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About Dr. Andrews

  1. Top of page
  2. About Dr. Andrews
  3. EC Cells to ESCs
  4. "There Is a Lot of Misunderstanding About the Term ‘Marker'"
  5. "It's Important to Recognize That Genetic Changes in These Cells Are Going to Be Inevitable"
  6. "There Is a Reasonable Possibly of Clinical Trials in the Next Few Years in the Area of Age-Related Macular Degeneration"
  7. "In the Next 10 Years There Will Be a Lot of Advances and It Will Be Quite Exciting"
  8. "You Need to Balance the Effort That You Put in Against What's Going to Come out"

Dr. Andrews obtained a B.Sc. in Biochemistry from the University of Leeds in 1971, followed by a D.Phil. in Genetics and Biochemistry from Oxford University in 1975. He then worked as a research Fellow at the Institut Pasteur in Paris and the Sloan-Kettering Institute in New York before taking up a position as a Research Investigator at the Wistar Institute in Philadelphia. While a professor at the Wistar Institute in 1989, he also completed an M.B.A. from the Wharton School at the University of Pennsylvania. In 1992 he moved to the Department of Biomedical Sciences at the University of Sheffield in the U.K., where he was Chairman of the Department from 1995 to 2003 and today is the Department's Arthur Jackson Professor of Biomedical Science. He has published more than 90 research papers in peer-reviewed journals and more than 50 reviews and other contributions covering the biology of human teratocarcinomas, embryonal carcinoma (EC) cells and embryonic stem cells (ESCs). With his colleague Dr. Harry Moore, he is currently Co-Director of the Centre for Stem Cell Biology at the University of Sheffield, which provides a focus in the university for research with human ESCs and hosts an annual training course in working with human ESCs in cooperation with the UK Stem Cell Bank. The Centre has derived eight human ESC lines, three of which are currently available from the UK Stem Cell Bank, whereas the others are at different stages of deposit and workup for general distribution. Future lines will be derived in their new Good Manufacturing Practices (GMP) Facility. Dr. Andrews is also Coordinator of the International Stem Cell Initiative (ISCI), a research program funded by the International Stem Cell Forum (http://www.stemcellforum.org) to develop standard criteria for working with human ESCs. The results of the first project (ISCI1), covering the properties of 59 cell lines developed and maintained in 17 laboratories and 11 countries, have recently been published (Nat Biotechnol 2007;25:803–816). A second project with a budget of 2 million dollars is currently in progress to compare different media for the culture of human ESCs and to document the common genetic changes that occur in these cells following prolonged culture. Dr. Andrews is also coordinator of ESTOOLS, a European FP6 Integrated Project with 21 partners across Europe, focused on developing basic tools for analysis of human ESCs and controlling their differentiation (http://www.estools.eu). 1

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Figure 1. Peter Andrews, D.Phil., M.B.A. The Centre for Stem Cell Biology, University of Sheffield.

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EC Cells to ESCs

  1. Top of page
  2. About Dr. Andrews
  3. EC Cells to ESCs
  4. "There Is a Lot of Misunderstanding About the Term ‘Marker'"
  5. "It's Important to Recognize That Genetic Changes in These Cells Are Going to Be Inevitable"
  6. "There Is a Reasonable Possibly of Clinical Trials in the Next Few Years in the Area of Age-Related Macular Degeneration"
  7. "In the Next 10 Years There Will Be a Lot of Advances and It Will Be Quite Exciting"
  8. "You Need to Balance the Effort That You Put in Against What's Going to Come out"

In the early 1970s, mouse EC cells, derived from tumors originating in the testicular germ cells, were seen as a key tool for exploring embryonic development, an early area of interest for Dr. Andrews. “There was a lot of interest in work with mouse EC cells. But many people were also interested in determining if there was an equivalent type of human cell, which would be important in giving us insight specifically into human development. When I arrived at the Wistar Institute to work with Barbara Knowles and Davor Solter, they had recently obtained a large number of cell lines from human testicular teratocarcinomas, and so these were a putative source for human EC cells. I focused my work on those cell lines, with the objective of trying to find the human EC equivalent of the mouse EC cells. We spent 2 or 3 years trying to define what human EC cells were, and initially we were quite surprised—everyone assumed that they would be very similar to the mouse EC cells and would express similar markers, but slowly it became clear to us that they didn't—they actually expressed several markers that were counterintuitive based on the mouse work. We also found a human EC cell line that would differentiate, TERA-2, and spent a long time characterizing that. Then, in 1981 Martin Evans and Gail Martin separately identified mouse ESCs from mouse embryos. They showed that they were very similar to mouse EC cells, and coupled with the development of molecular genetics, these became major tools for studying mouse development. So we began wondering at that time if it would also be possible to get human ESCs from embryos. When I came to Sheffield in 1992, I continued the work with EC cells, and with my colleague Harry Moore we started to think about the possibilities of human ESCs. Largely there was a logistical problem at that time, about making the right clinical connections and being able to obtain the embryos. Meanwhile, Jamie Thomson's lab succeeded in deriving monkey ESC lines and then human ESC lines in 1998. We got his human ESC lines from him fairly soon after that, in 1999, and we started comparing these to human EC cells. I was pleased to find that a number of things that we had identified and characterized in human EC cells actually translated to human ESCs. A lot of the surface markers, for example, that were expressed differently than in the mouse.”

"There Is a Lot of Misunderstanding About the Term ‘Marker'"

  1. Top of page
  2. About Dr. Andrews
  3. EC Cells to ESCs
  4. "There Is a Lot of Misunderstanding About the Term ‘Marker'"
  5. "It's Important to Recognize That Genetic Changes in These Cells Are Going to Be Inevitable"
  6. "There Is a Reasonable Possibly of Clinical Trials in the Next Few Years in the Area of Age-Related Macular Degeneration"
  7. "In the Next 10 Years There Will Be a Lot of Advances and It Will Be Quite Exciting"
  8. "You Need to Balance the Effort That You Put in Against What's Going to Come out"

The topic of surface markers is an important area in cell characterization, but one that Dr. Andrews feels is often misunderstood. “I think there is a lot of misunderstanding about the term marker. A marker is merely a surrogate for identifying a cell. An ESC is really defined by its origin from an embryo and the fact that it is able to undergo self renewal and is pluripotent, that is, it has the capacity to differentiate in to a wide variety of cell types; it's a functional test. Obviously, these tests are very difficult and time consuming to perform. People want to have a shortcut, so they look for markers—they look for something that is expressed that is a surrogate for all of those things, and certainly we've got a variety of surface markers that we've defined that are good surrogate markers; they are commonly expressed by ESCs and then are turned off when they differentiate. The important thing that a lot of people possibly don't always think about is that these antigens are not unique to ESCs—they are expressed on all sorts of other cells as well. So markers are only useful as long as you use them in the right context. For example, SSEA3 and SSEA4 are extremely valuable markers if you're looking at an ESC culture and you want to know if these cells are consistent with others cultures that we call ESCs, and if they are differentiating or not. But if someone just gives you a group of cells with no other information about them except that they happen to express SSEA3, you cannot use that to say these are ESCs. Another jump that people sometimes make is to say that if two different sorts of cell express the same marker antigen, then they must be related in the same lineage, but there is no rationale for assuming that at all.”

"It's Important to Recognize That Genetic Changes in These Cells Are Going to Be Inevitable"

  1. Top of page
  2. About Dr. Andrews
  3. EC Cells to ESCs
  4. "There Is a Lot of Misunderstanding About the Term ‘Marker'"
  5. "It's Important to Recognize That Genetic Changes in These Cells Are Going to Be Inevitable"
  6. "There Is a Reasonable Possibly of Clinical Trials in the Next Few Years in the Area of Age-Related Macular Degeneration"
  7. "In the Next 10 Years There Will Be a Lot of Advances and It Will Be Quite Exciting"
  8. "You Need to Balance the Effort That You Put in Against What's Going to Come out"

The genetic stability of ESCs is also something that Dr. Andrews has a deep interest in, especially since it takes him back to his roots in EC cells, the “malignant version” of ESCs. “We noticed some ESC lines which had acquired karyotypic changes, but the thing that caught our eye was that these changes were both nonrandom, such as continual examples of extra copies of chromosomes 17 and 12, and they were the same changes that are characteristic of EC cells. One of the things that that said to us was that the underlying causes of some of those changes is intrinsic to the cells, not related to the culture conditions, since EC cells and ESCs grow in very different environments. Cells in culture are inevitably going to acquire mutations, and there will be selection pressure in any stem cell system for those mutations that would tend to promote self renewal at the expense of differentiation or death. It's important to recognize that genetic changes in these cells are going to be inevitable and that we need to develop ways to work with this. Remember that mouse ESCs also undergo genetic changes in culture, but it hasn't stopped people from being able to use mouse ESCs to make germline chimeric mice and study mouse development.

"There Is a Reasonable Possibly of Clinical Trials in the Next Few Years in the Area of Age-Related Macular Degeneration"

  1. Top of page
  2. About Dr. Andrews
  3. EC Cells to ESCs
  4. "There Is a Lot of Misunderstanding About the Term ‘Marker'"
  5. "It's Important to Recognize That Genetic Changes in These Cells Are Going to Be Inevitable"
  6. "There Is a Reasonable Possibly of Clinical Trials in the Next Few Years in the Area of Age-Related Macular Degeneration"
  7. "In the Next 10 Years There Will Be a Lot of Advances and It Will Be Quite Exciting"
  8. "You Need to Balance the Effort That You Put in Against What's Going to Come out"

In terms of practical applications for human ESCs, Dr. Andrews envisions three general areas: regenerative medicine (using ESCs to replace damaged tissues), drug discovery and toxicology, and disease modeling and developmental studies. “It's my feeling that since both drug discovery and disease modeling don't require nearly as much safety testing as would be required in regenerative medicine, it's in those areas that one might expect the most immediate applications of stem cells. But in terms of regenerative medicine, we and several other groups have become interested in using derivatives of ESCs in age-related macular degeneration (AMD). This disease is the loss of retinal pigment cells in elderly people which leads to a gradual loss of eyesight. I would say there is a reasonable possibly of clinical trials in this area, possibly before anything else. There are several reasons for this. It turns out that a number of ESC lines are spontaneously able to differentiate into retinal pigment cells and these are easy to separate out of culture. There have been clinical trials showing that you can take retinal pigment cells from someone's own eye, from the periphery of the retina, and transplant them to the macula, and cure AMD. It's a very complicated and long operation, but it is a proof of concept. It looks like to do this you need very small numbers of cells, and you can monitor very easily what's going on because you can actually look in the eye and see what's happening. So this looks very promising for an early trial; perhaps testing could begin in the next few years, but even in the best scenario, turning this into a routine type of treatment could perhaps take another 10–15 years.”

"In the Next 10 Years There Will Be a Lot of Advances and It Will Be Quite Exciting"

  1. Top of page
  2. About Dr. Andrews
  3. EC Cells to ESCs
  4. "There Is a Lot of Misunderstanding About the Term ‘Marker'"
  5. "It's Important to Recognize That Genetic Changes in These Cells Are Going to Be Inevitable"
  6. "There Is a Reasonable Possibly of Clinical Trials in the Next Few Years in the Area of Age-Related Macular Degeneration"
  7. "In the Next 10 Years There Will Be a Lot of Advances and It Will Be Quite Exciting"
  8. "You Need to Balance the Effort That You Put in Against What's Going to Come out"

Dr. Andrews agrees that there are several important things that will be important for scientists to focus on over the next 10 years, before we will be able to use stem cells in many kinds of clinical treatment. “The crucial thing I think is understanding the basic biology of the stem cell state itself. We need to know what it is that allows them to maintain a pluripotent state, because in order to use these cells in any kind of clinical application we are going to have to grow large numbers of them while maintaining them as stem cells and minimizing any genetic variation in them. At the moment we can grow a lot of cells but they may acquire genetic changes and they also tend to differentiate when they want to; it's difficult to maintain a uniform population of undifferentiated ESCs. The other thing is that you have to be able to turn them into the cell types you want, and at the moment we only have rudimentary knowledge of how these cells select specific lineages and how to get them to differentiate into particular cell types. I think in the next 10 years there will be a lot of advances and it will be quite exciting.”

Induced pluripotent stem (iPS) cells are another area where Dr. Andrews expects a lot of exciting advances. He believes that iPS cells will have particular value for accomplishing things that can't be easily done with ESCs. “For example, making disease models. If you have a range of people with different genetic diseases, it will be relatively straightforward to make iPS cells from those individuals so that you would have stem cells with those specific genotypes. My problem with patient specific cell therapies is that making enough of these cells from a particular patient is going to be incredibly expensive. It will take a considerable amount of time to get a cell from a person, convert it into an iPS cell, grow it, and differentiate enough of those cells to the precise form that you need for the treatment. One of the main reasons cited for wanting to have autologous patient specific cells is the issue of immune rejection. But my feeling it that the immunologists will probably provide other solutions to that, so that you can use a stem cell off the shelf rather than a personalized one over the next 10–20 years, and that will be a much cheaper option. Of course another big problem is that we still have to work out how to turn these into the cells we want, and characterize them in great detail.”

"You Need to Balance the Effort That You Put in Against What's Going to Come out"

  1. Top of page
  2. About Dr. Andrews
  3. EC Cells to ESCs
  4. "There Is a Lot of Misunderstanding About the Term ‘Marker'"
  5. "It's Important to Recognize That Genetic Changes in These Cells Are Going to Be Inevitable"
  6. "There Is a Reasonable Possibly of Clinical Trials in the Next Few Years in the Area of Age-Related Macular Degeneration"
  7. "In the Next 10 Years There Will Be a Lot of Advances and It Will Be Quite Exciting"
  8. "You Need to Balance the Effort That You Put in Against What's Going to Come out"

Dr. Andrews believes that it is important for young scientists to truly enjoy their research and see it as a sort of game. “In science, the formality is that we develop a hypothesis and then test it. The reality is that we like playing, and often we do experiments like that. You may have a wild idea and you just try it. The thing to do is to remember that you shouldn't spend a lot of time playing with wild ideas if they're not leading you anywhere. I think one of the early lessons I was taught was that when you're doing experiments you need to balance the effort that you put in against what's going to come out. It's worth putting in a lot of effort if there's a good chance that something very exciting will come out, but there's not much point putting a lot of effort in if the result has a low probability of success or won't be that valuable. But on the other hand, you also have to be prepared to take some risks to get the rewards. You have to be prepared to play with ideas and test things and be imaginative and not too constrained by pre-existing prejudices. It's also important to collaborate with people. Lots of things we do depend on bringing various sorts of information to the table and its very unusual for one person to have everything that's needed. In my experience most of what I've done that has been of any value has usually come from working with several other people who each have brought something interesting along.”