The multitalented protein.
Text: Angelika Jacobs
30 years ago, Michael N. Hall and his team made a profound discovery. With far-reaching implications. Only after numerous setbacks, came success and recognition.
“This right here,” says Michael N. Hall, tapping a sketch on a sheet of paper before him, “is life.” He points to a circle that becomes two and then four new circles. “We are the product of an unbroken line of cell divisions ever since the first single-celled organism.” However, as Hall points out, the sketch actually shows two overlapping processes, one of which was long neglected: cell growth. Cell division without cell growth would result in progressively smaller cells, so it could not work.
The man sitting in an office in the brand new Biozentrum building has the considered demeanor of someone who has not let his fame go to his head. 30 years ago, Hall and his team discovered the link between nutritional intake and cell growth. Today, it seems hard to believe just how difficult it was to convince the scientific community of this discovery, which laid crucial foundations for the treatment of cancer, diabetes, depression and possibly Alzheimer’s disease.
It all began with a group of new substances that ushered in a breakthrough in organ transplantation in the 80s. By inhibiting the proliferation of immune cells, they prevented the body from rejecting the donor organ. But precisely how these new immunosuppressants worked remained a mystery.
Hall came to the Biozentrum in 1987, but his research initially made relatively slow progress. His postdoctoral fellow Joe Heitman, whose interest had been piqued by the new immunosuppressants, needed a new project. So, Hall obtained the drugs, among them rapamycin. In an attempt to get to the bottom of how they worked, the researchers decided to use yeast cells – a radical approach at the time. “A lot of people thought we were crazy, giving human drugs to yeast,” Hall recalls. Today, this is common practice, as yeast is easy to work with and most of its cellular mechanisms are similar enough to those of human cells to yield valuable insights.
On the wrong track
The gambit paid off: right off the bat, Hall and Heitman, with their collaborator Rao Movva, found that just like the immune cells, rapamycin prevented yeast cells from multiplying. Heitman decided to look for the “switch” in the cell that enables rapamycin to suppress cell proliferation. In the run-up to Christmas of 1990, with his return to the US looming, Heitman was still frantically running tests when he hit the jackpot. Practically on the way to the airport, he was able to confidently identify two genes required for rapamycin to take effect. The researchers named them TOR1 and TOR2, for “Target of Rapamycin”.
Their initial results appeared in Science in August 1991. Soon after, other research groups described the mammalian variant of TOR, mTOR. After Heitman’s departure, Hall’s team remained on the scent. In the beginning, the going was tough. The TOR genes turned out to be exceptionally large for yeast, making them difficult to characterize. Finally, the researchers managed to piece together the results of their painstaking efforts. The task of TOR appeared to be to regulate cell division, a function that was blocked by rapamycin. This turned out to be a mistake, however.
A eureka moment in Vienna
Due to this mistaken hypothesis, subsequent experiments failed. Michael Hall tells of a difficult period. The breakthrough finally came thanks to an invitation to Vienna in 1993. The cell cycle expert Kim Nasmyth asked Hall to present his results in a seminar. Hall knew that Nasmyth was skeptical of the hypothesis that TOR regulates the cell cycle. “I went in braced for a confrontation.”
Yet the discussion brought a crucial aspect to light: Whereas cells in which the known regulators of cell division are disabled do not divide, they nevertheless continue to grow. Not so the cells with inhibited TOR signaling: these cells do not divide, but neither do they grow.
This gave Hall an idea: What if TOR did not regulate cell division, but cell growth? “It was as if someone had suddenly switched on the lights.” Back in Basel, the team set up the appropriate experiments. Over time, Hall and his team figured out that the two TOR proteins essentially act as sensors for nutrients, controlling cell growth via two signaling pathways.
If nutrients are available, TOR initiates processes that produce cell components. At the same time, TOR inhibits degradation processes. Cells have to reach a critical volume to divide. In the absence of the corresponding signal from TOR, however, the yeast cells remained the same size, and therefore stopped dividing. Hall realized they had made a fantastic discovery: growth was not a passively regulated process, as they had thus far assumed – it was actively controlled, and he and his team had discovered the central regulator.
Waiting for the breakthrough
At first, the scientific community remained unimpressed. The manuscript endured no less than seven rejections before it was finally accepted by Molecular Biology of the Cell, a relatively young publication at the time, in 1996. Today, the paper is considered a milestone in the field of cellular biology. Hall has since been awarded prestigious research prizes, and is seen as a contender for a Nobel Prize. As he recounts, however, it was not plain sailing. Hall produced books and toured from one conference to the next to explain time and again that cell growth meant something different to cell division.
There were times when results in the lab were not forthcoming, causing his postdoctoral fellows to worry about their career and prompting some to quit the project. “For a while, we were sailors adrift on a sea of frustration, and the islands of discovery were few and far between,” the stoic 68-year-old recalls.
An antidote to aging?
TOR has since emerged as a highly versatile tool. By blocking this nutrient sensor, cells can be tricked into thinking they are starving, causing them to suspend growth. In cancer cells, TOR is often overactive, giving TOR inhibitors such as rapamycin an important role in cancer treatments. TOR could also play a part in determining lifespan: As early as 1935, researchers discovered that modest calorie intake prolonged the life expectancy of laboratory animals.
In the 2000s it became clear that TOR inhibitors can simulate such a calorie deficit, allowing animals to live longer. “If you look at rapamycin sales, there is no question that people today are self-medicating in the hope of slowing down the aging process,” Hall concludes. He sees little hope in conducting a clinical study with human subjects, however. “Aging is not a disease to be healed.”
For Hall, the next major medical application is the brain – for instance in treating Alzheimer’s, a disease in which protein clumps are deposited in the brain, damaging the nerves. Inhibiting TOR in this region could potentially help these damaging clumps break down faster, slowing down the progression of the disease. Meanwhile, in patients suffering from depression TOR appears to contribute to the success of the fast-acting antidepressant ketamine. The drug activates TOR, supporting the formation of synapses in the brain – which are in short supply in patients with severe depression.
“TOR just keeps on yielding breakthroughs in new fields,” Hall concludes. What is more, he owes the ceaseless excitement of his research career to the protein. The Nobel Prize is a subject he prefers to avoid, however. He says it won’t bother him if he never receives it – just so long as his gravestone doesn’t bear the inscription “Here lies the man who did not win the Nobel Prize.”
Michael N. Hall first joined the Biozentrum at the University of Basel in 1987 as an assistant professor. Since 1992, he has been involved in teaching and research there as Professor of Biochemistry.
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