The Quiet Revolutionary

Dr. Ihor Lemischka takes a low-key approach to groundbreaking stem cell research.

By P.H.I.Berroll

In 2007, Ihor Lemischka, Ph.D. was a professor of molecular biology at Princeton University, where he had worked for more than two decades. His research in stem cell biology and its possible medical uses had brought him international renown.

But he was not satisfied.

“Princeton has no medical institution,” he explains. “And in stem cell research, you sort of hit a glass ceiling when you don’t have access to a medical institution or school. I was mostly working with mouse cells, and I really wanted to get more involved in studying human stem cells and human diseases.”

So when Dr. Lemischka was offered the directorship of Mount Sinai’s Black Family Stem Cell Institute, he eagerly accepted – and now says, “My only regret is that I didn’t do it sooner.”

At Mount Sinai, Dr. Lemischka, who is also Professor of Gene and Cell Medicine at the Mount Sinai School of Medicine, is building what he calls “a world-class stem cell institute” where he is taking his research to the next level – to the threshold of a revolutionary breakthrough in the treatment of genetics-based disease.

Dr. Lemischka, a low-key personality who speaks in calm, measured tones, is careful to avoid hyperbole in discussing his work. But as he describes its potential – the hope that it could lead to a cure for such devastating conditions as diabetes and Parkinson’s and Alzheimer’s diseases – his enthusiasm comes through.

“I find it to be probably the most exciting time ever in my career right now,” he says.

 

From a Few Cells, a World of Knowledge

Dr. Lemischka, who holds a B.A. from Johns Hopkins and a Ph.D. from M.I.T., is a specialist in induced pluripotent stem cell (iPSC) research, which uses stem cells taken from adult patients to study the causes of genetics-rooted disease.

The research technique, derived from what is known as the Yamanaka technology (named for Dr. Shinya Yamanaka of Kyoto University, who first developed it) begins with the removal of skin cells from adult patients. Then three or four genes are introduced into the cells. The genes’ DNA “reprograms” the cells into pluripotence – meaning that they have the potential to turn into any of the 220 cell types in the human body. And because the iPS cells are genetically identical to those of the patient, they will contain the same genetic mutation that caused that person’s particular disease.

The significance of this is profound. “We now have a way to develop tools that allow us to understand the ideology of complex, genetics-based diseases,” says Dr. Lemischka, “and from there, to build a platform for better diagnostics for these diseases – and the discovery of drugs to treat them.”

In addition, Dr. Lemischka foresees a day when iPSC technology could be used to create healthy cells that could then be transplanted into patients, replacing diseased tissue in organs such as the heart.

“If you were to derive, say, some transplantable cells from a patient’s iPS cells and then try to put them back into the patient, because of the shared genetic identity there’s no problem of immune system rejection,” he observes. “For example, even if you were lucky enough as a researcher to get a biopsy sample of human heart tissue, you can’t grow human cardiac cells; but with iPS cells, we can make as many cardiac muscle cells as we want.”

 

An Early Breakthrough

Not long after arriving at Mount Sinai, Dr. Lemischka had his first opportunity to put his expertise to use.

Pediatric cardiologist Bruce Gelb, MD, the director of Mount Sinai’s Child Health and Development Institute, and his research team had discovered the first gene ever associated with two common genetic diseases, Noonan and LEOPARD syndromes (“LEOPARD” isan acronym for the first letters of seven symptoms associated with the disease). But Dr. Gelb wanted to learn more about LEOPARD’s deadliest symptom, hypertrophic cardiomyopathy (HCM) – a cardiac condition in which heart cells become enlarged and the heart muscle thickens and grows too stiff to function properly.

So the two researchers joined forces. Using skin cell samples from two LEOPARD patients, they used the iPS protocols to produce a limitless supply of heart cells – exact copies of those in the patients. And they found that the copied cells were enlarged in the same manner as the originals.

This was a major research achievement: through iPSC technology, Drs. Lemischka and Gelb had produced one of the world’s first in vitro (often referred to as “disease in a dish”) models of cardiovascular disease – an important advance in tackling one of the greatest challenges to global health.

“By getting a defective heart cell in a dish that recapitulates to a large extent – or even identically – a disease such as HCM,”  Dr. Lemischka explains,  “you can track the development of these heart cells and ask, ‘Where do you see the first example of something going amiss?’  Having pinpointed that, you can say, ‘Okay, let’s see if we can find small molecules that delay, or reverse, or block this first thing that’s gone wrong.’  And it’s not possible to do this in any other way.”

The work of Drs. Lemischka and Gelb was widely praised after they published their findings as the cover story in the June 10, 2010 issue of Nature, the world’s preeminent scientific journal.

Since that time, Dr. Lemischka and his staff at the Black Family Stem Cell Institute – which includes his wife, Dr. Kateri Moore, who came with him from Princeton – have moved ahead with research involving a wide range of afflictions, including cancer, diabetes, liver disease and spinal cord injury, in collaboration with specialists in other disciplines at Mount Sinai.

“It’s very exciting to work clinicians and translational researchers using human iPSC,” he says. “Bringing together different groups with different sets of complementary expertise makes for a synergistic effort that is much greater than the sum of excellent parts.”

Dr. Lemischka believes that even diseases affecting the brain are within the realm of possibility.

“I could imagine developing ways of treating Parkinson’s disease,” he says, “because we know quite a lot about it – we know which neurons are missing or damaged and we could make those neurons in a dish filled with stem cells. And with Alzheimer’s, to be able to study how the neurons might degenerate – in vitro, in a dish – allows you again to develop platforms for drug discoveries.”

 

“Education is the Key”

Still, Dr. Lemischka makes it clear that iPSC research is not yet “as far advanced” as embryonic stem cell studies, which remains the most fully developed form of stem cell research. “We know that in many ways, iPS cells closely resemble embryonic stem cells,” he notes, “but we don’t know how exact that similarity is. Before we can say, ‘These cells can replace embryonic stem cells,’ we’ll need to do in-depth comparative studies for quite a long time. We’re all very excited about iPS cells, but to jump to the conclusion and say they’re the same, and can already replace embryonic stem cell research, is way premature.”

And because of the continued value of embryonic research, Dr. Lemischka does not shy away from addressing its main point of controversy: the extraction of cells from frozen embryos which are destroyed in the process.

“I do not object to somebody’s personal moral, ethical or theological beliefs, such as the belief that a fertilized egg, an embryo, is the same as a human being – I’m respectful of that,” he says. “But when a minority of people influences the government to dictate policy for the whole country, I feel that borders on a violation of church-state separation – which is one of the things this country was founded on.”

Ultimately, says Dr. Lemischka, “education is the key” to changing minds. “I’ve seen it work,” he adds. “I’ve had experiences where I would give a half-hour talk to a group of non-scientists – a retirement community, for example – and people have come up to me afterwards and said, ‘I came here very anti-embryonic stem cell research, and now I have a different opinion. You’ve changed my mind.’”

And he is certain that concrete results will also help influence public opinion: “Once there’s some cure – let’s say, a child with diabetes is cured by stem cell transplants – it then becomes a very different ballgame, because then the outcry from the public of ‘How can you possibly deny my child this?’ would become huge.”

 

The Next Leap Forward

For all his enthusiasm, Dr. Lemischka cautions against predicting quick benefits from any form of stem cell research.

“We all believe that there will be stem cell-related cures,” he says, “but we can’t with any certainty say how soon. So it’s important – and again, this is where education comes in – to create a realistic set of milestones which you can take the time to explain to the public. You don’t say something like ‘next year, we’re going to be able to cure your father’s Parkinson’s.’ Because then, inevitably, there’s a public backlash – and it’s the public that largely pays the bills, since we run in large part on federal or state money.”

However, Dr. Lemischka acknowledges “that we see amazing advances happening every day. Keep in mind that there are already stem cell cures, such as cord blood transplantation” – a stem cell therapy widely used for leukemia, sickle-cell anemia and other diseases – “where you transplant a blood-forming stem cell from a donor to a recipient.

“It’s one of the best things about being in this area, the fact that you don’t know what’s next. It’s incremental, by and large – 99.9 percent of it. But every once in a while, you get something that moves the whole field forward with a leap. You can’t anticipate these things, but you have to be open to them.”

Originally published in Mount Sinai Science & Medicine magazine, 2011.

Download PDF

“It’s Overwhelming to Hear Their Stories”

Every other week, Laura Hoskins, PsyD, leaves her practice at North Shore University Hospital and flies to upstate New York, where she immerses herself in the treatment of wounded Iraq and Afghanistan war veterans at the U.S. Army base Fort Drum. The work of Dr. Hoskins, a neuropsychologist, is part of an initiative under North Shore-LIJ’s Welcome Back Veterans program, a fund of the McCormick Foundation, in partnership with Major League Baseball. Dr. Hoskins spoke with Philip Berroll about her experiences:

Describe your work in your own words. As a neuropsychologist, studying brain-behavior relationships, I’ve specialized in traumatic brain injury (TBI). The conflicts in Iraq and Afghanistan have produced a large increase in TBIs – it’s a signature injury of these wars. The closest parallel would be a severe concussion in football; like football players, many of these soldiers have repeated concussive events – often as many as three to six – because they’re exposed to a lot of blasts from improvised explosive devices (IEDs). And they need proper treatment should there be any long-term negative sequelae – pathological conditions.  I focus on mild TBI; the more severe injuries go to a place like Walter Reed Army Medical Center (in Washington, DC).

What is a typical day at Fort Drum like for you? I see one patient a day, with whom I meet at 8:00 a.m. for about an hour – going through their medical and psychological history, and focusing on the details of the concussive event(s) as they recall them. Then we have a three- to four-hour series of tests to assess cognitive status, memory, attention… get a good sense of how they’re functioning. If they’ve had a TBI, my job is to find out if there’s cognitive impairment as a result – and if so, is it related to the TBI and/or post-traumatic stress disorder (PTSD) or other factors. The good news is that with mild TBI, the vast majority of individuals recover within hours and days, with only about three percent having long-term, protracted sequelae post-injury.

How do you approach this other three percent? I have to look at all the variables that may be playing a role – which can include PTSD, orthopedic injuries or an overuse of pain medication. Then there are the “social” factors: the vast majority of these soldiers have been deployed multiple times; they have years of being away from their families and then coming back and re-integrating, which is often very difficult and is complicated by the strong possibility that they’ll be redeployed – why fully re-engage when you know you may have to disengage again?

What is the next step in the process? I provide my diagnostic conclusions and treatment recommendations, in collaboration with my rehab team. We use a very integrated, individualized treatment approach because no two cases are alike. One soldier may have cognitive issues such as a decline in attention or memory; another may have more behavioral issues – sleep changes, changes in mood; some may have both, as mild TBI often has both neurological and psychological symptoms. After that, the soldier may be referred to a three-week TBI treatment program, or to the Warrior in Transition Unit (WTU). Usually he or she will be considered on active duty, but may be put on a Temporary Duty Profile in which his or her responsibilities may be limited given their medical condition.

What if you feel a soldier isn’t ready to return to duty? I speak to the commander or someone in their unit. Because sometimes soldiers are reluctant to report a problem – they want to be “a good soldier,” they don’t want to let their unit down – and often with a mild TBI, they may look okay on the surface, but something may not be right with their thinking; they may have a slower response time, etc. And the commanders may not have prior training or experience in this area, so you have to explain it to them and say, “This guy should sit out for another week or two weeks or whatever.”

You’ve been working at Fort Drum since November 2009, when the Welcome Back Veterans Initiative started? Yes, I came on as a result of the program. They had received the funding to be able to hire me and cover my trips to Fort Drum and my services there.

Prior to that, were you doing any kind of work with soldiers? I was doing my fellowship at Dartmouth Medical School, and I was in the clinical service. I’d see the occasional veteran, but it was not specific to my job.

So what got you interested in doing this? I specialized in TBI during my fellowship and my clinical research work had focused on that area. So I felt I had a unique service that I could provide; and while I think it’s important to help these soldiers who have served our country, we can also learn a lot from their experiences.  

Has dealing with these men and women affected you personally? All my patients impact me – but especially this group. It’s overwhelming to hear their stories, and to realize that at such a young age – the vast majority of them are between 18 and 25 years old – they’ve left their families to enter this extremely high-stress situation. To me, that level of sacrifice and dedication is awe-inspiring.

Originally written for the newsletter of North Shore-LIJ Medical Center, 2010.

Download PDF

A Second-Generation Success Story

Dr. Janice Gabrilove, daughter of a Mount Sinai legend, has forged a distinguished career of her own.

By P.H.I.Berroll

As a child, Janice Gabrilove did not dream of a career in medicine – “I was thinking more of going into the performing arts,” she recalls. This is surprising, considering her family background: her father is Dr. J. Lester Gabrilove, a pioneering endocrinologist and a longtime leader of Mount Sinai’s Division of Endocrinology, Diabetes, and Bone Disease (which is named for him and his late wife Hilda).

But Janice later changed her mind – and has had a distinguished medical career in her own right as a researcher, educator and clinician.

Dr. Gabrilove is James F. Holland Professor of Medicine, Hematology and Medical Oncology and Professor of Oncological Sciences at Mount Sinai School of Medicine, from which she earned her medical degree. She also directs the school’s Clinical Research Training, M.S. and Ph.D. in Clinical Research programs, where trainees learn how to apply the observations gained from clinical practice to medical research. Those programs, now renamed the Center for Patient-Oriented Research, Education, Training and Development (CPORETD), recently had a major boost when Mount Sinai received a Clinical and Translational Science Award (CTSA) – a $34.6 million, five-year grant – from the National Institute of Health (NIH).  Dr. Gabrilove hopes to make Mount Sinai’s clinical research training “the centerpiece of the CTSA.”

The CTSA award is the culmination of years of work by Dr. Gabrilove to establish Mount Sinai as a world-renowned leader in clinical research – starting in 1998, the year she was appointed Chief of Medical Oncology and Deputy Director of the Cancer Center.

That year, the NIH created the Clinical Research Curriculum Awards to help medical institutions train a greater number of researchers; the Institute was concerned, Dr. Gabrilove says, “that clinical investigation was becoming a dying art and a dying science…  something that was kind of learned on the sly” due to a lack of funding.  The newly hired Dr. Gabrilove was assigned by then-Dean of Mount Sinai Medical School Dr. Arthur Rubinstein and then-Department of Medicine Chair Dr. Barry Coller to apply for an award. The application was successful, enabling Mount Sinai to establish a certificate program which was later expanded to include Master’s and Ph.D. degrees. “We recruited our first Ph.D. cohort last fall,” she says proudly. “Seven students were accepted.”

From One Small Cell, Dramatic Breakthroughs

Dr. Gabrilove decribes herself as “passionate about clinical research,” and it was such research that produced her crowning achievement to date:  the development of human granulocyte colony stimulating factor (G-CSF),a major breakthrough in both chemotherapy and bone marrow transplantation.

Dr. Gabrilove and her research team studied the neutrophil granulocyte, a white blood cell that plays a crucial role in preventing bacterial infection. In chemotherapy, these rapidly growing cells are injured or killed, resulting in a condition known as febrile neutropenia where the body’s defenses against infection are greatly reduced – “a significant cause of mortality,” she notes.

But the researchers were able to discover the normal growth factor for neutrophil granulocytes, which they tested after purifying the protein and then cloned in collaboration with the biotech company Amgen to produce G-CSF. Further tests and trials showed that G-CSF could reduce the incidence of febrile neutropenia by as much as 50 percent. Other researchers, building on Dr. Gabrilove’s work, subsequently used G-CSF to achieve greatly improved survival rates in diseases such as breast cancer and lymphoma.

Dr. Gabrilove and her team made another important discovery: G-CSF drives stem cells from the bone marrow out into the bloodstream, allowing doctors to collect the cells and use them in bone marrow transplants.  Previously, the cells had to be surgically removed; with a dosage of G-CSF, they can be obtained through a simple blood extraction. “It’s much less invasive,” says Dr. Gabrilove, “you get a better quality stem cell… and reconstitution is much faster.”

In talking about her Mount Sinai experience as a medical student and staff member, Dr. Gabrilove cites several doctors as inspiring teachers and colleagues.  Naturally, her father – whom she calls “just an unbelievable role model in the kind of person he was” – has been a particular influence. And she continues to benefit from his insights: Lester Gabrilove currently serves as Baumritter Professor of Medicine, Emeritus at Mount Sinai School of Medicine – while continuing his clinical practice – as he approaches his 93rd birthday.

“My father drops in now and again for a visit,” she says. “He’s a great guy.”

Originally published in Mount Sinai Science & Medicine magazine 2010.

Download PDF

 

An Activist at Home and Abroad

From Mount Sinai to West Africa, Dr. Jeffrey Freed works to help people in need.

Jeffrey S. Freed, MD, began his medical residency at Mount Sinai after graduating from public institutions where he had paid little or no tuition. “I had the good fortune to leave medical school with absolutely no debt,” he says.

And Dr. Freed – a colorectal surgeon and Associate Clinical Professor of Surgery at Mount Sinai Medical School – has tried to aid students who are not so fortunate. As a member of the Mount Sinai Alumni Association, serving as Board President from 2001 to 2003, he has worked to make medical education affordable for those students “so that the onerous burden of debt does not impede their careers.”

This kind of activism is why Dr. Freed is a 2010 finalist for one of Mount Sinai’s most prestigious honors, the Jacobi Medallion. Created in 1952 to mark the 100th anniversary of Mount Sinai’s founding, and named for Dr. Abraham Jacobi, a pioneer in pediatrics and a past president of the Mount Sinai Hospital Medical Board, the award recognizes Mount Sinai physicians for medical achievements and/or service to the hospital, the Medical School or the Alumni Association.

The accomplishments of Dr. Freed, who says he would be “humbled” to receive the Medallion, are both local and international: Since 2008, he has led an annual Mount Sinai medical mission to the West African nation of Liberia – helping to rebuild that country’s healthcare system, which had been shattered by decades of civil war.

‘A Full-Court Press’ to Help Medical Students
As Alumni Association Board President, Dr. Freed and his predecessor, Dr. Avi Barbasch, partnered with Mount Sinai’s Development Office to create a fundraising network of alumni and other donors. Dr. Freed has also worked with the Association’s chapters in other parts of the country to encourage alumni involvement in fundraising, primarily to endow scholarships. In addition, an alumni scholarship was recently donated in Dr. Freed’s name – “for some student(s) in need, with exceptional credentials,” he explains, “who would receive $50,000 a year, for five years.”

The need for such scholarships, says Dr. Freed, is urgent. “In a survey, we found that debt is a tremendous factor in medical students’ choosing their specialty training upon graduation,” he notes, “and that for minority students, fear of debt is a major reason that they shy away from pursuing any medical education. This led me to believe that a full-court press for raising money for scholarships was really necessary.”

Rebuilding from the Ashes of War
Dr. Freed faced even greater challenges on his first mission to Liberia. “There were between 35 and 40 Liberian doctors left in the country,” he recalls. “That’s about one doctor for every 100,000 people.”

Working at two local hospitals, Dr. Freed and his team of 16 physicians and seven medical students treated close to 200 patients for conditions including cancer, hernias and cataracts, trained local health providers and set up a chemotherapy suite.

Dr. Freed subsequently led two more missions, in 2009 and 2010, and is currently planning another for early 2011. In that time, he has seen significant progress.

“Their X-ray and sonogram capabilities have increased remarkably,” he says. “Nursing protocols have been put in so women in labor are more closely monitored. These are relatively simple, basic programs – and they are sustainable by the people there.”

Whether at home or abroad, as physician, educator or fundraiser, Dr. Freed is motivated by the same sense of compassion that has inspired his medical career.

“We are physicians to really help people,” he says. “That is the primary goal.”

– Philip Berroll

Originally published in Mount Sinai Science & Medicine magazine, 2011.

Download PDF

Newer Entries