Biophysical chemist Christof Grewer is part of an eight-year collaborative project backed by a $2.4 million National Institutes of Health grant, awarded to the Icahn School of Medicine at Mount Sinai and recently renewed until 2023.

Grewer is a professor of chemistry and the department’s undergraduate program chair. He’s also one of the world’s leading researchers of glutamine, an amino acid found naturally in the body that’s critical for a healthy immune system, and ASCT2, a glutamine transporter, or the “elevator” that carries the amino acid into cells to aid in the production of proteins.

“Cancer cells become addicted to glutamine as an energy source and they import it at a very high rate, so the idea is to target and prevent the glutamine from getting to the cancer cells,” Grewer says.

Avner Schlessinger, a computational biologist and associate professor of pharmacological sciences at Mount Sinai, partnered with Grewer to develop ASCT2 inhibitors. Grewer’s lab creates compounds and oversees functional testing, while Schlessinger’s lab conducts computational analysis and predictions.

“I wanted to collaborate with Christof because he is a top expert in the world in membrane transport biophysics,” Schlessinger says. “I knew I could learn from him and work with him to test both our hypotheses. It’s an ideal collaboration because we complement each other. He is kind and patient in sharing his data and knowledge, which enables us to do better science and really have fun while doing it.”

Grewer and Schlessinger first met during a 2012 conference in Switzerland. Grewer had already established himself as an expert in membrane proteins. During his post-doctoral fellowship at Cornell University in the mid-’90s, he studied glutamate receptors — glutamate is a neurotransmitter and an important molecule in cellular metabolism — and he became a pioneer in using lasers in his research.

After seeing the similar molecular structures in glutamate and glutamine transporters and studying how glutamate transporters responded to blockers, Grewer turned his focus in 2004 to glutamine and an ASCT2 inhibitor. To date, only a handful of labs in the world are involved in similar research.

Grewer and Schlessinger published a pre-print that includes a cryo-electron microscopy structure of ASCT2 and included one of their compounds. Three of Grewer’s doctoral students have assisted in the project; Elias Ndaru was included as a pre-print author due to his instrumental and prolific work in developing compounds.

The compound synthesis and the patent application filing are only the beginning of a long research and development journey. The steps toward potential clinical applications will involve developing the next generation of compounds at ideal potency levels, extensive pre-clinical testing for efficacy and safety, and eventually clinical trials, which will require additional research and development, funding and commercialization partners, such as startups or pharmaceutical companies.

The public tends to think of cancer as one disease when in reality it’s hundreds of different diseases, Grewer says.

“We’re learning every cancer is different and there is not going to be one silver bullet to ‘cure cancer,’” he says. “There are so many molecular aspects and so many different types of tissue involved that treatment may some day be individualized to the patient.”

Grewer has been teaching at Binghamton since 2008 and is thankful to be able work with students while continuing his research. “It’s a nice balance to be in the classroom and to be able to be in the lab,” he says. “It helps me keep up with the latest technologies and developments, and I think my students benefit from that type of experience.”

Fake “Frank” Lu, an assistant professor of biomedical engineering, uses stimulated Raman scattering (SRS), a molecule identification technique, to develop a multicolor imaging technology for brain cancer pathology during surgery.

A three-year, $750,000 R00 grant from the National Institute of Biomedical Imaging and Bioengineering (NIBIB) supports his research at Binghamton.

There are two steps to get rid of a brain tumor: removing the literal mass and then removing the lingering cancer cells at the edges. Removing the lingering cells can be tough, requiring evaluation to avoid destroying functioning brain structures.

Cancer cells are denser than normal cells, which helps them to be identified. Modern procedures involve a pathologist standing by for intraoperative consultation, using neuronavigation systems (such as an MRI scan) or fluorescence imaging to detect lingering cancer cells. Each of these techniques has drawbacks:

• With intraoperative staining-based histopathology, tissue samples are taken and evaluated in a nearby laboratory. Although accurate, this is ultimately a slow process, only allowing three samples to be evaluated during surgery.
• Neuronavigation systems can also be flawed as a result of the brain moving during the surgery, which is called “brain shift.”
• Fluorescence imaging uses fluorescent dyes to label and locate the cancer cells. Unfortunately, this is a messy process and isn’t accurate at distinguishing the margins of the tumor.

Lu’s technology is label-free, rapid and detailed. He expects that in the future, SRS can be used to evaluate 20-30 tissue samples during surgery to help delineate the tumor margin.

SRS detects “molecular fingerprints” by exciting the chemical bonds in molecules and reading the frequencies emitted by the vibrational states of the bond. This information is then used to assign different colors to the molecules, allowing for a detailed image.

Lu has also improved SRS so that it can create images of lipids, fatty acids that he says are important markers for the presence of cancer cells. Axons, the long, thread-like sections of nerve cells, are wrapped in lipid layers called myelin sheath. In areas affected by cancer, they break down, leaving lipid droplets that can be easily detected by Lu’s technology.

Lu envisions the technology being incorporated into a machine for operating rooms, and he is debating two options: a handheld probe to create images of the internal cavity, or a device that creates images of tissue samples from multiple locations. “We are providing a tool that is complementary to the current neuronavigation system,” he says.

The next step is to collect more data to solidify the efficiency of the technology. Lu is collaborating with SUNY Upstate Medical University and Brigham and Women’s Hospital to get larger data sets.

Eventually, Lu would like to implement machine learning into the technology for faster and more efficient diagnosis. He also hopes to apply this technology to other types of cancer diagnosis and even other neurological diseases, including Alzheimer’s, and do more work in live cell imaging.

Before joining Binghamton’s faculty in 2017, Lu completed a post-doctoral fellowship at Brigham and Women’s Hospital and Harvard Medical School, where he collaborated with cancer pathologists, surgeons and researchers to transform this technology. He also secured a prestigious NIH K99 Pathway to Independence Award, which is designed to facilitate researchers’ transitions from post-doctoral work to independent tenure-track jobs.

“Everyone contributes to the technical development of this technology, [but] Frank’s definitely the driving force behind the work,” says Sandro Santagata, a neuropathologist and assistant professor at Harvard Medical School and Lu’s post-doc collaborator. “He’s a team player, which is very important in scientific research.”

Lu, who was born in Shandong, China, received an undergraduate degree in optoelectronics from Zhejiang University in China and a graduate degree in bioengineering from the National University of Singapore.

He eventually realized he wanted to move toward healthcare applications of photonics rather than pure engineering and technology, which led him to Raman bioimaging. “For me, pure engineering work was not that exciting,” Lu says. “Later in my career I started thinking about practical applications of biophotonics in life science.”

As a kid, Lu was always tinkering, even attempting to develop a FM radio and an electric generator. Ever since, he has been on course to create innovations that would benefit society.

“To be successful in science requires a pretty remarkable drive,” Santagata says, “and he’s got it.”

At Binghamton University, Susan Bane thinks she’s found an answer: an ADC that uses a boronic acid to bind cancer-fighting drugs to the proteins on the surface of cancer cells, creating a chemical reaction that could be well-suited for drug delivery, with the potential to avoid the complications of chemotherapy and radiation.

“Killing non-cancer cells is where side effects come from, which is why this research is so important to pharmaceutical companies,” says Bane, a professor of organic and biological chemistry who received a $50,000 investment from the SUNY Technology Accelerator Fund (TAF) in June. “You can make antibodies that recognize very, very specific things on the surface of cancer cells, things that are in much higher abundance than they are on a normal cell. These antibodies can attach themselves to the cancers, making the specific bonds that you want to see between the drug and the antibody. There aren’t a lot of chemistries that can make that happen efficiently, but we believe this method will be fast enough to use in a clinical setting.”

For the past 30 years, Bane’s cancer work has focused on microtubules, intracellular structures that are involved in cell division and organization. In this most recent breakthrough, she was conducting basic research on microtubules, trying to speed up a chemical reaction, and decided to add boron. Bane expected the reaction to take hours; instead, it finished within seconds, providing an a-ha moment that pushed her research into a new direction.

“We found it by accident, while were working on a completely different project,” Bane says. “We thought that if we tried the reaction with boronic acid, we could make it faster. Not only did we make it faster, we made it thousands of times faster. We thought, ‘What just happened?’ Chemists had made these kinds of molecules before, using a much slower process, but our pieces just snapped together. We were completely blown away, and that’s how we ended up here.”

The result of this latest research, patented as “Rapid and efficient bioorthogonal ligation reaction and boron-containing heterocycles useful in conjunction therewith,” has distinct advantages over products currently on the market. First, there’s speed, which should make the molecule much easier to produce and much quicker to react. Second, its reagents are more biocompatible, so there aren’t any concerns about its toxicity in the human body. Third, it’s able to work well in water, even at highly diluted levels, and can be used without having to eliminate excess reagents after treatment.

Like other bioorthogonal chemical reactions, which are increasingly being used in personalized medicine, Bane’s product can be carefully controlled for consistency. Plus, this same patented process has potential applications in medical imaging, where it could create radioactive molecules to make PET scans safer, more efficient and less expensive.

“We think this reaction has a lot of potential utilities, and we’re interested in seeing where it can go,” Bane says. “One step is to reach across the academic community, let people know about our work and find out where they can take it. Another is to move outside academia, to places that have the resources to develop this. We’re at the stage now where we want to show this process can work on a larger scale and in a more controlled environment. But first, we have to get this into the hands of people with enough resources to take it to the next step.”

That’s where SUNY’s Technology Accelerator Fund comes in. To bring the patent closer to clinical trials, Bane is using her investment to manufacture experimental quantities of the novel chemical reagents and modified antibodies, purchase the commercial material currently available and begin testing the two head-to-head in her Binghamton laboratory. At the same time, she has begun leasing the technology to outside labs, where it’s being tested for a variety of potential biomedical and pharmaceutical applications.

“The more material that gets out there, the more people will be doing basic research, the more peer-reviewed publications we’ll have and the more interest will be generated for this type of chemistry,” Bane says. “Drug development is enormously expensive for pharmaceutical companies, and before we can find investors, we need to show that this process will work in a much more controlled environment. TAF is helping us reach the stage where our product will be more attractive to potential licensees, including the companies that could ultimately develop this for the marketplace. Getting the TAF grant is showing people that this project has commercial viability.”

Binghamton University biochemist Brian Callahan has discovered a new way to fight cancer, one that attacks only the cancer cells and promises fewer side effects.

He hunts hedgehogs. No, he’s not Elmer Fudd.

Hedgehogs are proteins that help govern how cells develop. Normally, once a person reaches maturation, the hedgehogs turn off. But in some cancers — prostate, pancreatic, ovarian and lung in particular — the hedgehogs somehow turn back on, and force uncontrolled cell growth: cancer.

“Pharmaceutical companies have been after hedgehogs for years,” says Callahan, an assistant professor of biological chemistry. One in particular, Erivedge, binds with the same receptors that hedgehogs activate, blocking the cancer development.

“We don’t want to compete with Big Pharma,” Callahan says. “We’re trying a new strategy; we’re going after hedgehogs directly.”

Callahan recently published two papers, one about zinc and hedgehogs in the May edition of the Journal of Biological Chemistry, and one about phenylarsine oxide in the January edition of Chembiochem, in partnership with researchers from Rensselaer Polytechnic Institute.

Both substances don’t simply block hedgehog reception; they shut hedgehogs down, preventing inactive hedgehogs from becoming biologically active and causing malignancies.

But before you start sucking on pennies or drinking phenylarsine oxide — an arsenic compound that will pretty effectively ruin your liver and kidneys — keep in mind that Callahan hasn’t discovered the medicine, just the method.

“It’s a proof of concept,” he says of his Department of Defense-funded work. “We can, with a small molecule, prevent the hedgehog from functioning. We think they bind a little differently. The arsenic seems to bind more tightly; it seems to be much more potent.”

The next step is a partnership with Michelle Arkin, an associate professor at the University of California San Francisco’s School of Pharmacy. During the next year or so, her lab will mirror Callahan’s first experiments with 80,000 or so compounds in its library.

“We’re looking for molecules that inhibit the functions that Brian found,” Arkin says. She expects a hit rate of between 0.1 percent and 0.5 percent — or maybe 100 or 200 compounds.

“There will be a lot of chemistry, a lot of tweaking,” Arkin says. “What we’ll get out of this is a puzzle piece,” an idea of a molecule that disrupts the hedgehogs without causing undue side effects.

The best candidates will be tested in lab animals, probably sometime in 2017, Callahan says. After that? It’s a matter of where the science leads.

“We want to get to molecularly targeted therapy,” Callahan says. In essence, a magic bullet that kills the cancer and not the patient.

Callahan does warn of one unavoidable side effect, though: Hedgehogs also govern hair growth. Turn them off, and the patient’s hair will fall out. Wascally hedgehogs.

Rosenberg, a professor of English at Binghamton University, says she found inspiration for the book in a real-life drama she heard about more than 30 years ago. A Pittsburgh man sued his cousin for a bone marrow transplant after the would-be donor changed his mind about the procedure. “It was just an instant novel in my head,” Rosenberg recalls. “What would it be like to be the surviving cousin? What would that do to a family?”

Rosenberg wrote to the justice who handled the case. They exchanged letters — this was before the days of e-mail, she notes — and he shared his views on the lawsuit. She even drove to Pittsburgh to discuss the case with him. “He knew that he could not force this person to do good,” Rosenberg says. “The powerful are sometimes powerless. And the seemingly powerless are sometimes powerful.”

Life and other projects got in the way, and Rosenberg shelved plans to write the book. But after her first novel, Home Repair, was published in 2009, Rosenberg’s thoughts returned to the project. “I was at a book club meeting in Binghamton for Home Repair when a book club member suggested to me, ‘What if it were cord blood?’ And I thought, ‘Wow, that’s really interesting.’”

That was just one of the crucial changes Rosenberg made for the novel. In the Pittsburgh case, two male cousins went to court. Her story would have one male cousin and one female cousin. And she decided it would take place in the present day on Long Island, where she spent the first 18 years of her life. “It felt remarkable to me to be able to go home in my fiction,” she says. “This is my hymn to Long Island.”

As Rosenberg describes the importance of place to her story, she refers to Eudora Welty’s views on the subject. It’s one of at least half a dozen references she makes to well-known authors in an hour-long discussion of her writing, moving effortlessly from Welty to J.K. Rowling and back to F. Scott Fitzgerald.

The setting, Rosenberg explains, allows her to explore the intense family connections of suburbia, differences in wealth and attitude and even the challenges of driving on Long Island. Indeed, traffic serves as a unifying metaphor in The Laws of Gravity. “There’s always something in your daily life that is an obstacle,” she says. “In Binghamton, it’s the weather. On Long Island, it’s traffic. You have to plan around the traffic.”

Rosenberg finds remarkable texture and vitality on Long Island, and she dismisses the idea that the suburbs are nothing more than a bland string of strip malls, diners and gas stations. Her novel fairly bursts with lively secondary characters: an eccentric aunt, a romantic rabbi and a scheming judge, to name just a few.

“The suburbs get short shrift,” she says. “I grew up in suburbia. It’s full of passion and it’s full of intrigue and suffering and beauty. It’s not as easy as it looks. People are on the verge of wealth or they’re on the verge of bankruptcy. They’re rushing to get to the train on time. There’s a certain kind of energy. Maybe it’s a little dog-eat-dog, but there’s also something that emerges from that energy. There are those surprising moments where the loyalties align in ways that defy gravity. Moments of beauty, of clarity, even of redemption, come out of feeling pressed all the time.”

In order to develop targeted therapies, scientists need to understand the activities these drugs disturb. If a compound seems to shrink tumors, for example, they need to define what’s going on inside the cells to produce that result.

Binghamton University researchers are helping to advance this work, which may pave the way for better cancer treatments.

Tracking an enzyme

Susan Bane, professor of organic and biological chemistry, and Susannah Gal, associate professor of biological sciences, deploy a novel tool in their study of an enzyme called tubulin tyrosine ligase, or TTL. Many cancer cells contain less-than-normal levels of this substance.

Bane and Gal are conducting their project with funding from the National Institute of General Medical Sciences. Their work focuses on microtubules, structures that provide part of the scaffolding that gives a cell its structure and also help chromosomes line up correctly during mitosis, or cell division.

Microtubules are made of proteins called tubulin. During the course of a cell’s life, an enzyme called carboxypeptidase clips an amino acid called tyrosine off the end of some of these proteins. Later, TTL puts tyrosine back on the tubulin. No one knows the purpose of this cycle, Bane says. “But we do know that if you don’t have that enzyme, you’ll die.”

In certain cancer cells, the cycle of removing and reattaching tyrosine has fallen out of balance: Too many tubulins lack tyrosine. “Patients who have that characteristic in their tumor have a poor prognosis,” Bane says. Those tumors tend to grow more aggressively.

Hoping to learn more about the role of TTL in cancer, Bane and Gal are studying the removal and reattachment of tyrosine in live cells. Bane has developed a way to mark tubulin with a fluorescent molecule, allowing the researchers to observe those molecules in action under a fluorescent microscope. The technique will help them explore questions such as what conditions allow tyrosine to reattach to tubulin and what conditions keep that from happening.

Marking tubulin isn’t easy. Most fluorescent markers will bond with any protein in a cell; they don’t distinguish between tubulin and other protein molecules. To mark just the tubulin, Bane and Gal essentially put a “hat” on that protein and then add a marker to that.

The hat is a special derivative of tyrosine that Bane created for the project. The researchers introduce this tyrosine derivative into a cell. They then add a fluorescent molecule that lights up when it bonds with the special tyrosine, but not with any other substance. In effect, they pin a glowing badge to the tyrosine hat.

TTL in the cell may pick up that hat and clamp it on the  “head”  of a tubulin molecule. Once the tubulin is wearing its luminous headgear, the researchers can tell it apart it from other objects in the cell and watch how it behaves.

Other methods exist for adding a fluorescent marker to a protein in a cell. The most common technique, using a fluorescent protein, presents certain disadvantages, says Dan Sackett, a biophysical cell biologist at the National Institute of Child Health and Human Development.

“The down side is that it’s a very large molecule, as big as the protein we’re trying to track,” says Sackett, who collaborates with Bane and Gal on their project. The marker may actually block the observer’s view of the protein under study.

The new technique, using a smaller molecule, provides an easier way to watch the behavior of microtubules as cells divide, Sackett says. “And since a lot of anti-cancer drugs target the mitotic spindle — the array of microtubules that moves chromosomes apart at mitosis — being able to observe that easily in multiple cell types is really an advantage.”

Cancer cells are often undergoing mitosis at a much faster rate than normal cells, making cell division a major target of cancer research.

Although Bane and Gal aren’t trying to develop a new cancer treatment, their efforts to learn the role of TTL in tumor growth could someday make it easier to choose a treatment for a specific case of the disease.

“Potentially, someone could send us their tumor sample, and we could put it in our labeling system and say,  ‘Yes, that has a problem with the TTL system, and therefore you should be more aggressive with it,’” Gal says.  “Or we could say,  ‘That’s probably OK, so you can treat it with normal chemotherapy.’”

Can painkillers kill cancer cells?

While Bane and Gal focus on microtubules, Yulong Chen strives to understand the role that opioids might play in cancer therapies. His work hinges on the fact that an opioid — the key ingredient in painkillers such as morphine — can block a crucial reaction in certain cancer cells.

Chen, an assistant professor of biology at Binghamton, investigates how the transmission of chemical signals within cells turns genes on and off. Most of his research focuses on neurons, the cells that make up the nervous system. Some neurons have something interesting in common with certain cancer cells: They both carry molecules called opioid receptors that send signals into the cell when they touch opioid molecules.

In the nervous system, that signal blocks the sensation of pain. Unfortunately, the reaction also may cause side effects such as respiratory depression and constipation, and it may cause opiate addiction.

In a cancer cell, contact with an opioid may cause either of two reactions: Sometimes, an opioid kills cancer cells; sometimes, it stimulates tumor growth.

Since doctors often give opiates to cancer patients, it’s crucial to know what effect a painkiller might have on the cancer.  “If the opioid will stimulate cancer cell growth, that’s a big problem,” Chen says.

Before joining Binghamton’s faculty in 2007, Chen worked in the Department of Pharmacology at the University of Minnesota Medical School. There, he identified an opioid antagonist compound that kills small cell lung cancer. It does this by blocking the transmission of a signal that is crucial for cell survival.

He also found that this compound doesn’t always produce the same results. When Chen introduced the same opioid antagonist to cells taken from three different individuals with small cell lung cancer, the compound killed 20 to 30 percent of the cells in one sample, 40 to 50 percent in the second and 90 percent in the third.

The difference depended on the strength of a reaction called phosphorylation at the critical survival molecule Akt when the compound binds to a molecule at the cancer cell surface. “Our study shows that if the level of phosphorylation at Akt is high, then you block the pathway using this compound, and the cancer cell dies,” Chen says. “If the level of phosphorylation at Akt is not so high, the cell doesn’t respond well when you block it.” Different phosphorylation levels in different cancer cells from different individuals show a stronger or weaker reaction to the opioid antagonist.

“This observation,” Chen says, “also provides one more reason for personalized medicine in cancer treatment.”

Chen’s study has enhanced scientific understanding of how an opioid may kill cancer, says Kalpna Gupta, assistant professor in the Department of Medicine at the University of Minnesota. It’s significant that Chen focuses on how opioids may kill cancer cells, rather than on how they may promote cell growth, as earlier researchers have done, she says.

“This is more appropriate, from a therapeutic point of view,” says Gupta, who studies opioid-mediated cancer-cell growth.  “That is why his study is very important. It not only provides a basic understanding, but an understanding of — once the monster is there — how do we get rid of it?”

Since coming to Binghamton, Chen has been laying plans to further explore the mechanism that allows an opioid to kill cancer cells. “I still don’t know what molecule it’s targeting,” he says. His next goal is to identify the key receptor on the cancer cell. “If I can identify this molecule,”  he says,  “then I can study whether it’s valid as a target for an anti-cancer drug.”

In the long run, Chen’s research on molecular signals in neurons and his research on cancer cells may lead toward a common goal. He hopes to find an opioid that reduces pain in cancer patients, doesn’t cause side effects or addiction and kills tumors.

“If the compound that we develop to kill the cancer cells also can block drug tolerance and dependence, that will be one drug that does two things,” Chen says. “That would be wonderful.”

Add to that the Cold War threat of nuclear attack and only nascent ideas of informed consent and you have the environment in 1960 when Dr. Eugene Saenger, radiologist and an expert in nuclear medicine, began his now-notorious clinical trials. Using patients  with advanced cancer at the University of Cincinnati College of Medicine, Saenger tested for the U.S. military the effects of total-body irradiation, sometimes with fatal results.

To the shock of those investigating his work, the patients — about 90 between 1960 and 1971, a majority black — served as proxies for soldiers, in part to better understand radiation effects from nuclear attack.

In his latest book, Contested Medicine: Cancer Research and the Military, Gerald Kutcher, associate professor of history at Binghamton University, re-examines Saenger’s work in a new context. Kutcher reinterprets the events through his unique experience as a radiation oncology physicist, a Cambridge-educated historian and through the application of the science studies approach, which seeks to delve into the cultural and ideological framework around scientific practices.

He wrestles with a question that has vexed many who have studied Saenger and his work for decades: Was this one of the most outrageous examples of ethically flawed medicine in the 20th century or a product of its times? Kutcher does not let the reader come away with such neat conclusions.

“I don’t judge the characters,” Kutcher said. “What’s more interesting to me is why they were accepted by colleagues.”

No one is absolving Saenger of responsibility, Kutcher said, but there is much we can learn in viewing past clinical trials not through a lens of today’s bioethical standards and concepts of informed consent — simply not fully formed during Saenger’s day — but in the context in which they operated at the time. All these decades later, judgments against Saenger remain ambiguous, despite the deaths and, by Kutcher’s count, nine investigations into his program. Families say their loved ones may have consented to the radiation, but they were not told of its deadliness or the military’s role.

That Saenger was not immediately or universally vilified after such disclosures reveals something fundamental about the character of medical research itself, Kutcher said: It was dynamic and very much a part of the world in which it existed.

A new perspective

Kutcher was well versed in the world of clinical trials and cancer treatment as chief of the clinical physics service at Memorial Sloan-Kettering Cancer Center before pursuing his doctorate in the history of science.

Dr. Samuel Hellman, a former colleague of Kutcher’s at Sloan-Kettering, where he was physician-in-chief, said Kutcher’s professional evolution could not be more unusual. “He has a remarkably different career than most people,” said Hellman, who is also a professor emeritus at the University of Chicago, where he served as dean of the Pritzker School of Medicine.

Kutcher started in medical physics and became a senior figure in that field, making contributions such as maximizing radiation to tumors while saving as much healthy tissue as possible. It was a great advance, Hellman said, and when computer technology linked ever more precision to radiation therapy, “Jerry was one of the most important people doing that.”

Kutcher, leading a clinical service of about 50 physicists who were responsible for the planning and delivery of radiation treatments to more than 3,000 patients per year, contributed to changing much in the field, including how prostate cancer is treated with radiation.

It is with that experience that he confronts a central point in the book — a detailed accounting of the emergence of informed consent. A turning point, Kutcher writes, came in the mid-1960s when James Shannon, director of the National Institutes of Health, pushed through a program that required all research funded by the NIH to go through local peer review. Around the same time, a New England Journal of Medicine article revealed 22 cases of unethical experimentation, which included injecting mentally disabled residents at Willowbrook State School in New York with hepatitis to see how it was spread. No effort at consent was made.

“It’s interesting,” Hellman said. “Most of the examples came from very prestigious professors at very prestigious institutions and published in very prestigious journals. They did not create a great ethical outpouring, most of them, and they were so egregious.”

Uncovering the Cincinnati trials

Saenger’s trials were halted in 1971 by the University of Cincinnati, but the troubling nature of Saenger’s work was first questioned in 1966. Documents released later detailed concerns by university faculty about the level of radiation and how Saenger was informing his patients, but it was not enough to stop the work. In fact, the Department of Defense not only funded the research through March 1972, according to congressional testimony, it approached the university with an offer to renew the contract for another term. The university refused and the experiments ceased.

It was also in 1971 that the press began to write about Saenger’s work. That proved the initial tug in unraveling the fabric of Saenger’s legacy and led to scores of investigations.

Martha Stephens, a professor emeritus of English at the University of Cincinnati, became aware of the trials through a short article in the Village Voice, published in October 1971. She was stunned to learn that radiation experiments were happening so close to home. She began pressing the university for more details, made her findings public, and continued investigating. Those efforts culminated in a 2002 book, The Experiment.

What laypeople may see as black and white, Kutcher views as another gray area of medicine, tinged by his own experiences in the field. “You are treating people right on the edge,” he said. “Scientists tend to rewrite their own history. They never tell you about all of their failures. No one is even close to typical idealized versions of science in the making.”

During Saenger’s experiments, patients were subjected to massive doses of full-body radiation. And they weren’t told of the military’s involvement until after outsiders started questioning the experiments.

Yet his work, Saenger believed, was part of developments in total-body radiation that by today have led to a nearly 85 percent survival rate among those diagnosed with childhood leukemia. He was among the first to discover that irradiation in children for benign conditions caused tumors and authored a 1968 study that proved radioiodine therapy didn’t increase incidences of leukemia. Saenger was also considered a leader in establishing radiation safety standards for medical workers.

A career of twists and turns

Kutcher’s career has followed a most unusual path.

“Toward the latter phase of my career at Sloan-Kettering, I became more and more convinced that I wanted (indeed, I seemed to need) to look at medicine from a more historical and social perspective,” Kutcher writes.

He recalled an incident at Thomas Jefferson University Hospital in Philadelphia. He noticed one patient lying on a gurney when a distress code sounded. The patient died.

“Later, I learned that the patient had advanced cancer and was a subject in a clinical trial testing partial-body radiation to alleviate the painful effects of distant metastases.  I remember thinking at that time: Who was looking out for this patient? Why was a patient on the verge of death participating in a clinical trial? Later, I would begin to appreciate something that perhaps I should have understood at the time, namely, that one of the ethical tenets of clinical trials is that often the most aggressive and certainly the most experimental of trials are tested in the sickest patients who are often the most vulnerable.”

However, that was not the central force in his career change. Rather, he said, it showed that his fundamental approach and interest in medicine would always extend beyond the scientific into broader social and ethical contexts: Where one person saw a patient or device, he would be connecting the dots.

Saenger’s legacy

Saenger died in 2007, at the age of 90. His legacy is mixed at best, lying somewhere between an “American Mengele” and misunderstood pioneer.

In 1999, a federal judge awarded his patients’ families $3.6 million, to be paid by the government, the University of Cincinnati, researchers and the city of Cincinnati, former operator of the hospital.

Despite the investigations and ongoing criticisms, Saenger continued for years after the experiments ended to write articles in his defense, Kutcher said. In the mid-1990s, Saenger was investigated by a number of government bodies, including the Advisory Committee on Human Radiation Experiments, established by then-President Bill Clinton.

“The political and cultural climate in which he was judged differed substantially from that of the early 1970s,” Kutcher writes. Bioethics had established itself as the most authoritative voice of ethical conduct, yet the committee was badly split. “When the committee attempted to compare Saenger’s research to that of his contemporaries, it could not distinguish his practices from his peers’ and could only reach an ambivalent judgment.”