• Paths of Progress Spring/Summer 2010

    Setting a New Standard

    How Baruj Benacerraf Turned Modern Immunology on Its Head
    By Robert Levy

    Baruj Benacerraf, MDBaruj Benacerraf, MD
    Photo © Yousuf Karch
     

    In the summer of 1980, Baruj Benacerraf, MD, barely had time to furnish his new office at Dana-Farber Cancer Institute before the world came crowding to his door.

    A scant few months after becoming president of Dana-Farber in July, Benacerraf took an early-morning phone call from a reporter asking if he'd heard that he had won that year's Nobel Prize for Medicine or Physiology.

    Benacerraf replied, flabbergasted, 'Are you sure?"

    When he arrived later that day at Harvard Medical School, where he was chairman of the Pathology Department, Benacerraf was met by a throng of well-wishers offering champagne, handshakes, and hugs.

    A hastily called press conference was followed by a party at Dana-Farber, a celebration at the medical school, television interviews, and countless calls from reporters and dignitaries, including the president of Benacerraf's native Venezuela.

    The hoopla, and the festive pageantry of the prize presentation in Sweden that fall, testify to a body of work that remade the scientific understanding of the immune system – the set of specialized organs, cells, and proteins that protects the body from foreign substances and helps it heal from disease.

    Benacerraf (left), in Stockholm, receives his Nobel Prize from Sweden's King Carl XVI, in 1980.Benacerraf (left), in Stockholm, receives his Nobel Prize from Sweden's King Carl XVI, in 1980. 

    This year, the 30th anniversary of Benacerraf's Nobel Prize, is an appropriate moment to look again at the research that earned him the honor and made a substantial impact on medical care.

    Recently, when Dana-Farber scientists and others reported encouraging results in a trial of a prostate cancer vaccine, the investigators owed a debt to Benacerraf and his co-investigators.

    The development of cancer vaccines would not have been possible without Benacerraf's insights into the basic 'operating manual" of the immune system and the resulting ability to manipulate the system to benefit patients.

    Like many scientists before and after him, Benacerraf was drawn to immunology by a fascination with the exquisite selectivity of the immune system - its ability to distinguish friend from foe, normal cells from foreign ones, and to attack only those that pose danger.

    'The immune system has to deal with organisms and molecules with which it has had no previous contact, and with foreign cells that are often very like our own," says Benacerraf, who served as Dana-Farber's president for more than a decade and recently retired from active research.

    'To handle all these without mistakes, the system needs great powers of discrimination."

    In the mid-1950s, when Benacerraf began his research at New York University, scientists had only a rudimentary idea of how the immune system works.

    They knew about antigens – proteins that cells wear as identification badges – and they were familiar with T cells and antibodies, two of the agents that carry out an assault on foreign or diseased cells.

    However, the steps by which antibodies and T cells identify antigens on unwanted invaders was a mystery.

    A new understanding of the immune system

    T cells, it turns out, do not respond to protein antigens carried by foreign microbes, but to antigens that have been digested by infected cells, ground into fragments called peptides, and displayed on the surface of infected cells' surface in a bracket, like a jewel set in a ring. This is known as the "major histocompatibility complex," or MHC.

    "Baruj Benacerraf showed that what was thought to be antigen wasn't really antigen," Cantor says.

    "T cells don't recognize protein antigens per se, but pieces of them, in the context of the MHC. The structure and shape of each MHC, in turn, is dictated by immune response genes. The revolutionary part of this was that immunologists had gotten half of the immune system – the part involving T-cell recognition – wrong."

    Benacerraf discovered that T cells in the immune system recognize foreign invaders through antigens that have been digested by infected cells, ground into fragments called peptides, and displayed on the infected cells' surface in a bracket. This bracket is called the "major histocompatibility complex," or MHC.Benacerraf discovered that T cells in the immune system recognize foreign invaders through antigens that have been digested by infected cells, ground into fragments called peptides, and displayed on the infected cells' surface in a bracket. This bracket is called the "major histocompatibility complex," or MHC. 

    Says Fred Kantor, MD, of Yale School of Medicine, another of Benacerraf's early colleagues, "Recognizing that the immune response was controlled by specific –immune response genes,' later found to be part of the MHC, was his brilliant insight."

    For T cells, as for human beings, presentation is everything. Our ability to identify people or objects is very much bound up with the environment in which they are found. We're more apt to recognize a lemon meringue pie as a delicacy if it's served on fine china than if it's plopped on a piece of plywood.

    The MHC provides a consistent showcase for antigen peptides, ensuring that the T-cell response is orderly and controlled. Kantor and others were as struck by Benacerraf's skills as an "experimentalist" as by his intelligence.

    "Unlike most lead investigators, who worked primarily at the conceptual level, Baruj also did experiments in the lab right along with us," says Victor Nussenzweig, MD, PhD, now a professor of preventive medicine at New York University (NYU) Langone Medical Center, who worked in Benacerraf's NYU lab in the early 1960s.

    Benacerraf's discoveries also engineered a fundamental change in the way scientists think about the immune system.

    Previously, it had been viewed "as an army facing outward, ready to defend the body, which was otherwise helpless," Cantor comments. The new understanding showed that the body's cells are very much participants in the immune response, digesting foreign invaders and displaying pieces of them to T cells and antibodies.

    Knowledge of the role of MHC genes in the immune response has since taught scientists much about basic disease processes such as infection, autoimmune disorders (in which the immune system mistakenly identifies normal, healthy tissue as dangerous), and cancer.

    Knowing how MHC genes operate is critical for organ transplantation, which requires tamping down the T-cell attack on foreign tissue, and cancer vaccines, which seek to do the exact opposite: intensify the immune assault on tumors.

    Reflecting on his discoveries and the personal qualities that led to his pursuits, Benacerraf today says, "When people came to work with me, I told them that research is simply a challenge to find the truth. You have to be moved, and try and try again. Don't accept what exists already as final. If you derive pleasure from that, you're a scientist."

    Paths of Progress Spring/Summer 2010 Table of Contents 

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