Basic Medical Research Award
We live in a dangerous world, surrounded and threatened by two types of foreign invadersone political and the other microbial. Protection against these invaders depends on the efficient operation of two different systems of defenseone dedicated to our nation's security and the other to our body's immunity. As I discuss the work of this year's Lasker Basic Award winner, you'll see that the immune system shares many features with the government's security system, albeit with notable differences in their effectiveness.
Our national security is organized around a two-tier operationthe CIA and the FBI. In a perfect world, these two agencies would interact and cooperate. The CIA's mission would be to identify potential enemies, gather information on them, and analyze the intelligence for presentation to the second tier, the FBI. The FBI would receive the CIA's intelligence, act on it, and eliminate the foreign invaders before any damage is done. But, unfortunately, we don't live in the fictional world of movies and novels, and the CIA and FBI more often than not fail to connect the dots.
The New York Times reporter and two-time Pulitzer Prize winner, Tim Weiner, has just written a riveting book on the history of the CIA entitled Legacy of Ashes. The CIA was established just after World War II by President Harry Truman. According to Weiner, in its 60-year history, the CIA has rarely accomplished its mission of intelligence gathering.
The man whom President Truman appointed as the first CIA director was a fellow Missourian whose main claim to fame was that he had run Piggly Wiggly supermarkets. In a White House ceremony, Truman presented his new CIA chief with a black cloak and a wooden dagger. J. Edgar Hoover, the FBI chief at the time, was not amused.
President Eisenhower's view of the CIA was less jocular than Truman's. When Eisenhower left office in 1961, he reprimanded the fifth CIA director, Allen Dulles, telling him: "I will leave my successor a legacy of ashes." To this day, our nation's security system remains in shattered disarraytrue to Eisenhower's prophesy.
Now to our body's immune system, which like our nation's security system, is a two-tier operation that gathers intelligence and then eliminates the enemy. But there is one difference between the two systems: Our immune system was creatednot by a U.S. President, but by Mother Nature—and it has been perfected, not by 60 years of Congressional hearings but by 500 million years of evolution. Evolution has left us a "legacy of marvels"a marvelous molecular machine that protects us against the millions of microbial invaders that assault the human body every day. To quote the second law of Leslie Orgel, the great British chemist, "evolution is smarter than you are."
This year's Basic Award winner, Ralph Steinman, is a scientific sleuth, who without cloak and dagger uncovered the intelligence-gathering component of our immune systema monumental achievement in the 200-year history of immunology.
To explain Steinman's discovery, I first have to define the term antigen, which is any foreign or abnormal substance, like a bacteria, a virus, or a tumor cell, that stimulates the body to produce antibodies. Antigens are detected by a network of so-called antigen-presenting cells, which constitute the intelligence-gathering component of the immune system. Antigen-presenting cells are stationed like sentinels beneath all the body's exposed surfacesthe skin, airways, gastrointestinal tract, and genital tract. When a pathogen breaks through one of these epithelial barriers and invades the body, the antigen-presenting cells ingest the invader and fragment its antigenic proteins into small peptides, which are then displayed on their cell surface like a billboard. The antigen-presenting cells now become activated and undergo a vigorous maturation: They become uprooted from their local environment and travel to the nearest lymph node. Here, each dendritic cell presents its antigen to a resting lymphocyte called a virgin T cell, which responds by proliferating at a rapid rate, secreting cytokines, and differentiating into one of two types of mature T cellsa helper T cell or a killer T cell. The job of helper T cells is to instruct B cells to manufacture antibodies for neutralizing pathogens throughout the body. The job of killer T cells is to destroy body cells infected with pathogens. I'll come back in a moment to how the antigen-presenting cell conveys the proper instructions to the virgin T cell, telling it whether the body needs antibodies or cell killing.
When Steinman began his research in the early 1970s, the prevailing dogma held that macrophages were the predominant antigen-presenting cells. After all, everyone knows that macrophages are the quintessential phagocytic cells that engulf and destroy pathogens and damaged cells. The first Nobel Prize in cellular immunology was awarded in 1908 to Ilya Metchnikoff for his discovery of macrophages and phagocytosis. Not surprisingly, when macrophages ingest pathogens, they do present antigens on their cell surface. But surprisingly, no one had ever shown that macrophages were the authentic antigen-presenting cells that activate T cells and tell them how to respond to foreign invaders.
Dorothy Parker, the American author celebrated for her caustic wit, famously quipped that "you can't teach an old dogma new tricks." But Steinman's research, carried out in dogged fashion over 35 years, did teach the old dogs of immunology a few new tricks: Macrophages are not the major antigen-presenting cells in the body. This distinction belongs to a new type of white blood cells called dendritic cells, which communicate directly with T cells to initiate the immune response. From Steinman's discovery, we now know why macrophages do not activate T cells. They stay put in their tissue locations, battle the invaders directly, and do not travel to lymph nodes where the virgin T cells reside.
The story of how dendritic cells were discovered began in 1970 when Steinman joined the laboratory of the late Zanvil Cohn at The Rockefeller University. Cohn was a leader in the field of macrophage physiology who studied the immune response to infection. The original goal of Steinman's project was to learn how antigens provoke antibody production in a major lymphoid organ of mice, the spleen. In the course of this work, Steinman encountered a very minor population of cells in the spleen that exhibited an unusual shape with long, slender projections that resembled the branches of a tree. Since these newfound cells had never previously been described, Steinman studied them intensely and showed that they possessed properties distinct from macrophages. Since it's a rare opportunity in this day and age for a scientist to name a newly discovered cell, Steinman thought long and hard about his decision. Impressed by the cells' long slender projections and their graceful movements, his initial instinct was to call them "claudiacytes" in reference to the long arms and legs of his elegant wife, Claudia, who has also been his ballroom-dancing partner for 40 years. But for reasons known only to him, Steinman ended up choosing the less romantic name of "dendritic cells," derived from the Greek word "dendreon" for tree.
Over the next 15 years, from 1975 to 1990, Steinman worked out methods for purifying dendritic cells, learned how to grow and expand them in cell culture, and showed that pure dendritic cells (rather than macrophages) are the major antigen-presenting cells that stimulate T cells to divide and differentiate into helper T cells and cytotoxic T cells. In the mid 1990s, he followed up these cell culture studies with a series of elegant experiments in living animals.
A key concept to emerge from Steinman's in vivo studies is that dendritic cells mature in different ways, depending on the type of pathogen that triggers their maturation. When an antigen-presenting dendritic cell activates a virgin T cell, the T cell needs to know whether the antigen came from a bacteria, a virus, or from a parasite, each of which requires a different type of response in terms of activating T helper cells or T killer cells. The T cells also need to be able to measure the severity of the infection so that the immune system is able to mount a response that is proportional to the danger posed without overreacting inappropriately.
The key to dendritic maturation is a family of receptors on the surface of each dendritic cell that are tuned to recognize virtually every conceivable pattern of structural features contained in the universe of microorganisms that invade the human body. These so-called pattern recognition receptors are the molecular eyes, ears, and nose of dendritic cells. They measure the nature and severity of the microbial invasion and transduce this information into the program of antigen presentation, which is then communicated to the T cells. The late Charles Janeway of Yale played a key role in the discovery of the pattern recognition receptors in the mid 1990s.
Dendritic cell maturation is one of the most ingenious biological systems devised by Nature. It is the perfect way for one component of a complex defense system to convey accurate information about an impending threat to the second component whose job is to eliminate the threat. The central challenge of any intelligence-gathering systembe it our immune system or our national security systemis the problem of "noise," the fact that useless information is vastly more plentiful than useful information. Too much noise produces fiascos like the government's repeated warnings on duct tape and code orange. In the immune system, maturation of dendritic cells solves the noise problem.
One of the important clinical spin-offs from Steinman's research is the development of a new approach to the treatment of cancer, called dendritic cell vaccination. In a typical scenario, tumor cells from a patient are removed from his or her body and incubated in a test tube together with the patient's own dendritic cells. Once the dendritic cells become loaded with the tumor's antigens, the mixture is injected back into the patient to prime his or her T cells, which in turn produces a vigorous immune attack on the tumor. In animal studies, dendritic cell vaccines have produced striking results in shrinking tumors, and they are now being tested in more than 70 patient trials involving many types of tumorsmelanoma, prostate cancer, lymphoma, and kidney cancer.
Single-handedly, Ralph Steinman opened a new field of biomedical science. For two decades, he and his team were virtually the only scientists in the world who worked on what turns out to be the preeminent initiating step in immunity that governs the action of T cells. In 1993, Scientific American devoted an entire issue to the immune system with articles by 12 of the world's leading immunologists. Dendritic cells were never mentionednot even once in 164 pages. Macrophages were still king. Then, around 1997, almost overnight, Steinman's concepts went from heretical to conventional.
Why were Steinman's studies neglected, ignored, and sometimes denigrated by the immunological community for 25 years? The power of the century-old macrophage dogma apparently lulled scientists into brushing aside Steinman's painstaking experimentation, viewing his novel ideas on dendritic cells as some sort of Victorian curiosity not relevant to the Holy Trinity of Immunitythe macrophage, the T cell, and the B cell. Stirred but not deterred, Steinman passionately believed in a different doctrinethe Divine Doctrine of the Dendreonand his unshakable self-confidence and faith propelled him to a higher immunological truth.
Of the two defense systems that protect us from the hostile world of foreign invaders, our body's immune system is far superior in effectiveness to our nation's security system. If the operations of the CIA and FBI were reorganized around the principles of cooperative interaction exemplified by the Steinman doctrine of dendritic cells and T cells, then our national security system might someday rise from the ashes. To paraphrase Leslie Orgel's second law, Nature's immune system is smarter than your government's security system.
Thank you Ralph for your great work and dedication to science.