A Trailblazer on the Genetic Frontier
Dr. Margaret A. Liu, vice-chairman of Transgene SA (TRGNY ) and visiting professor at Karolinska Institutet in Stockholm, is working on developing new technologies for new vaccines and cancer immunotherapy. These cancer treatments are similar to a vaccine in that they use the body's immune system to attack the cancer. Not preventative vaccines, they would be given as a therapy to treat cancer. She spoke with BusinessWeek Correspondent Amy Barrett about innovations in vaccines and the hurdles that need to be overcome.
Q: What is the innovative concept in vaccines today? A:
Q: What is the innovative concept in vaccines today?
A:Up until the early-to-late 1980s, it was felt that the thing to do was to get purer and purer vaccines. So with hepatitis B, for example, you weren't delivering any part of the virus, just one protein from the surface of the hepatitis B virus. The whole field was moving toward purer and purer vaccines.
What has been a major shift in thinking is that, for many diseases, you need a complex immune response. T cells, B cells [cells that make antibodies], and cytokines [molecules that help the T cells and B cells do their jobs] are all elements in the immune system. It is [somewhat like] a symphony [orchestra] working together. You need a more complex immune response. So people are trying to dial in other components. In our cancer vaccine, for example, we utilize not just the gene for the antigen on the tumor, but we also use a gene that codes for a cytokine. We've included a way to help augment the type of immune response we want.
That's been a huge shift in thinking: realizing we don't just need the violins, we need the brass and woodwinds as well.
Q: So what is the big challenge here? A:
Q: So what is the big challenge here?
A:The fact that it is all so complex. That makes it harder. Nobody has yet made a vaccine based purely on cellular response. So we don't know exactly what response will give protection [from disease]. The scientific hurdles are always there. But the bigger issue is the social environment [in which we're] trying to develop these new [approaches]. Because [many of the new technologies for cancer] are gene-delivery technologies, the level of concern is much greater when there is a death, vs. when that happens with cancer-drug [treatment]. [The public] accepts [that] cancer drugs are poison. When something happens with a gene-delivery system, the reaction is: "This is DNA and it's scary."
Q: How has that hampered innovation? A:
Q: How has that hampered innovation?
A:There is a different mindset. What that has meant is that these new approaches have to be tested in patients [where the] disease is so far along [that people find the perceived risk acceptable]. But that stacks the deck against [getting positive results from] those technologies. I think that also deters the big companies from funding those technologies. Most of the big companies have not put the same effort behind these technologies that they did with [traditional] small-molecule drugs. And a lot of good [small] companies have disappeared.
Q: Has the financial equation changed at all to make vaccine development more attractive in general? A:
Q: Has the financial equation changed at all to make vaccine development more attractive in general?
A:Now vaccines are seen potentially as a good business. Part of that is a recognition of the flip side of globalization, which is if you have unhealthy populations in poorer nations, it can be destabilizing. Plus, there is a huge middle class in countries like India and China that are good markets. So even at a lower [price vs. the industrialized markets], it is a worthwhile business.
Q: Are there certain parts of the world that seem to generate more of the innovation in vaccines? A:
Q: Are there certain parts of the world that seem to generate more of the innovation in vaccines?
A:If you look at venture capital, funding for biotech companies, etc., the U.S. used to have a huge lead. I don't know if that's true anymore. I think the other countries have made a conscious effort to increase their attractiveness [for investment]. One of the things that makes a big difference is the regulatory environment. In the past, if you came to the U.S., you dealt with the FDA and you had a population of 300 million people. But in Europe, you would have to deal with so many countries' [regulatory agencies]. Now with the EU and efforts to harmonize, that is changing.
Q: What is different about the vaccines you are working on vs. older, traditional vaccines? A:
Q: What is different about the vaccines you are working on vs. older, traditional vaccines?
A:If you look at diseases like measles, mumps, and rubella, those are antibody-based vaccines. Antibodies attack the virus directly or the bacteria directly. [The newer vaccines are focused on] a cellular immune response.
Q: What is the cellular immune response? A:
Q: What is the cellular immune response?
A:It doesn't directly kill the virus or pathogen. But it kills the infected cells or the cells that look different. Those can either be cells infected with something like HIV or tumor cells that have been changed in some way that they look different.
Usually, to make a vaccine, people take the bacteria or virus and kill it. Or take a virus and weaken it so it won't cause the disease. If you think about something like HIV, the HIV virus is similar to influenza. In that, the outside of it -- what we call the envelop -- changes very easily. So if you base a vaccine just on [what the outside looks like], that won't be very effective. On the other hand, the inside of proteins, from one strain to the next, look the same.
Q: So you want what are called T cells to go after the virus in question. How do you do that? A:
Q: So you want what are called T cells to go after the virus in question. How do you do that?
A:When a virus infects a cell, it takes over the cell's protein-making machinery. That infected cell starts churning out viral proteins. Pieces of those proteins sort of decorate the outside of that cell. Those decorations are things the T cells can recognize and [identify as] a foreign protein. So [T cells] kill the cells that have some foreign proteins.
Q: You are working on DNA vaccines, which involve delivering a gene that carries the code of those "decorator" viral proteins, right? A:
Q: You are working on DNA vaccines, which involve delivering a gene that carries the code of those "decorator" viral proteins, right?
A:Yes. The idea behind a DNA vaccine is to have a way to deliver the gene [for those proteins]. Now those cells produce these viral proteins, and the body then has this T-cell immune response. Think about it: If you tried to make a vaccine with a weakened HIV virus, you could get these responses potentially. But it's too risky [in terms of someone actually being infected by a weakened HIV virus]. A DNA vaccine should be safer. And you could just pick the genes for what proteins you want to target.
Q: So the vaccine is just DNA that codes for those proteins? A:
Q: So the vaccine is just DNA that codes for those proteins?
A:We are using plain DNA, but also using viral vectors. So you take a virus for some other disease and you take out enough pieces out so those viruses don't infect. It's sort of like a Trojan horse.
Q: Has the big innovation been moving beyond antibody responses to include other elements of the body's immune system? A:
Q: Has the big innovation been moving beyond antibody responses to include other elements of the body's immune system?
A:The whole emphasis of the vaccine field in trying to induce new types of immunity has been a big change. Vaccines have probably had the largest impact on health of any medical intervention. Vaccines have eliminated small pox from the planet. Polio is nearly eliminated. Most people would agree that vaccines have been very successful. But you look at some diseases: If the world has been so successful in controlling so many diseases with vaccines, why can't we easily do it for things like HIV and cancer? The reason is, we have to add the cellular responses to the antibody responses. That has been a big shift in the pragmatic approaches in the vaccine field.
Q: But you were doing some of the early work in DNA vaccines more than 10 years ago. Why is it taking so long? A:
Q: But you were doing some of the early work in DNA vaccines more than 10 years ago. Why is it taking so long?
A:Part of the challenge has been going from preclinical [testing in animals] to the clinic [where you test in people]. The human immune systems are different from mice and other animals. The challenge is to raise the immune response enough to provide protection [against the disease]. For the cellular responses, no one has been able to say [that] if you raise this type of cellular immunity to this level, you get protection. We don't know how much to raise it. The biology isn't completely elucidated yet. We know what general area we are aiming for.