Paul van Helden
From the Special Topic of
According to our Special Topics analysis on
tuberculosis (TB) over the past decade, the work of
Professor Paul van Helden ranks at #4 by number of papers,
based on 95 papers cited a total of 1,754 times. Two of
these papers also appear on the lists of the top 20 papers
over the past decade and over the past two years. In
addition, these two papers are designated as Highly Cited
Essential Science IndicatorsSM from
Professor van Helden is the Director of the South African Medical
Research Council's Center for Molecular and Cellular Biology and
Co-Director, DST/NRF Centre of Excellence for Biomedical TB Research, which
operates out of the Department of Biomedical Science, part of the Faculty
of Health Science at Stellenbosch University.
Below, he talks with
ScienceWatch.com about his TB research.
Would you tell us a bit about your
educational background and research experiences?
I was born in Cape Town of rather humble beginnings. My parents, not
wealthy, saved and sacrificed and sent me to a local junior school, but
then determined to send me to a good government boys-only high school
(SACS) some distance from our home, which I attended from 1964-1969.
Education was not free in South Africa in those days. If I had attended the
local high school in the area where we lived, I doubt that I would be where
I am today. My parents could not advise me on a direction, other than to
get a good qualification.
I have been fascinated by science and scientists since early junior school.
From high school days that interest became more directed towards biological
science, although I was concerned that career options in the more
ecological/zoological sciences were not that good. I was quite keen to be a
game ranger, but realized that opportunities were very limited and that one
should at least have a four-year degree for this. Thus, I determined that I
should at least have four years of university training.
For my undergraduate studies in South Africa, I started with basic courses
with the intention to major in chemistry and physics. However, by the end
of my first year, I became aware of a "new" subject, namely biochemistry. I
therefore changed direction slightly and majored in chemistry,
microbiology, and biochemistry for my bachelor's degree. In South Africa,
to continue with post-grad studies, one must take another degree, called
Honours. I did this one-year course in biochemistry, and discovered that
science was a lot more interesting at higher levels, compared to undergrad!
None of my known family had ever had a university qualification and thus
after this four-year qualification, I searched for a job and was offered
one as a QC chemist in a local municipality.
This “PCR” instrument was developed in
the lab of Prof. Paul van Helden in 1989. It was
made entirely in-house and is based on 4
supermarket hairdryers. The
“developers” are shown, from left to
right: Prof. Tommie Victor, Prof. Paul van Helden,
Rene du Toit (Technologist), Frank Peiser
(electronics), Cor Wijtenburg, (metal
On the way home from my interview and job offer and just before I signed
acceptance, I stopped over at my university teaching department and
wandered into the professor's office to tell him what I had decided to do.
He (Prof. Claus von Holt) told me that I had more in me than that and that
if I would change my mind, he would accept me as a Ph.D. student. I went
home to discuss this with my parents, who were not particularly pleased
with this turn of events. I think their reaction is easy to understand with
the wisdom of hindsight. They grew up in the Depression years and my father
was a soldier in WWII for six years, returning home with nothing. Turning
down a "good" job offer was just not in their realm of thinking.
Fortunately, I decided that research was more interesting than being a QC
chemist. So, I went back to being a student and completed my Ph.D. in
protein (histone) sequencing at the end of 1978.
After this, I accepted a job based in the Health Science Faculty of
Stellenbosch University in Cape Town, where I have been ever since, with
the exception of a post-doc period at the Roche Institute in New Jersey,
USA, during 1981-2. This was an important experience, for while it did not
equip me for the details of research projects back home in South Africa, my
thinking was influenced, and learning new ways to do science, as well as
learning new techniques and being exposed to a different culture was
What influenced your decision to research
Being associated with—and later employed (1990) by—the South
African Medical Research Council, I came into contact with scientists
specializing in fields that I had never heard of as a molecular
biologist/biochemist. These included fields such as epidemiology, health
systems research, and the like. Some of these people introduced me to
concepts such as the "burden of disease."
Since I was in a medical environment, I began to question what I was doing
and what relevance it may have in a developing country. I began to think
that we had some responsibility to use our limited finances carefully and
to perhaps apply them to our most pressing problems. I gave thought to how
we might do this, using new molecular biology tools. At that time, PCR had
just recently hit the news and was the new kid on the block.
Putting these thoughts together, I realized that TB was a major problem in
South Africa and that the diagnostic test being used (microscopy smear) was
essentially over 100 years old, and due for a change! Together with Prof.
Tommie Victor (my Ph.D. student at that time), we decided that we should
try to investigate TB diagnosis by PCR from sputum. We could not afford to
purchase any sophisticated equipment (there were all sorts of sanctions in
place against South Africa at that time and our funding was very limited),
so we got together with our electronics technician to see what we could do.
Our electronics technician, Mr. Frank Peiser, is a real MacGyver type of
person, and he soon built us what we think was the very first PCR
instrument in Africa (see fig. 1). This was based on airflow from four
domestic-quality hairdryers bought from a local supermarket! This
instrument was the key to unlocking our new research and our first TB
papers. It also meant that the lab used to get quite hot!
One of your highly cited papers is the 1999
NEJM article, "Exogenous reinfection as a cause of recurrent
tuberculosis after curative treatment" (van Rie A, et al.,
341: 1174-79, 14 October 1999). Would you tell our readers a
little bit about this paper—its goals and conclusions?
At that time, and still today, people talk about "relapse" in TB. This is
regarded to be the phenomenon seen when a patient is treated, appears to be
cured, and then has a second or subsequent episode of disease. The
explanation for this was that some bacilli remained "hidden" within the
patient, are not "killed" by treatment and at a later stage reactivate to
It seemed to us that this might not be the case, since with such a high
incidence and prevalence rate, it was self-evident that individuals would
be likely to be exposed to a source case multiple times in their lives. In
addition, our people had been vaccinated by Bacille Calmette-Guérin
and the high rates of TB suggested no protection from infection. We
reasoned that if these ideas were true, then we could expect to see
different strain types in some patients experiencing a subsequent TB
By this time, we had quite some experience at using "fingerprinting" or
genotyping and had a good collection of TB isolates from a high-incidence
community available since 1993. This included a number of individuals who
had had TB twice, after cure. We therefore looked at the strain types and
noted that in the majority of cases subsequent episodes of TB were
associated with a new strain type. The conclusion was simple: reinfection
and not relapse was responsible for most cases of subsequent TB in our
high-incidence community, provided the patient was treated properly and had
no other complicating illness, e.g., diabetes (patient compliant and not
drug-resistant or HIV-positive).
"...reinfection and not relapse was
responsible for most cases of subsequent TB
in our high-incidence
This paper was part of the Ph.D. work of Annelies van Rie, now a professor
herself in the USA. I recall some interesting experiences with this paper,
one of which was arguing with the editorial staff at the NEJM about the
usage of English, which illustrated the differences between UK and South
African English and American English!
A further thought regarding this result is that in these patients, an
initial episode of TB is not protective. This can be the starting point of
hours of conversation and debate amongst TB researchers, particularly
epidemiologists, immunologists, and vaccinologists! It also was a major
driving force behind a number of other important (in my opinion) papers
from our lab, such as those showing that TB patients with a first episode
are more likely to have a second episode (Verver S, et al., "Rate
of reinfection tuberculosis after successful treatment is higher than rate
of new tuberculosis," American Journal of Respiratory and Critical Care
Medicine 171: 1430-5, 15 June 2005) and that many TB patients have
mixed infections (Warren RM, et al., "Reinfection and mixed
infection cause changing Mycobacterium tuberculosis drug-resistance
infections," American Journal of Respiratory and Critical Care
Medicine 172: 636-42, 1 September 2005). Finally, it triggered some
thoughts about mathematical modeling and has driven some efforts of ours
along those lines, which I find particularly interesting and stimulating
(see papers by P Uys et al.).
Another of your highly cited papers is the 2006
BMC Microbiology paper, "Mycobacterium tuberculosis complex
genetic diversity: mining the fourth international spoligotyping
database (SpoIDB4) for classification, population genetics and
epidemiology" (Brudey K, et al., 6: art. no. 23, 23 March 2006). What
types of information can researchers get from this database?
We are not the originators of this database, nor do we maintain it. Our
group merely contributed towards it. Any researcher worldwide can access
this data, which enables them to identify a strain they have genotyped
using this technology and to find out what family of strains their isolate
belongs to. This information is very user-friendly, open-access, and a
Many of your papers deal with, unsurprisingly,
outbreaks of tuberculosis in South Africa, and WHO has also pointed to
sub-Saharan Africa as a region of concern for this disease. Why is
this; what makes tuberculosis more common in South Africa than
There is no easy or single answer, but the following factors may play a
Genetics and immunology: the population of Africa has not been exposed to
TB for centuries like some other parts of the world, thus the people of
Africa may be inherently more susceptible.
Poverty and nutrition: TB is a disease of poverty and poor nutrition. The
poorest continent on earth is Africa; therefore it is not surprising that
TB is at high levels there.
Health systems (related to poverty): if we do not have a good health care
delivery system that will catch, hold, and treat all (or at least 85%+) TB
patients in a timely fashion and properly, we cannot win. There is probably
no country in Africa that can claim that their system fulfills this level
Diagnosis: we still do not have a good, simple, cheap, PoC (point of care)
effective diagnostic. Even in communities around Cape Town, which are quite
aware of TB, we lose up to 20% of potential TB cases between the first
appearance at a TB clinic and the subsequent visits to confirm diagnosis.
We do not have the resources to follow up with these people. How can one
win under these conditions? Delay or failure to treat implies that
transmission will continue and the epidemic will persist.
Why does South Africa in particular have such a high incidence rate? I do
not know what the definitive answer is. One can speculate. Firstly, factors
such as those listed above play an important role. Secondly, I question
that the statistics and figures from all African countries are correct or
accurate. Other countries may have even higher rates of TB, but lack the
resources to measure them accurately. Even in South Africa, which is
regarded as a resource-rich sub-Saharan country, we regularly question
figures such as those used as denominators in epidemiology estimates.
"...I realized that TB was a major
problem in South Africa and that the
diagnostic test being used (microscopy smear)
was essentially over 100 years old, and due
for a change!"
South Africa also has a relatively high population density. Yes, of course,
countries such as Rwanda also have a very high population density, but this
is somewhat more rural (hence better outdoor living and ventilation
conditions?) and evenly spread. In South Africa, in contrast, we have had
very high densities of underprivileged people living in urban environments
for decades. The same has not been the case in other African cities for as
long. This is equivalent to the tenement slums/ghettos seen in European
cities at the start of the industrial revolution around the late 1700s,
where TB rates were the same as we see here now. Once those living
conditions (and nutrition) started to improve, TB rates dropped in Europe.
We have also had a lot of migration within the country, and disease could
easily have used this social factor to spread.
Finally, in early colonial times (and remember, South Africa was settled by
Europeans from 1652), South Africa was regarded as the perfect place for TB
sufferers from Europe to effect the "solar cure." The climate is largely
hot and dry, with lots of sunshine. In addition, over most of the country,
we do not have the other tropical diseases, such as
schistosomiasis, malaria, yellow fever, etc., making it a
healthy place in general. The result was fairly large-scale importation of
TB from Europe and from the East, via trade and limited slavery in very
early years. Thus, it is likely that TB gained a foothold in South Africa
far earlier and at much higher levels than elsewhere. Perhaps this is the
main original driver for the disease to have gained a stronghold.
Have you observed any appreciable changes in the
trends of tuberculosis incidence in the past decade?
Yes. Sadly, the incidence rate has not really declined at all. Of
course, much of this is ascribed to the HIV epidemic sweeping the
What would you like the "take-away lesson" about
your research to be?
The more we research TB, the worse it gets! No, more seriously, I would
like to make the following observations:
No man is an island. My successes are not only a reflection of myself as an
individual. I have been fortunate and privileged to have some wonderful
colleagues, such as my wife Eileen Hoal (who has worked with me since
1983), and Tommie Victor, Rob Warren, Ian Wiid, Gerhard Walzl, Peter
Donald, Nulda Beyers, and many others, as well as long-lasting support from
the MRC (South Africa) and the University of Stellenbosch. Some funding
from GlaxoSmithKline really helped to kick-start our research in 1993 and
helped to leverage funding from other sources.
We have tried to constantly challenge dogma and to live with the idea that
research is not just a "job." One must be driven and passionate to succeed.
I think that there is a real danger that research done, particularly on
disease trends, in developed or relatively developed countries lead to
generic policy guidelines being developed, which are slavishly implemented
or adopted worldwide. There is a very real danger in my opinion, that such
information is not necessarily correct or applicable for different
environments. Thus we need research in every environment, with tailor-made
solutions where relevant. Yes, maybe it is more expensive, but if we carry
on as we have, we will continue to get what we've got. I have nothing
against developing generic guidelines, but these should be a starting
point, not seen as the final one-size-fits-all solution.
The new trend by funding agencies towards funding only very large
multinational consortia has its place and can be very important. However,
in the process, I think we will destroy much of the creative individual or
small-group research, which is usually where breakthroughs are made. The
reason is simple: the consortia frequently run projects on a large scale,
e.g., recruit patients for some measurement. Thus, everyone must follow an
exact protocol in order to minimize deviation and make results valid. There
is no or little room for individuality and creativity. Much of the funding
is spent on administration and process control, rather than research. The
small but creative individual or small times are being left behind in this
rush to obtain large grants and should not be left out in the
Professor Paul van Helden
Director, Center for Molecular and Cellular Biology
South African Medical Research Council
Co-Director, DST/NRF Centre of Excellence for Biomedical TB Research
Department of Biomedical Science
Faculty of Health Sciences
University of Stellenbosch
Stellenbosch, South Africa
KEYWORDS: TUBERCULOSIS, EPIDEMIOLOGY, DIAGNOSIS, PCR, TB
STRAINS, EXOGENOUS REINFECTION, RECURRENT TB, HEALTH SYSTEMS,
POVERTY, POPULATION DENSITY, CLIMATE, FUNDING, TAILORING