The doubling time for E.coli bacteria is 20 minutes. With uncontrolled growth, it would take a mere two days for the weight of bacteria to equal the weight of the Earth. What rules determine the actual numbers of bacteria? Why is the world green; why don’t insects eat all the leaves? How does the body maintain homeostasis? What determines the uncontrolled growth of cancers? What happens when you remove natural predators from an ecosystem?
You can find the answers in Sean Carroll’s new book The Serengeti Rules: The Quest to Discover How Life Works and Why It Matters.
Everything is regulated: every kind of molecule, cell, and process in the body is maintained in a specific range and governed by a specific substance or set of substances. Diseases are mostly abnormalities of regulation. Too little insulin = diabetes. Uncontrolled cell multiplication = cancer. To intervene in disease, we need to understand the rules of regulation.
Carroll calls them the Serengeti Rules because of the ecological rules that regulate the predator/prey ratios in Africa. But the same rules apply everywhere, at every level of biology.
Fascinating stories about scientists
Carroll is a great storyteller. He tells rip-roaring adventure stories about scientists who risked their lives on Arctic expeditions, treated patients on the battlefields of WWII, helped the French Resistance by hiding incriminating documents in the leg of a stuffed giraffe just outside the lab, climbed 20,000-foot mountains in the Andes, and a researcher whose experiment required prying starfish off the rocks with a crowbar and throwing them out to sea.
He introduces us to Janet Rowley, a pioneer in research about cancer-related genes. A mother of four, she said, “I want to work in your lab but you’ll have to pay me so I can hire a babysitter.” As an 88-year-old grandmother she was still bicycling to the lab every day. When she was dying of ovarian cancer, she pre-arranged her own autopsy to contribute to scientific knowledge about her disease.
What are the rules of regulation?
…in general, increases in [prey] numbers were held in check by predators, pathogens, parasites, and food supply. Extinction was avoided…because as a prey became scarce, predators would switch to other quarry, allowing numbers to recover.
But how do the rules of regulation work? Ecologists rely mainly on observation; physiologists can do experiments to find out. The rules they deciphered in bacteria turned out to apply to all kinds of processes in all sorts of living organisms.
When bacteria are fed with a new kind of sugar, they start making an enzyme to digest it. How do they “know” to do that? Clever experiments teased out the mechanism. The presence of the new sugar induced the production of the necessary enzyme. But not directly. They found that there was a protein whose job was to repress the production of that enzyme, and the new sugar inhibited the repressor.
There are four general rules of regulation:
- Positive regulation: A increases the abundance or activity of B
- Negative regulation: A decreases the abundance or activity of B
- Double-negative: A decreases B, B decreases C; therefore A increases C
- Feedback: the accumulation of C feeds back to negatively regulate A and the production of B and C
But how? They eventually discovered that it has to do with the shape of molecules. Protrusions on substrate molecules fit into receptacles in enzyme molecules like a key in a lock and that alters the enzyme’s shape so it no longer functions. Understanding these processes is crucial to understanding disease and discovering treatments.
Examples small and large
These rules govern the processes that keep our blood pH within a narrow range, produce just enough thyroid hormone, make the right number of new red blood cells to replace the ones we lose, and regulate all our physiologic processes. Genetic mutations can inactivate the repressors that control cell growth, leading to cancer. Research on oncogene mutations and tumor suppressor gene mutations eventually led to cancer treatments tailored to a patient’s specific cancer. Gleevec, the first of these new drugs, was a spectacular success.
Statin drugs regulate enzymes that control blood cholesterol levels. Carroll tells the intriguing story of their development, complete with all the errors, setbacks, and serendipities.
The same rules operate on a larger scale to regulate animal populations. Sea otters are a keystone species at the top of a trophic cascade. Sea otters suppress the numbers of sea urchins; sea urchins suppress the growth of kelp. In the absence of sea otters, sea urchins eat all the kelp, creating kelp-free barrens. When sea otters are re-introduced, the sea urchin population drops and flourishing kelp forests return. Sea otter predators cause the increase of kelp through double-negative regulation.
There are many other examples: wolves eat moose, moose eat trees; re-introducing wolf predators to Yellowstone increased the number of trees.
A puzzle about why the population of buffalo and wildebeest was expanding at a greater rate than other, similar animals on the Serengeti was traced to a keystone virus, rinderpest, with a reservoir in domestic cattle. As cattle were vaccinated against rinderpest, it no longer killed the particular species of wild animals that were susceptible to it. The resulting spike in wildebeest and buffalo populations meant that more grass was being consumed, resulting in fewer dry-grass wildfires, resulting in more young trees, resulting in more food for giraffes, resulting in an increase in the giraffe population. And there was more prey for lions, so the lion population increased. Herb, grasshopper, and butterfly populations were also affected. All regulated by the presence or absence of a virus.
When an insect, the brown planthopper, threatened Asian rice crops, farmers sprayed pesticides. Instead of suppressing planthopper numbers, there was an 800-fold increase. The pesticide increased the rate of egg-laying by 2.5 times. It turns out the pesticide killed off the spiders that had been eating the planthoppers and keeping their numbers under control. Oops.
He describes successful interventions to restore the ecosystems in American lakes, Yellowstone, and a national park in Mozambique.
We have figured out the drill for combating any disease: identify the most important players, figure out the rules that regulate them, and target what is broken or missing.
Carroll tells the smallpox story with details that were new to me. There was skepticism about the vaccination campaign in high places, mainly because it didn’t seem possible to vaccinate every person on Earth. But understanding the ecology of the disease led to a new strategy of ring vaccination, creating a ring of vaccinated people around each infected patient. That strategy was able to stop outbreaks with only 15% of the total population vaccinated. Smallpox was eliminated from the globe in 1977, and a similar campaign was successful in eliminating another disease, rinderpest in animals.
He tells the story of the last case of smallpox: Ali Maow Maalin, a hospital cook, rode along with infected children in a Land Rover to show the driver how to get to an isolation area. Two weeks later, he developed a rash and fever that was initially diagnosed as chickenpox because they assumed he had been vaccinated. The vaccine was mandatory for all hospital employees; but on the day it was given, Ali had managed to evade the shot because he was too afraid of the pain. The ring vaccination strategy prevented his case from spreading to anyone else, and smallpox was no more.
The same basic rules govern regulation of everything from genes to elephants, from bacteria to trees. Understanding those rules is essential for solving problems in human health as well as in global ecology. Carroll is optimistic. He quotes Greg Carr: “Choose optimism because the alternative is a self-fulfilling prophecy.”
This book is a great way to learn about the rules of regulation and about how science works. It’s not just a painless way to learn, it’s positively fun. You couldn’t ask for more.
This article was originally published in the Science-Based Medicine Blog.