Alumni News

An Interview with Hynda Kleinman

The Matrigel-Maker’s Story

BY LAURA STEPHENSON CARTER

Hynda Kleinman revolutionized cell-culture research when she co-invented Matrigel cell-culture substrate at NIH in the 1980s. Until then, scientists mainly grew cells in a flat layer in plastic culture dishes.

Matrigel is the most popular trade name for a protein mixture, secreted by certain mouse tumor cells, that assembles into a three-dimensional matrix that closely resembles the natural environments in which most mammalian cells grow. This invention allows researchers to grow and study cells that were previously difficult or impossible to culture and to observe complex cell behaviors in a more realistic environment. Today, Matrigel has widespread applications in research laboratories worldwide for studying angiogenesis, cancer, stem-cell differentiation, and other processes.

Kleinman worked at NIH from 1975 to 2006 in the National Institute of Dental and Craniofacial Research (NIDCR) and served as chief of the Cell Biology Section in NIDCR’s Laboratory of Cell and Developmental Biology (1985–2006). Her laboratory was the first to report the wound-healing effects of thymosin beta 4 (TB4), a synthetic version of a naturally occurring molecule. Her research accomplishments also include defining various angiogenic and antiangiogenic molecules and identifying sites on laminin for adhesion, migration, neurite outgrowth, angiogenesis, metastases and inhibition of metastases, and the respective receptors.

She has more than 400 publications; has 11 patents, including two for Matrigel, which was one of the top royalty generators at NIH; served on several editorial boards; and received many awards and fellowships within the NIH as well as from many outside organizations. In the 1990s and 2000s, she served on the Task Force on the Status of NIH Intramural Women Scientists (as chair from 1992 to 1994), which developed recommendations to address gender-inequity issues.

Kleinman received her B.S. in chemistry from Simmons College (Boston) in 1969 and her M.S. and Ph.D. degrees from the Massachusetts Institute of Technology (MIT; Cambridge, Mass.) in 1973. She did postdoctoral training at Tufts University (Boston) before coming to NIH in 1975. She is currently a consultant to several biotech companies, an adjunct professor at George Washington University Medical Center (Washington, D.C.), and a guest researcher in NIDCR.

The following is an edited interview with the NIH Catalyst.

CATALYST: Are you surprised that Matrigel was so successful?
KLEINMAN: I’m shocked that it’s this useful. I’m also shocked that no one has invented anything better. Because it’s a no brainer that you could make it from lots of other tissues, but it’s still made the exact same way we made it 25 years ago. It was just a wild tumor. There must be so many thousands of tumors—you can go into a bank and pull out all kinds of tumors and make it. Nobody’s done that. No company’s done it.CATALYST:

CATALYST: What got you hooked on science?
KLEINMAN: My family was very interested in nature. We were the only people in our neighborhood with a garden, and we always went fishing and hiking in the woods. I was more interested in that side of the world as opposed to sitting and reading a book or playing sports. My father worked in the retail furniture business, but was trained as a geologist. When we went on hikes he would collect rocks and look for arrowheads. In school, I was more interested in the biological and chemical sciences than I was in literature, reading, and history. In college, I applied for summer jobs in labs. I got a National Science Foundation fellowship to work at Yale University [New Haven, Conn.]. From then on, it was absolutely clear what my path was going to be.

CATALYST: What did you do at Yale?
KLEINMAN: I worked on transfer RNA from mycoplasmas. Mycoplasmas are smaller than bacteria but larger than viruses. They cause pneumonia and a whole bunch of other things. My job was to culture them in giant flasks, harvest them, and then isolate the RNA. I would put the pelleted organisms in plastic containers with phenol to extract the RNA. Then I had to go in the cold room and shake them for an hour. [laughs] I was freezing.

CATALYST: What challenges did you face as a woman scientist early in your career?
KLEINMAN: During my interview for grad school at MIT in 1969, they asked me what my husband did and what his plans were. He was a graduate student at Harvard. I said, “If you want to interview him, you should call him.” They were a little surprised at that.

CATALYST: But you were accepted?
KLEINMAN: Yes, but initially only into the master’s program. They were concerned that I would disappear with my husband to wherever his career took him. I did go on to get my Ph.D., however.

CATALYST: How did you manage not to get discouraged?
KLEINMAN: Well, I just loved the science and the work I was doing.

CATALYST: What sorts of things did you do to help women advance in science?
KLEINMAN: I had gone to an all-girls high school and an all-girls college. Then I went to male-dominated MIT. So my antennae were up. When I went to publish my paper on Matrigel, I looked at the journal’s editorial board and saw it was all men. So I wrote a letter complaining about that. George Martin [then chief of NIDCR’s Laboratory of Developmental Biology and Anomalies] signed it. We did that with other journals, too. Later, when I felt more comfortable, I would sign the letters myself. I learned that if I was going to complain, I also had to give them a list of five women to consider. People at NIH knew that I was writing these letters [laughs]. So they thought of me when Bernadine Healy [NIH Director, 1991–1993] created the committee to investigate the status of women at NIH.

CATALYST: Have things improved for women scientists at NIH?
KLEINMAN: For awhile things seemed a little bit better. I think the women who survive are the ones with good mentors who protect them and support them and promote them.

CATALYST: Who was your mentor?
KLEINMAN: George Martin. He was at NIH for 30 years—in NIDCR and later as the scientific director at the National Institute of Aging. He’s an emeritus and a consultant now.

CATALYST: How did he encourage you?
KLEINMAN: He was very accessible and generous with his time. He offered us [his mentees] ideas and opportunities. He would encourage us to go to meetings, to give talks, and to ask questions at seminars. He really promoted us. He introduced us to other scientists when they visited and even invited us to have lunch with them. Things like that are normal today, but not back then. He was unusual for his time.

CATALYST: How did you wind up at NIH?
KLEINMAN: I had been working at Tufts on complex carbohydrates and teaching organic chemistry at Simmons College. A friend who was working at NIH invited me to give a seminar on heparin sulfate proteoglycans in cells from people with and without diabetes. When I came, I met with George Martin and he offered me a job. At the same time my husband was offered a job at CDC’s National Center for Health Statistics in Hyattsville, Md. So we thought about it for a weekend and then said we should go.

CATALYST: What do you find most satisfying in your career?
KLEINMAN: What I’ve enjoyed the most are the students and postdocs. It’s been fun watching them grow and seeing how much they can do. They did very well. I try to keep in touch with most of them. It’s so much easier now with Facebook. Most of the students went on to medical school.

CATALYST: You have 11 patents, including two for Matrigel. What are some of the others?
KLEINMAN: There are two patents for TB4, a small actin-binding protein. One is for wound healing and the other is for hair growth.

CATALYST: Are those being used commercially?
KLEINMAN: They are in clinical trials and are not yet approved by the FDA. But some are being marketed on the Internet: thymosin shampoos for hair growth; injectable TB4 for body builders.

CATALYST: How does TB4 work?
KLEINMAN: It prevents cell death and stimulates stem cells to do repair. So whether the repair is a damaged muscle or an injury from a bullet to the brain or a burn to the skin, it works on all of them. It doesn’t matter where you inject it, it knows where to go.

CATALYST: How well is it working?
KLEINMAN: It works very well in the eye for different kinds of eye problems such as dry eye. For the skin, there have been three clinical trials for pressure ulcers—for stasis ulcers, caused by malfunctions in leg veins, and for a genetic disease called epidermolysis bullosa, in which the skin is so fragile that it blisters easily. So far, the TB4 seems to have a positive effect on accelerating the rate of healing.

CATALYST: Was it easy to patent Matrigel in the 1980s?
KLEINMAN: To patent discoveries, we typically wrote an invention report and included as much data as we could. We could not have previously disclosed this data anywhere, not even at meetings. We’d file the report with a Health and Human Services (HHS) Patent Branch—this was before the NIH Office of Technology Transfer (OTT) was established—and they would decide whether to go forward. The NIH lawyer rejected my report for Matrigel. He said it lacked usefulness. I had already given it to all these people at NIH so I just asked them to send me their data. I got pictures of all the data and I went over to the guy’s office and said, “I want you to see all these things it’s been used for.” He said, “Okay.” And that was it. And then he sent it through.

CATALYST: How do you know when a discovery is something that’s worth patenting?
KLEINMAN: Sometimes you know what other people are patenting, and you say, “Okay, I’ve got something that’s better than that.” Other times you don’t know, it’s a guess. I urge scientists to patent their discoveries. The success rate is 25 percent, which is higher than the grant-application success rate. It’s an easy process. The OTT handles patents and licenses now. [Until the early 1990s, the Patent Branch of HHS’s Office of General Council handled patents and the Department of Commerce handled licensing. For details on OTT’s process, see http://www.ott.nih.gov.]

CATALYST: What do you do as a consultant?
KLEINMAN: For one company, I manage their material-transfer-agreement portfolio. For me, that’s a lot of fun because it still connects me to the science. I also deal with patents. When they get rejected, I work with lawyers to try to get around the objections. I’ve even gone to a European court to defend a patent. We were successful.

CATALYST: What do you like to do outside of work?
KLEINMAN: I bike, run, and do a lot of travel. I go to Italy for two months a year. I did a sabbatical there in 2004 and loved it so much that I keep going back. I also read a lot of historical fiction. When we’d go to Italy, one suitcase was filled with books. Of course now we have Kindles [laughs] so I’m in much better shape.

CATALYST: One last question. I understand you were listed in the credits for the 2001 horror movie classic Session 9. How did that come about?
KLEINMAN: My husband’s cousin was a movie set director and needed sets for a lobotomy lab. Session 9 was being filmed at an abandoned mental hospital in Massachusetts. I went to the National Library of Medicine to look up lobotomies. You are not allowed in the stacks yourself, so the librarians bring the books to you and in the case of very old books they turn the pages for you. I got to see books with pictures of lobotomy tools and of people who had had lobotomies. Of course we didn’t have tools like that in the lab, but our giant tweezers and tongs that we use to pick up beakers of hot liquids could pass as lobotomy tools. I collected a bunch of old lab equipment and got permission to send them to my cousin-in-law. He outfitted a lobotomy lab with old beakers that had cracks in them and other things that could pass for old lobotomy tools—at least on a movie set. So that’s how I got a credit in the movie. I never even saw it myself.

To read more about the Matrigel story
Semin Cancer Biol 15:378-386, 2005
Curr Opin Cell Biol 22:677-689, 2010

To see a video of Hynda Kleinman's presentation at the Philip Chen, Jr., Lecture on November 15, 2012, go to http://videocast.nih.gov/launch.asp?17665.