CWRU Magazine - Fall 2000  |  F e a t u r e : The Investigator

Behind his bow tie and friendly presence, Sandy Markowitz is a study in determination as he leads CWRU research teams toward the goal of vanquishing colon cancer.


The team from Sanford Markowitz’s lab has spent an hour and a half listening to Steve Fink’s research update and examining his transparencies, which are projected on their conference room’s east wall. Then Dr. Fink decides to add a little drama to his presentation. He covers a transparency with a piece of paper and inches it slowly down a column of data to reveal the final results of his experiment.

There’s a moment of restlessness in the room, and Dr. Markowitz takes his hands away from his laptop computer. The Ingalls Professor of Cancer Genetics in the CWRU School of Medicine’s Department of Medicine with a co-appointment in the Department of Molecular Biology, Dr. Markowitz has been a friendly but low-key presence in the room: He asks questions and makes observations in a voice that is hardly louder than the chatter coming from the room next door. He begins to chuckle, however, as Dr. Fink, a postdoctoral fellow in his lab, jiggles the paper down the line of data.

“Ah,” says Dr. Markowitz—known far and wide as “Sandy”—as he adjusts his signature bow tie. “It’s the Gypsy Rose Lee method of presentation!”

At no point in this meeting does anyone mention the words “colon cancer,” even though this is what brings them together day after day in their lab at the bottom of Cedar Hill, down in the crease between Cleveland and Cleveland Heights. Dr. Markowitz and his team—about twenty crackerjack researchers, including postdocs from around the country as well as a handful of CWRU graduate and undergraduate students—have their attention focused on the deepest and most mysterious recesses of the human body. They are searching for the many faulty interactions within the colon’s epithelial cells—those that form its smooth inner lining—that transpire year after year in a person who is developing colon cancer. They are looking for the tiny flaws in the cells’ DNA that trigger other flaws that go on to trigger other flaws, like a line of dominoes that crash across the floor in sequence. Often, victims don’t realize they have colon cancer until the final domino topples to the floor—in other words, when it’s too late to do anything about it.

Precise, Tenacious, Careful

“The important thing about colon cancer is to catch it early,” says Dr. Markowitz later in another, smaller conference room, this one jammed with mismatched chairs and medical journals. He maintains a busy clinical practice at the comprehensive cancer center associated with University Hospitals of Cleveland (UHC) and CWRU, so he’s also well-acquainted with cancer outside the test tube. In fact, the Ingalls chair was endowed by one of his patients, Frances Ingalls, who was so grateful for Dr. Markowitz’s daily attention during her losing battle with the disease that she made a generous gift to the University.

“If the cancer is only attacking the colon,” he says, “we can remove it surgically and stitch the colon back together again. Once the cancer has spread beyond the colon, once it involves the lymph nodes around the colon, it becomes much harder to cure. Once it spreads to vital organs like the liver, it becomes virtually incurable. But if we catch it early, we have an excellent chance of curing it.”

Undetected, colon cancer is indeed a scourge: It is the nation’s number-two killing cancer, just behind lung cancer, and snuffs some 70,000 lives each year. Many people have colon cancer twining through their family tree like a parasitic vine; they watch it strangle many family members within a generation, some when they are only in their thirties. It is fortunate for them that Dr. Markowitz and his colleagues at CWRU are successfully hacking at the twisted roots of this disease. Although the School of Medicine has had a concentration in colon cancer research only since 1987, the group has made significant breakthroughs that may lead to early detection, new medications, and gene therapy. Along the way, they have also built CWRU’s colon cancer research hub into one of the leading centers in the country.

Their short list of accomplishments is impressive. Five years ago, Dr. Markowitz and James Willson, professor of medicine and director of the UHC and CWRU cancer center, rocked the world of cancer research with an important discovery, which was published in Science. They found that in families with an inherited form of cancer on the right side of the colon, the epithelial cells have a defective part called an RII (short for “TGF-beta-receptor two”). Because the RII doesn’t function as it should (it fails to snag a growth-curbing hormone called TGF-beta—for “transforming growth factor”), it permits the unregulated cell division that leads to cancer.

“Sandy’s work was of major importance, because he was one of the first to show that a defect in one of these TGF-beta receptors was associated with the development of colon cancer,” says Michael Sporn, the Oscar M. Cohn ’34 Professor of Pharmacology and of Medicine at Dartmouth Medical School, who identified the molecular properties of TGF-beta in the 1980s. “This work was done with a very high level of molecular precision, a characteristic of Sandy’s work which, together with a high degree of tenacity and carefulness, make him such a fine researcher.”

Two years after that breakthrough, in 1997, Dr. Markowitz was named an investigator by the prestigious Howard Hughes Medical Institute, a philanthropic organization with a $9.6-billion endowment that funds medical research in cell biology, genetics, immunology, neuroscience, and structural biology. Dr. Markowitz was the first scientist in Cleveland to receive this honor, and his efforts were flushed with research dollars—$6 million over six years, which allowed him to put together a separate Hughes lab within the University, hire the 20 researchers in the lab, and share access to the work of other Hughes investigators around the country.

Yet another boost to his efforts came earlier this year, when Dr. Markowitz was invited to join other leading cancer researchers on the medical advisory board of the National Colorectal Cancer Research Alliance, launched by Katie Couric, co-anchor of NBC’s Today Show, and Lily Tartikoff, widow of Brandon Tartikoff, former president for entertainment at NBC and former president of Paramount Pictures. Both of these women’s husbands were killed by cancer, and their organization is dedicated to raising funds for research into colorectal cancer and boosting public awareness of the disease. Ms. Couric’s show is the perfect venue for generating such biomedical buzz: After she discussed one of the CWRU colon cancer group’s projects in front of her television audience, the lab was flooded with 5,000 calls from around the country.

Did Nathan Berger, School of Medicine dean and CWRU vice-president for medical affairs, expect all these fireworks in 1987 when he recruited Dr. Willson and Dr. Markowitz, then an oncology fellow at the National Cancer Institute, to launch colon cancer research at CWRU? Perhaps not exactly these headline-grabbing successes, but, says Dean Berger, “When you recruit faculty to make sparks fly, you’re not exactly surprised when the fireworks appear.

“We wanted to focus on colon cancer, because of the large opportunity, the expertise of the investigators, and the large size of the problem,” Dean Berger continues. “Now we have a critical mass here, and other people want to be part of it. It brings researchers and patients, and it certainly provides excellent opportunities for students. Sandy brings many students into his laboratories, including undergraduates and even high school students. He’s been an important building block in making this an outstanding program. People come here because they want to work with him.”

Twenty years ago, Sandy Markowitz chose to become a colon cancer specialist for both personal and professional reasons. As a young man growing up in Pittsburgh, he always had an interest in science. He went on to major in physics and chemistry at Harvard, then polished off his academic years at Yale, earning both an MD and a PhD in cell biology in six years. While he was a resident in internal medicine at what is now the University of Chicago Hospitals & Health System in the early 1980s, he became interested in the new technologies then being used to study simple cells and apply them to the study of more complicated cells like cancers.

“It wasn’t clear how powerful the technologies were going to be,” Dr. Markowitz recalls, “but even back then, it was clear we were going to be able to look at individual molecules, genes, and proteins and ask how they were different in healthy cells versus diseased cells.” He decided to specialize in medical oncology. At about the same time that he was making this decision, his father was diagnosed with colon cancer, and Dr. Markowitz’s interest became even more narrowly focused. (His father survived and is alive today.) When Dean Berger asked him to come to CWRU and pull together a team to study the molecular biology of colon cancer, he was ready to make the move.

Fatal Flaws

Thirteen years later, Dr. Markowitz and upwards of thirty CWRU colleagues—twenty in his Hughes lab, ten to fifteen in two other labs—are continuing to attack colon cancer on a number of fronts. One group is following up on the discovery of the fatal role of RII, the flawed protein receptor in the colon’s epithelial cells. Dr. Markowitz describes the RII as part of a structure on the outside of the epithelial cell that looks something like a basketball hoop. A normally functioning RII holds the hoop out in order to catch the hormone called TGF-beta. This hormone travels through the colon carrying a critically important message, which is delivered when the TGF-beta drops into these hoops.

The message? That it’s time for these particular cells to die, slough away, and allow fresh cells to take their place. Epithelial cells suffer an enormous amount of environmental wear and tear from all the dubious things humans ingest, and the body intends these cells to live for only five days. When these cells cling to the colon and continue to grow, the intestinal climate is right for polyps—wart-like growths that protrude into the colon—usually followed by cancers.

The reason RII doesn’t function properly is because of a glitch in the epithelial cell’s DNA: The genes don’t program the protein receptor to recognize the TGF-beta and allow it to drop into the hoop, and the cell never gets the message to die. People with flawed RII, however, were not born with this glitch in their DNA. So the researchers are looking further back on the chain of cause and effect, at another part of the epithelial cell called hMLH1.

What’s the connection between hMLH1 and RII? It turns out that hMLH1 is part of a marvelous little cellular machine, something Dr. Markowitz compares to a computer’s error checker. Each of us inherits two double helices of DNA, one strand of matching pairs from our mother and a second strand of matching pairs from our father. Our cellular error checker’s job is to bustle up and down these helices, spot places where a mutation has occurred in the strands of DNA, and then fix the mistake.

It turns out that some people with inherited forms of colon cancer are born with a faulty error checker, because the part of their DNA that instructs hMLH1 to do its part in the error-checking process is flawed. This flaw has massive repercussions—in fact, when people have faulty error checkers, their DNA accumulates flaws a thousand times faster than other people’s. And one of the first parts of the DNA to break down is the code for RII. “The gene sequence for RII is very, very difficult for the body to get right,” says Dr. Markowitz. “Whenever cells divide, this is a sequence they always have trouble copying correctly. So the error checker is critical to keeping this gene healthy, and, if you take it away, you lose the gene. We’ve seen it over a hundred times now.” The people who inherit a faulty error checker usually develop cancer early in life: It’s like a time bomb that begins ticking when they are born.

The trail of damage has even more branches to it, and this first group of researchers is also investigating other genes in the TGF-beta pathway that become damaged and fail to carry out their role in the critical process of cell death. Other researchers in Dr. Markowitz’s labs are investigating still another conundrum: Not everyone who develops colon cancer as a result of flawed hMLH1 was born with this flaw.

Some people develop nonfunctioning hMLH1 as “an accident of living,” Dr. Markowitz explains. “You eat that charbroiled steak and all those chemicals wash through your gut, and there’s a chance for an awful lot of things to bind to your cells. We live in a world in which we are constantly damaging our DNA as the price for living. It happens every time we get sunburned, every time we eat something with a carcinogen in it.” People whose error checker stumbles as a result of these accidents of living generally get cancer in midlife.

While some of the people with nonfunctioning error checkers have damaged them beyond repair, many of them actually have no genetic damage to their hMLH1. What they do have are molecules of methyl—the same stuff that’s in antifreeze and moonshine—covering up the DNA so that hMLH1 doesn’t respond to its genetic programming. No one really understands why the methyl accumulates there or how to avoid the build-up.

This second group in the CWRU colon cancer research hub is studying later-blooming cancers and has published papers on two different drugs that show promise, at least in the laboratory. One scrubs the methyl away from the hMLH1 and might make colon cancers more responsive to chemotherapy. The other kills epithelial cells in which the error checker has gone bad.

Hope and Hard Work

Dr. Markowitz estimates that a third of all people with colon cancer have flawed RII, some of which was allowed to mutate by an error checker that didn’t do its job, some of which was damaged in another, yet unknown way. But there are thousands of other people who get colon cancer in midlife, and specialists believe that many of these cancers are also related to genetic flaws. A third group in the CWRU labs has been working on a study to try to get at the genetic roots of the disease in older people. Their project is called the Colon Neoplasia Sibling Study, and Katie Couric has helped push it into the national limelight.

Several years ago, a Sloan-Kettering Institute study showed that siblings of someone who developed colon cancer before the age of sixty have a twenty percent probability of developing the disease themselves, compared with six percent in the general population. For the last two years, research groups headed by Dr. Markowitz, Dr. Willson, and Georgia Wiesner, CWRU assistant director of genetics and medicine and acting director of the Center for Human Genetics at University Hospitals, have been tracking down siblings in cancer-prone families and recruiting them to their study. The researchers offer the siblings free colon cancer screening by flexible sigmoidoscopy and, already, have found polyps in twenty-nine out of eighty-five participants. The only cost to the siblings is a tube of blood.

The promise of next-generation cancer treatment lies in those tubes of blood. The researchers hope to get blood samples from at least two siblings in each family who themselves have either colon polyps or colon cancer. The researchers then extract DNA from their blood and start looking for similarities. Siblings are genetically half identical—i.e., fifty percent of their DNA is the same—so scientists know that the genes that are responsible for colon cancer lurk in their shared DNA.

Still, there are some 40,000 genes in the human genome, and it would be impossible to pinpoint the colon cancer culprits in the DNA shared by only two siblings. So, after the researchers trace the shared DNA between these two siblings, they compare it to the shared DNA of two other siblings from another family, then compare what these four have in common to the shared DNA of two other siblings and so on. By narrowing down the genetic similarities among all these afflicted siblings, they will eventually discover the one or more genes that are responsible. Dr. Markowitz and his colleagues have determined that they will need to look at sibling groups from 300 families to find these genes. In the first two years of the study, they gathered 40 families into the survey. Now they have expanded to 90 families, an increase that is due, in part, to the exposure Ms. Couric gave the sibling study project during her March 2000 series on colon cancer.

Dr. Markowitz believes that the benefits for public health will be enormous when researchers are able to pinpoint the genetic roots of disease and develop simple tests to show who is genetically susceptible—and who isn’t. “My hope for health care is that, in ten years, we won’t all be drowning in a sea of recommendations,” he says. “The truth of the matter is that we’re not all the same. Some of us can get away with eating a liberal diet. Some of us need colonoscopies frequently, some don’t. If we get to the point where we recognize the patterns of genes that make certain folks susceptible, then we can individualize what we tell people about diet, exercise, preventive screening, and so on. Now we make these recommendations to 250 million Americans. Someday, we’ll be able to tailor them just to the people who need them.”

Dr. Markowitz’s fourth and newest project is aimed at finding better ways to kill cancer once it starts. Just as all people are not genetically the same, all tumors are not the same. A cancer is a cluster of cells with damaged DNA that allows it to grow and grow, accumulating more and more genetic flaws the bigger it gets. Then there is a qualitative change in the tumor once it becomes metastatic: Instead of just growing in one spot, it starts to eject cancer cells into other parts of the body where they colonize other healthy tissues.

Pushing past the mismatched chairs in the small conference room to make a series of fanciful drawings on the blackboard, Dr. Markowitz compares cancer to a dandelion. He points out that if you catch the dandelion in the spring, you can pull it out by the roots. If you wait until summer when the dandelion has bloomed and its seedlings have drifted away, it is almost impossible to rid your lawn of the weeds without a full-scale chemical assault. In this fourth project, he and other researchers are comparing early and metastatic cancers to try to find the specific genes that trigger metastasis.

They are using sophisticated new tools called gene chips, glass slides that function as molecular dipsticks: When they are exposed to tumor specimens and then read with a laser beam, they show which genes are at work in the tumor and which aren’t. The gene chips are made with the same kind of technology used to fashion silicon chips and are very expensive—each costs $10,000—but they allow the researchers to search for the activity of all 40,000 human genes on one slide. Using the gene chips, Dr. Markowitz and his colleagues will be able to compare 100 metastatic tumors with ones that have been cured and find the genetic discrepancies.

This is why the influx of Howard Hughes Medical Institute dollars, the public’s monetary support through the National Institutes of Health, and partnerships with high-tech companies are so important to this work: Top-shelf research is expensive. Of course, there is nothing like the good old-fashioned thinking that Dr. Markowitz does late at night in his lab, when everyone else has gone home, and nothing like the brainstorming that takes place in his Tuesday morning lab meetings. But even meetings such as these couldn’t take place without massive financial support, because it takes a great deal of money to bring that kind of talent together.

“We have opportunities now to make breakthroughs that we’ve never had before,” says Dr. Markowitz, an earnest face silhouetted by his own fanciful drawings of dandelion seeds taking wing. “The speed at which these opportunities can be turned into new cures is determined by how much money goes into the work. It seems like a lot, but when you compare it to the money spent on cosmetics and cigarettes, the amount spent on medical research is a drop in the bucket. Still, those of us privileged to do this work are very grateful for it.”

Kristin Ohlson, whose last story for CWRU Magazine was “The Rimm Way,” in the spring 2000 issue, is a Cleveland writer whose work has been published in the New York Times, Ms. Magazine, and Food & Wine, among many others.