From SBS’ President
A Personal Note: Thank You SBS
By Ricardo Macarron
My first SBS meeting—the 1996 conference in Basel, Switzerland—was a blast! I was a young investigator working on the development and execution of biochemical screening assays to be used in the search for novel bioactive metabolites in microbial extracts. My understanding
of drug discovery was very limited.
Like any good science-driven organization, pharmaceutical companies nurture continuous learning. The need for knowledge is especially strong in the complex field of drug discovery, which encompasses
so many disciplines. But learning through colleagues, papers, books, and even at a university is not enough, especially during a technological revolution.
Attending the SBS scientific conference and commercial tradeshow provided many benefits and insights, for me and for the GSK group led by Emilio Diez in Tres Cantos, Spain, where I was working as leader
of a team of three scientists. We learned that our struggle with one of the first HTS robotic units on the market was not unique, and after discussions with the vendor and other customers, we were able
to improve its performance. We also learned that the 96-well plate, which we felt was high density and a strong industry standard, was starting to tumble as the 384-well plate emerged in the market.
At the same time, Peter Ramn’s imager was introduced as a prototype; it attracted a great deal of attention, and experts in the emerging field of screening discussed its potential to provide a
fast and universal reader for most, if not all, assay technologies.
Last but not least, the meeting provided an opportunity to make some new friends and socialize with colleagues from my company who were also attending the meeting. Among them was Bob Hertzberg,
leader of the GSK screening group in Upper Merion, Pennsylvania, who became my boss a few years later.
In essence, a four-day meeting turned into the bright start of a long journey that, 11 years later, I am still thoroughly enjoying. What has happened to me and to the field in these years has been a
grand ride in which SBS has been a major force.
SBS Board: A Rewarding Service
When I moved from Spain to Pennsylvania in 1999, my new boss, who became SBS’ President in 2002, encouraged me to put my name on the ballot for SBS Board member elections. It was a pleasant surprise
to receive the endorsement of voters, enabling me to join this select group. Being a member of the Board provided rich exposure to very different challenges from the ones associated with making assays
work in microtiter plates, managing a small group of scientists, or securing funds for a new automation project.
The energy, diverse skill sets, and genuine devotion to SBS’ success—which every one of the Board members and SBS officers has brought to the many meetings, e-mail discussions, and teleconferences
I have participated in since 2000—continue to amaze and energize me. The same is true of the members of the committees and special interest groups that contribute strongly to SBS’ offerings
and success. Networking at an SBS event is always a rewarding experience. Networking on an SBS committee, or the Board, for that matter, is an even richer experience, and helps to establish invaluable
lasting links with colleagues from other companies, disciplines, and even levels of seniority.
“You Can Get It If You Really Want”
The title of a famous reggae song applies to the SBS symposium, Current Challenges in Biomolecular Screening, which was held in Madrid, Spain in November 2003. My colleagues at GSK-Spain and I had long
nurtured the dream of organizing an SBS meeting in our home country. It took persistence, a great deal of work, and a lot of help from many friends, but we made it. More than 230 participants enjoyed
two days of good science, networking, and yes, red wine and tapas.
By then, my team at GSK had grown to 25 scientists, and my title was Director of Molecular Screening in Upper Merion.
SBS Pays Back Big Time!
In the summer of 2005, I was enjoying a new role at SBS as chair of the Conference Committee, and leading an assay development unit at GSK. It was an unexpected honor to be invited to serve as SBS President-Elect.
I accepted without hesitation. By the time I assumed the role of SBS President in April 2007, I had been promoted to Vice President of GSK’s Global Compound Management operation, leading a group
of 105 scientists in five sites.
I am quite certain that being an active SBS member, continuously learning from many talented members about screening, drug discovery, human enterprises and culture, has helped my professional career
immeasurably. I have given a lot of my personal time to SBS, but I have received back much more in friendship, knowledge and fun.
Looking Ahead
Where is the field 11 years after I began my journey? SBS and its members have helped shape the field of high-throughput screening, leading the way to an unprecedented industrialization of compound testing.
We drove a transition from the initial emphasis in quantity (throughput) to quality (output). We are now expanding to new areas, including chemical biology, high-content screening, systems biology, and
stem cell research (hope to see you in Anaheim in November!) And one of our core assets as a society, being an interdisciplinary team that celebrates diversity, ensures that we will continue to play
a key role in the new biological revolution that we are experiencing right now.
My advice to the reader who has reached this point in my personal note and is thinking about contributing to SBS progress: Now is the time to jump on board! Send an e-mail to SBS (email@sbsonline.org)
or call the SBS office at +1 (203) 743-1336 and let us know how you would like to get involved.
I’ll end by thanking all my companions on this wonderful journey, and SBS founders, officers and staff for having made it possible.
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Cutting Edge
Stem Cells & Primary Cells: Moving into the Mainstream in Drug Discovery
G. Sitta Sittampalam, Ph.D.
Eli Lilly & Company, Indianapolis, IN, USA.
Maria Webb, Ph.D.
Pharmacopeia, Princeton, New Jersey, USA.
SBS is pleased to present Back to Pharmacology: Stem Cells & Primary Cells in Drug Discovery on November 7-8, 2007, in Anaheim, California. Drs. Sittampalam and Webb are co-chairing this ground-breaking symposium, which will highlight the use of primary cells in drug discovery,
including as a tool for ADMET; stem cells and target validation; and emerging applications of stem cells. See www.sbsonline.org for more information.
The potential applications of stem cells in medicine is a hot topic nowadays! Many political developments in the United States have attracted attention. Proposition 71 established the California Stem
Cell Research and Cures Initiative in 2003. Similar initiatives followed in Wisconsin (2004), New Jersey (2005) and other states. Many of these initiatives have multi-million dollar state grants to promote
stem cell research, independent of the federal government.
Countries in Europe and Asia are also heavily investing in stem cell research, since the potential economic bonanza is estimated to be approximately $100 billion by year 2015. The investment is justified.
The latest research shows that both embryonic and adult stem cells are capable of regenerating and repairing damaged tissues in many life- threatening and disabling diseases. The US Department of Health
and Human Services has declared that regenerative medicine will be the next wave in the health care revolution in medicine by 2020.1
The downside of the political and investment attention is that it has obscured the reality of the research and utility of stem cells. The purpose of this short article is to re-capture the focus on
that underlying science.
“Superstar” Cells
What are stem cells? Why are they important in screening? By definition, stem cells are capable of indefinitely renewing themselves, and undergo differentiation on certain cues to produce multiple cell
types and tissues found in living organisms (see Figure 1, p.4) This unique ability makes them “superstar” cells that can be tamed to benefit research in basic and developmental biology.
The key challenges are to isolate, store and grow human stem cells reproducibly, and to control their differentiation potential so they can be used in cell-based therapy and in drug discovery. These
challenges will take years of focused research by a diverse set of scientists.
We have known for centuries that lower vertebrates such as starfish and newts regenerate missing parts of their bodies. However, only in the last 50 years or so have we learned that stem cells in higher
animals are also capable of differentiating and regenerating damaged tissues. Early studies in embryology demonstrated the existence of primitive germ cells and stem cells that differentiate into various
types of cells. In humans alone, stem cells formed in the early embryo give rise to more than 200 different tissues.
Pluripotent embryonic stem cells derived from the inner cell mass of the early blastocyst are shown in Figure 2 (see p.4) Excitement and hope have been building since the isolation and culture of human
embryonic stem cells by James Thompson and co-workers in 1998.2 Common sources of human embryonic stem cells for research include discarded and unusable embryos from in-vitro fertilization (IVF) clinics,
and other fetal tissues, with informed consent from the donors. The use of IVF-derived material is highly controversial due to moral, ethical and political issues that need to be carefully resolved.
Even before these breakthroughs, the advent of successful bone marrow transplants in the 1970s showed that stem or progenitor cells can be harnessed to regenerate failing bone marrows. These mesenchymal
stem cells were also shown to have the potential to differentiate into other cellular lineages, such as vascular epithelial and muscle cells. In addition, several adult tissues such as skin, muscle,
liver, lung, and brain have been shown recently to possess tissue-derived stem or progenitor cells.3 Hence, the possibility now exists that endogenous tissue-derived stem cells could be stimulated to
heal damaged tissues in humans.
These discoveries have renewed interest in stem cell research worldwide,4 and have generated considerable discussion in the media and scientific circles on the use of stem cells in cellular therapy
and translational medicine. The debate and deliberations are centered on science, ethics and the politics of acquiring and using stem cells of human origin for biomedical research and subsequent applications
in medicine.
Implications for Drug Discovery
In a seminal paper in 2003, Peter Shultz and co-workers demonstrated by screening 100,000 kinase-specific sets of compounds that pluripotent mouse embryonic carcinoma cells (P19 cells) can be stimulated
to differentiate into a neuronal progenitor lineage. The team further demonstrated that the mechanism of action of these compounds is by inhibiting a particular kinase, GSK-beta, which modulates the
Wnt signaling pathway.5
Schultz and colleagues have since shown that small molecule modulators can stimulate cardiogenesis6 in P19 cells. A review of small molecules, biochemicals and drugs such as Gleevec and Prozac by the
same authors shows that these molecules may influence stem cell fate and proliferation,7 further establishing the concept of small molecule effectors of stem cells for the treatment of degenerative diseases
and cancer. The application for drug discovery would be in screening for molecules that can induce endogenous stem cells to regenerate damaged tissues, and to produce cellular lineages that serve as
physiologically relevant vehicles to study disease pathways in phenotypic screening.
Recent work at the University of Wisconsin-Madison has highlighted the use of human and mouse embryonic stem cells in predictive toxicology and metabolomics.8 Work at Pfizer emphasizes stem cell-derived
cells for applications in target identification, validation and safety studies.9 Clearly, drug-discovery scientists are realizing the potential of these cells and their lineages for the study of mechanisms
of efficacy and toxicity of new chemical entities.
Further extending the application of stem cells in disease in the past five or so years is the isolation of cancer stem cells from various tumors in colon, breast, prostate, lung, pancreas, and others.10
It is currently believed that metastasis and relapse of various cancers are due to drug-resistant cancer stem cells that survive radiation and chemotherapy.11
Screening for molecules that specifically target these cells is an attractive option. However, this approach, and the screening for stimulators of tissue regeneration mentioned above, is fraught with
obstacles in the understanding of the cells’ biology and canonical signaling pathways. Therefore, finding chemical and biochemical probes to explore the biology of these cells is quite imperative,
and requires an interdisciplinary approach among academia, industry and government laboratories.
Another significant development is the advent of somatic cell nuclear transfer (SCNT). In this approach, nuclei from skin cells, for example, could be transferred to an enucleated egg cell of the same
species, and the resulting cells could be induced to form embryos. The embryos then could be transplanted into the uterus to grow into a fetus—a feat that was first reported in the cloning of the
sheep Dolly in 1997.12 Recently, mice were reported to have been cloned from skin cells using a similar technique.13 It is also possible to envision using SCNT to generate healthy replacement tissues
or diseased human tissues for screening and lead optimization applications.
The use of primary cells in the high-throughput screening (HTS), hit-to-lead (HTL), and lead optimization (LO) phases of drug discovery is another area that has advanced. Primary cells have not been
immortalized by viral transformation and, unlike immortalized cell lines, they have a finite number of passages in cell culture before they cease to proliferate. However, because they have not been transformed
or grown for years in culture, these cells are likely to be more physiologic. Companies have used “primaries” in HTL and LO for years because the throughput of compounds is smaller and the
assays can be used to complement and verify other datasets. In the last few years, primaries have also been used for HTS because screening technologies have improved.14 Therefore, despite the growth
in compound collections, we can frequently use primary cell lines and get robust, reproducible data.
Science, Ethics, & Politics Converge
The developments described above mean the time is right for the convergence of several emerging fields in drug discovery. The ability to do phenotypic and pathway screening with high-content Imaging (HCS)
technology has significantly matured in the last five years.15 The emergence of screening with primary cells14 and the realization that screening with cells grown in 3-dimensional “tissue-like” spheroids16
may provide more physiological “drug-like” environments for target modulation bode well for the use of stem and primary cell-derived reagents14 as important next-wave tools in drug discovery.
The potential of stem cells in cellular therapy and regenerative medicine underlies both the excitement and the concern about stem cell biology. The discoveries highlighted in this article have fueled
interest in stem cell research worldwide, and have also generated considerable misinformation in the mass media and political circles. The public debate is centered less on science and more on the ethics
and politics of acquiring and using stem cells of human origin for biomedical research and subsequent applications in medicine.
To further the scientific discussion, SBS has organized Back to Pharmacology: Stem Cells & Primary Cells in Drug Discovery (see page 1). By bringing together leading experts in this interdisciplinary
field, SBS will facilitate discussion of the uses and limitations of stem cell and primary cell biology in drug discovery and regenerative medicine. Participating scientists from academia, biotech companies,
non-profit institutes and major pharmaceutical companies will gather in a dynamic environment with poster sessions and an exhibition featuring 35 life science innovators. We look forward to seeing you
there!
Promising Source of Stem Cells
The controversial source of embryonic stem cells from IVF clinics and fetuses may soon be a thing of the past! At press time, three groups of researchers published studies showing the reprogramming of mouse fibroblasts to embryonic stem cells by transfecting four genes.17 These “induced pluripotent stem cells” (iPS), were able to divide continuously and form colonies and teratomas. When the iPS cells were introduced into a developing mouse embryo, they produced chimeric mice with iPS DNA. The next step is to reproduce this work with human cells, thus leading the way to the generation of hES cells without the use of human egg cells, IVF embryos or fetuses for screening and cellular therapy.
References:
1. U. S. Department of Health and Human Services, Washington, DC (2005). A future for Regenerative Medicine: 2020 A New Vision.
2. J. A. Thomson, et al. “Embryonic Stem Cell Lines Derived from Human Blastocysts,” (1998) Science, 282, 1145.
3. A. Pessina, L. Gribaldo. “The Key Role of Adult Stem Cells: Therapeutuc Perspectives” (2006), Cur. Med. Res. Opin. 22, 2287
4. S. Everts, “Taming Stem Cells” (2007), Chem. & Eng. News, 85, 19.
5. S. Ding, et al. “Synthetic Small Molecules that Control Stem Cell Fate”, (2003), PNAS, 100, 7632.
6. X. Wu, et al. “Small Molecules that Induce Cardiomyogenesis in Embryonic Stem Cells”, (2004) J. Am. Chem. Soc. 126, 1590.
7. S. Ding, P. G. Schultz. “A Role for Chemistry in Stem Cell Biology” (2004) Nat. Biotech. 22, 833.
8. K. W. Chaudhary, et al. “Embryonic Stem Cells in Predictive Cardiotoxicity: Laser Capture Microscopy Enables Assay Development”. (2006), Toxicol. Sci., 90, 149.
9. J. McNeish, “Embryonic Stem Cells in Drug Discovery”, (2004), Nat. Rev. Drug Discovery, 3, 71.
10. W. N. Keith. “Cancer Stem Cells: Opportunities for Novel Diagnostics and Drug Discovery”. (2006) Eur. J. Cancer, 42, 1195.
11. S. Bao, et al. “Glioma Stem Cells Promote Radioresistance by Preferential Activation of the DNA damage Response”, (2006), Nature, 444, 756.
12. K. H. S. Campbell, et al. (1996). “Sheep cloned by nuclear transfer from a cultured cell line”. Nature 380, 64.
13. J. Li, et al. “Mice Cloned from Skin Cells” (2007), PNAS, 104, 2738.
14. C. Rossi, Padmanaban, D., Ni, J., Yeh, L.A., Glicksman, M.A., and Waldner, H. Identifying Druglike Inhibitors of Myelin-Reactive T Cells by Phenotypic High-Throughput Screening of a Small-Molecule
Library. J Biomol Screen. 2007 May 3.
15. P. Raman. “Image-based Screening: A technology in Transition”, (2005) Curr. Opin. Biotechnol. 16, 41.
16. L. A Kunz-Schughart, et al. “The Use of 3_D Cultures for High Throughput Screening: the Multicellular Spheroid Model”. (2004), J. Biomol. Screening, 9, 273.
17. D. Cyranoski. “Simple Switch Turns Cells Embryonic”. (2007) Nature, 447, 618.
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Advancing The Science of Drug Discovery
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