Out of the lab and into the clinic, nuclear fallout prompts BMT for humans
Part 1 of this post described how researchers involved in the Manhattan Project had discovered the negative effects of radiation on the body, and that Bone Marrow Transplant (BMT) had the potential to remedy the resulting radiation sickness. The Manhattan Project completed its primary objective, the creation of a nuclear weapon, with the bombing of the Japanese cities of Hiroshima and Nagasaki in August of 1945. Like all explosives, a nuclear bomb has a radius of physical destruction and death. However, unlike conventional weapons, nuclear weapons also include a another, larger, radius of intense nuclear radiation. Those not killed by the blast, could still be close enough to suffer from radiation sickness.
Though these bombs effectively ended World War II, they ushered in a new era for radiobiology. Radiation sickness had only affected a handful of people before the war, but the cause of their demise only became apparent much later, since there were too few cases for doctors to recognize a pattern. Once the fighting was over, doctors and researchers had the unfortunate opportunity to observe tens of thousands of people in Japan battle, and often succumb, to radiation sickness. Such a large number of cases allowed them to diagnose the disease,quickly gaining a more comprehensive understanding of how it progressed in humans and which regions of the body were most affected. Fortunately for both the researchers and the patients, the progression of radiation sickness in humans was markedly similar to that observed in animal models. With the previous BMT successes in treating and curing these same animal models, this meant that the procedure likely had the same potential for humans.
Renewal and rejection, the immune system presents another challenge
World War II presented other medical challenges on a scale never seen before, namely the massive numbers of injured soldiers and citizens who needed skin grafts and blood transfusions. Skin grafting involves taking a section of healthy skin from an unaffected region on a patient or a healthy donor and placing it over an area of tissue damage, like a large burn or amputation site, with the hope that these grafted cells will begin to grow and reestablish skin function for that region. Similar to radiation treatment, skin grafts and blood transfusions were still in their infancy. Blood or tissue taken for grafts from alternative healthy donors often caused complications in the recipient. Doctors identified this as the recipient’s immune system rejecting the donor graft due to unique proteins, called major histocompatibility complexes (MHCs), which cover most of the cells in the human body. MHCs are used by the immune system to identify the bodies own cells. Certain immune cells, responsible for identifying and destroying foreign threats like viruses and bacteria, would find donor graft cells covered in MHCs from another person and identify them as foreign. This triggers a massive immune response in the recipient, attacking the cells from the healthy donor, with several organ systems in the recipient’s body often taking collateral damage.
Researchers working on BMT had also seen signs of similar rejection and complications in their subject animals being treated. However, the BMT associated rejection was not uniform between animal species and was often relatively minor compared to the human response associated with skin or blood graft rejection. Unfortunately, the first human patients receiving BMT treatments in the 1950s showed intense immune rejection of the bone marrow cells. This intense rejection, later termed Graft versus Host Disease (GvHD), often killed these preliminary BMT patients before the radiation sickness.
Identifying therapies to combat the GvHD that followed BMT proved incredibly challenging. Not until the 1980s and 90s were doctors able to find the intricate balance of immune suppression, allowing the body to accept foreign bone marrow cells without letting an infection kill the patient. One of the key tools for achieving this balance was, ironically, controlled, low-level radiation. As doctors gained a greater understanding of the extent with which specific cells were affected by radiation, they then harnessed this destructive force as a helpful tool for medicine. Controlled radiation, along with chemotherapy and other pharmaceuticals, allowed them to temporarily suppress the immune cells described previously. This gave the donor bone marrow cells a chance to establish in the recipient’s body, often completely replacing their now depleted immune system.
As immunology research expanded during the late 20th century, researchers realized the components most needed in a blood donation, the red blood cells which carry oxygen and the fluid they are contained in known as plasma, lacked the MHCs. Red blood cells are also unaffected by low level radiation; thus, hospitals began treating all blood donations with radiation to destroy any other cells covered in MHCs and remove the risk of rejection. This made the current massive blood donation network possible, since only a simple blood type needed to be matched between donor and patient. Additionally, skin grafts required more simple immune suppression, since these foreign cells were isolated. Sufficient suppression for a skin graft can be achieved via a drug cocktail, without the need for radiation or chemotherapy.
Expanding therapeutic relevance, BMT pivots to cancer
Once researchers harnessed the ability to modify blood and the immune system via radiation, they used this new tool to probe related diseases, including immune deficiencies like AIDS and blood cancers such as leukemia. Radiation sickness and blood cancers are alike in that both affect the body’s ability to produce blood cells at the correct ratio. They differ in that radiation destroys the source for these cells, the bone marrow, whereas in blood cancers, one type of blood cell is overproduced, leaving no space in the marrow for production of the remaining cells. If radiation sickness wasn’t bad enough, patients exposed to radiation are far more likely to develop cancer throughout their lives due to mutations in cells caused by the radiation. They are especially prone to blood cancers, since the marrow cells were most susceptible to mutation.
Thankfully, doctors were able to utilize the same immune suppression techniques, radiation and chemotherapy, used to prevent GvHD to reduce the cancer patients over production of their bone marrow cells. Once in temporary remission, the patient is given either their own marrow, previously collected and screened for cancer cells, or marrow from a healthy donor with very similar MHCs, often a sibling or parent. These new bone marrow cells are hopefully able to repopulate the depleted marrow regions in the body, rebuilding the patient’s immune system, and ideally, recognizing any remaining cancer cells as foreign, attacking and destroying them. This final, ideal feature is one of the best ways a cancer patient can achieve long-term remission; it is currently incredibly difficult to remove all bone marrow cancer cells throughout the body via radiation and chemotherapy alone. However, finding the immune suppression balance and reconstitution of each patient’s immune system is still a challenge for doctors and only succeeds sometimes. For this reason, BMT is still only a therapy and not a cure. However, doctors and researchers are investigating new ways to supplement, strengthen, and customize BMT, so that it can achieve this ideal result in every patient.
Individual medicine and custom cells, the future for BMT
Current cutting edge research in BMT and cancer treatment primarily focuses on promoting the patient’s immune system to fight the cancer and customizing treatment regimens to each cancer case. Family history, specific mutations, physical characteristics, and even diet make each person’s cancer unique, affecting both how the cancer manifests and the most effective ways to fight it. Because of this, doctors are beginning to tailor every aspect of treatment, including types of drugs and chemotherapy, diet, amount and cell type of bone marrow given to a patient, and treatment frequency and pacing. This technique is part of a larger strategy called individual medicine that is being used to treat a number of diseases including cancer. Additionally, experiments are currently testing ways to better harness the immune system by customizing immune cells. Bone marrow and immune cells collected in preparation for BMT are being modified and even trained in lab to increase the likelihood that these will see cancer cells as foreign after being put into the patient.
There is immense potential present in current research to make BMT even more powerful and expand its application; revolutionize cancer treatment; offer patients hope, better quality of life, and more time. However, this potential relies on future investment and priority being placed on basic research. While the origins of BMT are founded in destruction and war, there is an opportunity for its future and legacy to be one of healing and promise. The challenge is to learn from the past and invest in basic research with the realization that it will better life, not simply to wait until the next world war for a lucky windfall.