wieschaus and Nusslein-Volhard’ s team was that hedgehog molecules don’t wander far, so their levels vary by location within the embryo. Cells closest to the center of a body segment received a strong signal, and those further away received a weak one. This signal strength tells cells where in the developing embryo they are and helps cells decide what to become when the time comes to differentiate into certain body parts. This scheme allows hedgehog signaling to effectively drive body segmentation.
If that were the whole story, smoothened would have remained firmly entrenched in relative obscurity like the vast majority of Drosophila genes with quirky names discovered over the years. Instead, some version of SMO, along with the rest of the proteins involved in the hedgehog signaling pathway, has been found in numerous other species including humans.
What does this mean for humans?
While human bodies look vastly different from those of fruit flies, there are striking similarities in how the body plan of both species is laid out. And while SMO and the other genes of the hedgehog pathway dictate body segmentation in the fly, they were found to be the driving factors of skin growth in humans. The pathway was active, of course, during development, but it also gets activated when skin has been injured to assist in repair functions.
Hedgehog signaling has since been found to be responsible for nearly every aspect of development in humans. For their part in discovering the hedgehog pathway Nusslein-Volhard and Wieschaus, along with biologist Edward Lewis, accepted the Nobel Prize in Physiology or Medicine in r995.
While the influence of the hedgehog pathway was beginning to be fully appreciated, developmental biologists and oncologists realized that a lot of the same cellular machinery active during the body’s development could be responsible for the pervasive, unwanted growth seen in cancer.
Without patched continuously keeping smoothened in check, smoothened mindlessly sends out “grow” signals. And PTCH, the gene, it turns out, is actually fairly susceptible to mutations resulting from prolonged exposure to the sun’s harmful ultraviolet rays. Mutated PTCH genes can no longer produce enough patched protein to restrain smoothened. The result is that smoothened is let loose to send its signal to grow. Before long, this unchecked growth becomes cancer, particularly basal cell carcinoma (BCC), the most common form of cancer in humans. Faulty PTCI-1is not always to blame for BCC, though; direct mutations of SMO can also lead to BCC as well as medulloblastoma, a type of malignant brain cancer. Inherited mutations in PTCI-I and SMO also occur and are usually lethal or linked to serious developmental defects.
Drugs to treat BCC could theoretically be targeted to any part of the hedgehog pathway, but since it’s biologically easier to deactivate a gene than it is to boost the production of a gene, most treatments have focused on shutting down SMO. Numerous compounds have been able to rein in SMO, causing tumors to shrink dramatically. I-lowever, tumor cells mutate much more frequently than do normal cells. Drugs essentially have no affect on SMO once it mutates, so in many cases cancer will eventually return.
One drug that has been found to be an effective antagonist of SMO is Genentech’s vismodegib (marketed as Erivedge), the first drug targeting the hedgehog signaling pathway to be approved by the Food and Drug Administration (FDA). In 2or2, the agency approved vismodegib for use in treating adults with locally advanced basal cell cancer who are not candidates for surgery or radiation and for patients whose cancer has spread to other parts of the body. Vismodegib is also in trials for a variety of cancers including medulloblastoma, metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, and chondrosarcoma, a bone and joint cancer.
SMO’s journey from anonymous fruit fly gene to the focal point of a high-profile cancer treatment strategy is reflected in Nusslein-Volhard’s r995 Nobel acceptance speech: “None of us expected that our work would be so successful or that our findings would ever have relevance to medicine.” Twenty years later, SMO is still finding ways to surprise.