Genesis of biochemistry: a problems approach.
Article: Soluble and insoluble nickel compounds exert a differential inhibitory effect on cell growth through IKKalpha-dependent cyclin D1 down-regulation.[show abstract] [hide abstract]
ABSTRACT: It is well-known that insoluble nickel compounds possess much more potent carcinogenic activities as compared with soluble nickel compounds. Although it is assumed that the different entry and clearance rate are responsible for the difference, the mechanisms underlying the different carcinogenic activities are still not well understood yet. In the present study, we found that exposure to soluble, but not insoluble nickel compounds, caused a significant inhibition of cell growth and G1/G0 cell cycle arrest, which was concomitant with a marked down-regulation of cylin D1, an essential nuclear protein for controlling G1/S transition, while both soluble and insoluble nickel compounds showed similar effects on NFkappaB activation, HIF-1alpha protein accumulation and TNF-alpha transcription and CAP43 protein expression at same doses range. The down-regulation of cyclin D1 is due to protein degradation rather than inhibition of transcription, because the nickel compounds treatment did not change cyclin D1 mRNA level, while MG132, the proteasome inhibitor, can rescue the degradation of cyclin D1 caused by soluble nickel compound. Moreover, the soluble nickel-induced cyclin D1 degradation is dependent on its Thr286 residue and requires IKKalpha, but not HIF-1alpha, which are both reported to be involved in cyclin D1 down-regulation. Taken together, we demonstrate that soluble, but not insoluble nickel compound, is able to cause cyclin D1 degradation and a cell growth arrest in an IKKalpha-dependent manner. Given the role of cyclin D1 and cell proliferation in carcinogenesis, we anticipate that the different effects of soluble and insoluble nickel compounds on cyclin D1 degradation and cell growth arrest may at least partially account for their different carcinogenic activities.Journal of Cellular Physiology 10/2008; 218(1):205-14. · 3.87 Impact Factor
Cell Biology Education
Vol. 1, 16–17, Spring/Summer 2002
Genesis of Biochemistry: A Problems Approach
William B. Wood
Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, 347 UCB,
Boulder, Colorado 80309-0347
Submitted December 4, 2001; Accepted March 25, 2002
Keywords: experiential learning, problem-based learning, case studies approach.
When I began teaching as a young assistant professor at
Caltech in 1966, my assignment was to take over the un-
dergraduate biochemistry course taught for many years by
Henry Borsook, who was about to retire. Students dreaded
this course. Henry insisted on teaching it at 8 AM, and his ap-
during my graduate training at Stanford, I was determined
to put some life and intellectual challenge into the subject but
to a more civilized hour, which gained me some quick popu-
larity but did not address the real problem. I knew I could get
in the 1950s had been largely a descriptive science, based on
the cataloging of biomolecules by natural products chemists
and physiological chemists. Generally, the subject was still
taught that way in the mid-1960s. Students were asked to
learn a bewildering array of structures and metabolic path-
ways, without much discussion about the roles they played
in the overall function of a cell and why they might have
evolved to their present forms.
Two sources of inspiration helped to steer me in a favor-
able direction. The first was Al Lehninger’s remarkable little
book Bioenergetics (Lehninger, 1965). It was the first coher-
ent explanation and rationalization of energy metabolism in
terms of simple thermodynamics and cell function that I had
encountered, and it demonstrated how metabolism could be
taught as an intellectually challenging discipline, with clear
relevance to biological function and evolution. I became ex-
cited about introducing these ideas to students. The second
challenging the standard ways of teaching young children. I
own kids, who were beginning elementary school. It was a
time of heady ideas for changing many things, and education
was high on the list. John Holt in How Children Fail (1964) and
Corresponding author. E-mail address: firstname.lastname@example.org.
ing (1966), Jonathan Kozol in Death at an Early Age (1967), and
In its place, they were advocating student-centered teaching,
open classrooms, and more active involvement of students
in their own education. These writers, at the time considered
takes place that have since been tested and documented by
academic educational researchers since the mid-1960s (sum-
marized, for example, in the National Research Council re-
port entitled How People Learn, 1999). The ideas of these
iconoclasts were refreshing and inspiring, and they argued
convincingly that most real learning must be active and ex-
periential, through doing rather than just listening to lectures
and reading books.
There was no laboratory associated with my course, so lab-
oratory simulations and problems seemed like the next best
thing. As the course matured over the next few years, it at-
tracted creative colleagues who shared my interests in bio-
graduate students, became a teaching assistant in the course
dergraduates at Caltech, took the course as a junior and was
recruited to be a teaching assistant in her senior year. When
Lee Hood joined the Caltech faculty in 1968, we expanded
the course to include new topics such as immunology and
molecular evolution, and he and I shared the lecturing. At
one point, I organized an informal seminar with a few other
interested students to read and discuss differing views, from
B.F. Skinner to Carl Rogers, on what a teacher can actually
do to promote learning, besides simply transmitting infor-
mation. In the course, we experimented with simulated labo-
ratory exercises, of the same sort that can now be done much
more effectively with good software programs—we used in-
dex cards to provide the results of experiments proposed by
card game, Krebs Cycle Poker, helped students to master the
citric acid cycle (do not bet on your apparent straight unless
you are sure about all the intermediates). And, we gradually
accumulated a substantial number of problems related to all
aspects of the course, problems that required the students to
think analytically and quantitatively, integrating the material
in ways beyond those we had discussed in class.
C ?2002 by The American Society for Cell Biology
Biochemistry: A Problems Approach
It was John Wilson’s initiative that ultimately led to the
problems becoming a book. When his pitch to an editor at
W.A. Benjamin (the publishers of Lehninger’s Bioenergetics
and Watson’s Molecular Biology of the Gene) elicited some in-
terest, we recruited Bob Benbow, another Caltech graduate
student who had served as a teaching assistant, to be a co-
author and began to make plans. Our initial idea was sim-
ply to take the collection of problems and answers we had
and publish them in some sort of a binder for use as a sup-
plement to existing textbooks. However, as we got into the
project, we realized we wanted to do more. The comprehen-
sive biochemistry texts used in most courses were becom-
ing thicker and more intimidating for students with each
new edition. Might it not be useful to write a short book
that briefly summarized the most essential concepts in each
area, and then expanded them with a series of problems?
And answers—we soon realized that much of the teaching
value of the book could come from detailed explanations of
the answers to problems that students had already wrestled
So that is what we did, and Biochemistry: A Problems Ap-
proach was published in 1974 (Wood et al., 1974). We pref-
aced the book with an “ancient Chinese proverb” (I do not
in fact know if it is either), which seemed to encapsulate our
I hear, and I forget.
I read, and I remember.
I do, and I understand.
In the preface we wrote, “Listening to lectures, reading, and
memorizing factual information are important components
of learning, but confronting experimental data and solving
concrete problems lead to a deeper working understanding
that cannot be acquired passively.”
Of course we realized we had not invented anything new
in general. Physics and chemistry, and biology, genetics,
had always been taught using problems as effective learn-
ing tools. But at the time it was unusual for biochem-
istry. The book became widely used and was translated
into several languages. A second edition, improved and ex-
panded, was published in 1981 (we were particularly proud
of the new computer-generated triptychs of molecular struc-
tures and our directions for how to visualize them three-
dimensionally without a viewer: wall-eyed or cross-eyed,
ditis elegans genetics in Shanghai in 1987, some of the Chinese
students brought their copies into class for me to sign. But
unfortunately, that was as far as it went. During the 1980s,
the four authors moved in different directions, both geo-
graphically and professionally, and although the book is
still used in a few places (as we know from our continu-
ing two-figure royalty checks), it never progressed to further
How much of an influence this book had in spreading
the problems approach to other areas I do not know, but
medical training (the case studies approach) and many other
disciplines, and it has become an accepted general teaching
paradigm at the secondary and college levels (see, for exam-
ple, Allen, 1997).
In rereading our 1974 preface, I was interested to find the
statement, “The challenge of the future will be to compre-
hend, as completely as possible at the molecular level, the
more complex systems we call organisms. To do so, we must
understand not only the internal chemistry of cells, but also
the chemistry of communication between them.” That is the
direction my own career took, working to understand animal
development through genetics and molecular biology. As a
result of the recent explosion of knowledge in this area, the
field of developmental biology has become, from the stand-
point of students, discouragingly similar to early 1960s bio-
chemistry: an intimidating array of ligands, pathways, sig-
naling components, and transcription factors, all referred to
tated on exams. The time seems ripe for a problems approach
here as well.
ular biologist, has recently become Dean of Humanities and
Sciences at Stanford, and is still deeply involved in educa-
tional issues. Whether or not there is any causal relationship,
an unusually high proportion of her Caltech ’73 classmates
who took the biochemistry course also went on to high-level
positions in academic biology. And John Wilson, among his
other endeavors as a Professor of Biochemistry and Molec-
ular Biology at Baylor College of Medicine, is still creating
challenging problems—watch for Molecular Biology of the Cell:
A Problems Approach, coming soon!
Allen, D.E. (1997). Bringing problem-based learning to the introduc-
tory biology classroom, In: Student Active Science, eds. A.P. McNeal,
and C. D’Avanzo, New York: Saunders, 259–278.
Hentoff, N. (1966). Our Children Are Dying, New York: Viking Press.
Holt, J. (1964). How Children Fail, New York: Pitman.
Holt, J. (1967). How Children Learn, New York: Pitman.
Kozol, J. (1967). Death at an Early Age, Boston: Houghton Mifflin.
Lehninger, A.L. (1965). Bioenergetics, Menlo Park, CA: W.A.
National Research Council. (1999). How People Learn: Brain,
Mind, Experience, and School, Washington, DC: National Academy
Wood, W.B., Wilson, J.H., Benbow, R.M., and Hood, L.E. (1974).
Biochemistry: A Problems Approach, Menlo Park, CA: W.A.
Vol. 1, Spring/Summer 200217