The Lasker Awards, which honor fundamental discoveries and clinical advances that improve human health, were given on Thursday to scientists for discovering hidden complexity in cells, new states of biological matter, and a potent treatment for cystic fibrosis.
The prizes are named for Mary and Albert Lasker. Ms. Lasker was an advocate for medical research, and her husband is sometimes referred to as the father of modern advertising. The prizes are among the most prestigious in medicine, and scores of Lasker winners have gone on to receive the Nobel Prize. Recipients in each category share a $250,000 prize.
Lucy Shapiro of Stanford University received the Lasker-Koshland Special Achievement Award in Medical Science. Over the course of her 55-year career, she made profound discoveries about how proteins bring cells to life.
In the 1960s, when Dr. Shapiro started her research, scientists typically investigated proteins one molecule at a time. But Dr. Shapiro wanted to know how thousands of proteins work together in living organisms.
“Nobody was saying, ‘How do you build a cell?’” Dr. Shapiro recalled.
To understand life at this grand scale, Dr. Shapiro studied a simple organism: a common type of bacteria called Caulobacter. It reproduced by dividing into two cells, one with a stalk that anchored it to a surface, and one with a tail for swimming.
At the time, biologists dismissed bacteria as mere bags of loose proteins. But Caulobacter’s ability to make a tail at one end of a cell or a stalk at the other left Dr. Shapiro skeptical of the convention wisdom.
She soon discovered that the interior of a bacterial cell is more like a carefully organized factory than a random molecular stew. Caulobacter moved certain proteins to specific spots in its cell. Only at those spots could they do their jobs. When the microbe made a new copy of its DNA, it carefully folded the stringlike molecule into intricate loops.
In the 1990s, Dr. Shapiro uncovered another kind of complexity inside bacteria, inspired by a comment from her husband, Harley McAdams.
Dr. McAdams, a physicist at Stanford, was struck by the way biologists drew figures filled with arrows to show how different proteins regulate one another inside a cell. Some proteins spurred the cell to make more copies of other proteins. Others shut the production down. They reminded Dr. McAdams of electric wiring diagrams.
“Harley said, ‘We’ve got to think of this as a circuit,’” Dr. Shapiro recalled.
Dr. Shapiro and Dr. McAdams charted the wiring diagram of Caulobacter. They combined their labs of biologists and physicists to map some 200 proteins that Caulobacter uses to divide its cell in two. They succeeded in tracing them all back to a single master regulatory protein.
This effort helped establish systems biology as a new branch of science. Other researchers went on to find similar genetic circuits with master switches in other species. The same wiring rules that Dr. Shapiro and her colleagues uncovered in bacteria also allow a single fertilized human egg to divide into 37 trillion cells, ranging from muscles to neurons, in the human body.
“It’s the chemical logic of life,” Dr. Shapiro said.
The Albert Lasker Basic Medical Research Award was presented to Dirk Görlich and Steven McKnight for discovering jellylike blobs in cells, which are essential to the survival of living things.
“It’s a new kind of biological matter,” said Dr. Görlich, a biochemist at the Max Planck Institute for Multidisciplinary Sciences in Göttingen, Germany.
Dr. Görlich stumbled across these blobs as he studied the nucleus, the sac inside our cells that houses our DNA. Every nucleus is pierced by thousands of pores. Scientists puzzled over how certain proteins pass through the pores, while others cannot enter.
In a 2001 study with Katharina Ribbeck, who now teaches at the Massachusetts Institute of Technology, Dr. Görlich investigated the traffic through the pores, showing that a thousand proteins a second flowed through each pore into a nucleus.
“We were amazed at how fast it was,” Dr. Görlich said.
Further experiments revealed the secret: Each pore is filled with a gelatinous plug.
On their own, most proteins can’t penetrate the plug. Only a special set of transporter proteins can get through because they are decorated with certain atoms. Those transporter proteins grab onto the proteins needed in the nucleus and quickly ferry them through the jelly.
A few years later, Steven McKnight of the University of Texas Southwestern Medical Center in Dallas independently came across similar gelatinous blobs. He had been studying a protein called FUS. When he and his colleagues purified the protein, it took on a jellylike consistency.
“In all my years, that had never happened” with other proteins, Dr. McKnight recalled.
Typical proteins have a fixed, stiff structure. But FUS had flexible segments that caused the protein to bend and squirm — and to stick weakly to one another, forming a gelatinous mesh.
It turned out that the nuclear pore proteins Dr. Görlich studied also transformed into jelly with the same squirmy segments. And researchers have found many similar blobs created by other proteins throughout cells. Those blobs are crucial for tasks such as transporting molecules and building proteins from genes. Because the connections they form are weak, they can be quickly dismantled when they’re no longer needed.
Mutations to those proteins, Dr. McKnight and his colleagues have found, can cause them to glue together too strongly, forming hard, durable clumps. Those mutant clumps may play a role in Alzheimer’s and other diseases.
To Dr. McIntyre, those diseases are proof of just how important it is for cells to be able to make these strangely delicate blobs. “There’s a value to weakness,” he said.
The Lasker-DeBakey Clinical Medical Research Award honors Dr. Michael Welsh, of the University of Iowa, and Jesús González and Paul Negulescu, who have both worked at Vertex Pharmaceuticals. The three men’s research was instrumental in the discovery of drugs that transformed life for people with cystic fibrosis. The genetic disorder clogs the lungs with mucus, blocks the release of enzymes from the pancreas and can block the liver’s bile duct. Those with the disease typically died very young.
In 1989, researchers found CFTR, a gene that, when mutated, caused the disease. But it was not clear how to find a treatment.
The three scientists found a way.
The problem with the most common mutation in the cystic fibrosis gene, Dr. González explained in an interview, is that the protein it directs cells to make unravels and loses its shape, getting stuck inside cells.
The first discovery, by Dr. Welsh, was that when cells carrying the most common cystic fibrosis mutation are chilled, the protein directed by the mutant gene is more stable and more of it reaches the membrane that encases cells. That gave the researchers an idea. Perhaps they could find a drug that would attach itself to the mutated molecule and stabilize it by mimicking the effects of low temperature.
But, as Dr. Eric Sorscher of Emory University noted in a paper about the winners’ research published Thursday in The New England Journal of Medicine, “whether such molecules even existed was far from certain.”
Dr. González had found a way to look for them. He invented dyes that would light up a cell if a candidate molecule stabilized the cystic fibrosis protein. The dyes allowed him, Dr. Negulescu and their team to search through over 10,000 compounds a day. In the end, Vertex screened more than a million compounds and found drugs that worked.
The result is a three-drug combination, Trikafta, which was approved in 2019. It “transformed C.F. from a death sentence into a manageable condition for more than 90 percent of people with the disease,” the Lasker Foundation said in its citation.
Or, as Dr. Sorscher wrote, “the results could best be described as miraculous.”
Carl Zimmer covers news about science for The Times and writes the Origins column.
Gina Kolata reports on diseases and treatments, how treatments are discovered and tested, and how they affect people.
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