Lab Times Summer Read (8) - “I Really Love Shoes”
(August 3rd, 2017) Digging deep into our archive, we found quite a few gems from the past, worth a second read. Here's a 2006 interview with geneticist Leena Peltonen-Palotie (†2010) about population studies in Finland and the European and US science spirit.
Mrs. Peltonen, from your CV we gather that you are an extremely busy and highly productive scientist. Do you have time for one of the favourite occupations women normally think of, namely buying shoes?
Shoes! We saw a picture of you wearing very elegant high heels.
(laughing heartily): You notice the details. Yes, I admit, I really love shoes. Especially high heels because they are something female scientists are not supposed to wear.
Do you like doing things you are not supposed to do?
To some extent yes, I like to break some rigidities of the mould cast for serious science professionals, women scientists can love shoes and nice clothes but also act as females without losing their credibility as top professionals.
In 2002 you came back to Finland to live and work in Helsinki, a town with a mean temperature of 4.8 degrees Celsius. High heels appear not to be suitable footwear there. However, they fit better to Los Angeles, where you worked for several years. How did you once move from the unknown Finnish seaport Oulu to the famous capital city of film business?
Oulu is not so unknown, at least not amongst biomedical researchers. The town received a boost in the late 70s when young eager investigators, that later became famous biochemical scientists, were recruited to start biomedical research in the medical faculty. At that time, I was a medical student there and these young enthusiastic research groups attracted my attention.
I believe your primary goal though was to become a paediatrician.
Yes, because of my brother – he developed diabetes as a child – I definitely wanted to become a paediatrician. I did my M.D. PhD and continued with postdoctoral training in the US for two and half years. That brings us to 1978 – the year when the very first human gene was cloned...
...The gene for growth hormone...
...That’s right. At that particular moment it became very obvious to me that if you ever want to understand human diseases you have to understand the genome, understand how human genes start to work on the DNA level instead of the protein level.
That was in the times of Southern hybridisations and chromosome jumping, long before the genome project.
Yes, that was what I call the tedious era. Initially, when I got back to Finland we tried to use the existing very sparse marker maps of the human genome. Based on hybridisation techniques of that time and using the peculiar population of Finland we started to tackle disease gene positions. In the isolated population such a sparse set of markers worked and having found their locations we wanted to walk to the genes. That was tedious work. But then the human genome project kicked in and that project provided many, many wonderful tools. In addition, PCR was invented and transformed the whole world of molecular biology. However, many of the disease genes we isolated were done by the former tedious way.
Today population geneticists with the support of a sophisticated HapMap can perform genome wide association studies. What is the advantage of this setting?
It‘s simply wonderful: Doing only one experiment for any given disease we can figure out the difference, the imbalance in gene forms or alleles between cases and controls. The important point is: Thanks to the HapMap we do not any longer need pedigree information of the study participants. All my former research relied on knowing the genealogical links between the currently living individuals and those who originated from the same ancestor to be able to define which allele one received from father or mother, respectively. We still benefit from genealogy; you can rely only on a limited number of disease alleles. However, genome wide association allows you to reduce the number of DNAs to be genotyped from the population drastically. I would still advocate doing this kind of research in homogenous populations because you obtain more information than using very heterogenous populations. That‘s especially true if you work with diseases where several predisposing genes are involved.
You said, that the Finnish population is peculiar compared to island populations. In what sense is it peculiar?
The Finnish population is extremely homogenous.
More homogenous than island populations?
Yes. Iceland, for example, was inhabited by Scottish, British, Swedish and Norwegian people. Not so in Finland because Finland has been inhabited some 2,000 to 4,000 years ago by just two major immigrant waves. In addition, in Finland we have the world’s best coverage of health care data and an extremely good health care infrastructure. You should know that Finland has a very long tradition in genetics and thanks to high quality national health care, people are eager to participate in genetic studies. Just like Iceland, we also have very good population genealogy records. Together these factors provide a unique niche for doing population genetic studies.
What about the compliance of the population? In other countries like Germany and even in Iceland people are very concerned to uncover their medical history and genetic constitution.
Fears such as US-citizens may have that they could lose their health care insurance don’t exist in Finland because every citizen has health care insurance. The population is well educated about the concept of “Finnish genes”. There‘s a good tradition of genetics and clinical research. That combination makes people trust in research and the Finnish medical system.
Therefore, Finnish people are not afraid that anybody could abuse the genetic data?
No. Indeed they are sort of proud of their special genes. They are eager to participate in the studies. It was and still is easy to collaborate with clinicians and with families. I once calculated that some 10,000 people actively participated in genetic studies, provided their DNA samples and clinical information and they brought their children to the clinics in the early years when we found the special Finnish disease genes. That‘s great and absolutely unique within Europe.
What kind of special genes?
That‘s were it all started. Thanks to the wonderful clinicians and old time geneticists in Finland it was very obvious that Finland, being a relatively isolated location in a remote part of Europe, provided a unique setting to identify disease genes.
So Finnish people suffer from special “Finnish” diseases?
Yes and no. Some diseases are special; some are only more common than anywhere else in the world. When I started, none of the causative mutations had been identified for 37 diseases found in Finland. Today we know the mutation for 35 of them. The website (www.findis.org) contains the actual listing. These diseases exist all over the world but they are significantly more prevalent in Finland and that’s what has made them easier to identify using DNA tools.
Nowadays, every gene identified, especially a human gene with known functions in a disease, gets patented to make money from it. What about your data? Have you patented any of the disease genes you identified?
Only very few. The issue of intellectual property wasn‘t raised in earlier times. Also, most of the genes are rare gene forms and the major benefit lies not in developing any drug against the disease but in DNA diagnostics. The Finnish government has set up the DNA tests in University labs to do genetic diagnoses and screen for carriers. However, some of the genes have been patented, namely those that might carry the potential to understand the more common biological features in humans.
Can you give us an example?
The gene called AIRE has been patented. That gene was originally identified in a very rare set of Finnish families. It’s the genetic basis of a rare condition in APECED patients, who show symptoms of many autoimmune diseases and is common in Finland and in Japan. We identified a novel gene behind this disease in Finnish families and it turned out to be a very critical gene for understanding human autoimmunity generally, thus the failure to detect our own tissues as our “own” and to start to destroy them, like insulin-producing pancreatic islet cells in diabetes or Addison’s disease destroying your adrenal glands. Autoimmune diseases are common health problems and the molecular details of them are relatively poorly understood. After our AIRE gene identification, accumulating data from around the world indicates that this gene is a kind of switch that operates during fetal life and keeps our immune system in condition so that we don’t start to reject our own body parts. I think it is scientifically fascinating that some families, suffering from the really rare diseases, have actually provided novel information of human biology in general. When I started my career so many of my grant applications were treated like “this is like a stamp collection project, not important for human health generally”. That has been proven to be wrong. We have learnt wonderful things from these rare diseases. Now we are using the same approach to tackle much more common diseases like cardiovascular and neuropsychiatric disorders, but again using Finnish families.
Are you proud now that your argument on the usefulness of learning more about rare diseases has turned out to be correct?
What makes me proud is that such a wonderful team of technicians, students, scientists and clinicians have worked together and utilised a kind of national resource in a very meaningful way and for that accomplishment I am really proud.
The gene that probably made most headlines was the gene for lactose intolerance. Many groups in the world were hunting that gene but you found it. What was the trick?
Again the Finnish population served us really well. In Finland, clinicians had identified large pedigrees with lactose intolerance, affecting 18% of Finns. So we thought: hey, there might be only one mutation in all theses cases. No one else in more heterogenous populations could make that assumption. SNPs outside the coding regions of the lactase gene showed strong association in Finns. We simply trusted our data and targeted our sequencing efforts from the gene and indeed we found the same mutation in all of the lactose-intolerant Finnish persons. This mutation lies 14 kB upstream and breaks the regulatory domain. I think nobody else dared to make the effort to search so far upstream of the gene. We were also lucky that this mutation is the global variant.
There‘s only one mutation responsible in all lactose-intolerant people worldwide?
In most people. However, quite recently at least two other variants have been identified in the same region of the gene in Africans. It actually turned out that not intolerance, but lactose tolerance is a mutation. Isn‘t that fascinating? In public opinion you always think that the “disease” is caused by a mutation that took place in our history. The story of lactose intolerance teaches us the direct opposite. In “normal” people the gene is turned off in the intestinal cells of humans after weaning, making adults lactose-intolerant. That was the situation when people migrated out of Africa. At that time, no adult could use lactose. A mutation was introduced to the human genome some 8-10 thousand years ago and resulted in lactose tolerance; people could happily enjoy milk even as adults.
As well during development of the dairy culture people with the tolerance mutation were shown to be better off.
Exactly. The mutation has been useful in our history, especially in the cold, northern part of the globe. That‘s a nice philosophical lesson; common “disease” mutations are common because they have been beneficial during our history as a species. The other lesson I learned from this and other stories is: especially late onset diseases are a matter of incorrect gene regulation.
Does environment play a role in late onset diseases?
Yes it does. We have obtained good evidence for this statement from our twin studies.
... an EC-project that you co-ordinated for 6 years...
... and that I’m still co-ordinating because we‘ve got an extension for another 6 months. We have produced more than 300 papers in total from this huge twin project and amongst them are papers that support the idea that environment influences the action of disease genes. We have been able to define genetic and life style risk factors for example in obesity and cardiovascular diseases.
Is life style more important for developing a disease than genetic predisposition?
I would challenge that as a general concept. Rather the diseases represent the outcome from the cross-talk between our genes and our environment and life style. We increasingly understand that the response elements in the genome, that turn on and off the genes, are critical, they are responsive to changes in our life style. You are born with some predisposing genes and then environment and lifestyle triggers the genes to act unfavourably. There is a constant cross-talk between environment and your genes. The details of that communication need to be defined.
Your biology gives the basis for environmental triggers to be able to have an effect. Therefore, I would say that somehow I don‘t like the statements that claim that genes are responsible for 40 to 60 percent of disease. History tells us that in different eras of human history some genes were extremely useful, think of obesity genes. These Stone Age genes were wonderful, enabling us to store fat and survive over periods with scanty food supply like winter. Now in the McDonalds era they turn out to be the risk genes making it necessary to restrict food uptake.
Using data from the twin studies you have also potentially identified the first gene controlling human height.
Yes and that’s so exciting. We are very close to some novel obesity genes, too. We have also identified novel genes which are critical in cardiovascular diseases based on their operation in fat. The most important achievement of the project – as I see it – was in harmonising diagnostic criteria for building up a European database enabling us to exchange data. People have pooled their genome-wide scan data and interesting new initial gene regions have emerged. We have also made some advances in targeting some genes involved in the development of migraine
Coming back to my initial question: What about your relationship to the USA.
Right now I am sitting in an office of the Broad Institute in Boston. This institute collaborates between MIT and Harvard University and was created with enormous philanthropy, a generous gift from Eli and Edythe Broad. I work here for several weeks of the year.
Are you torn between the two countries?
I moved to California and to UCLA – as you mentioned – and worked almost 5 years as a founding chair of the Department of Human Genetics. During those years I recruited good faculty members and got it running well. In 2002, I was given massive funding from the EC that attracted me back to my home country. Now I live permanently in Finland but some weeks of the year I spend in Boston. The attraction to this institute comes from the wonderful combination of the best population to study in the world, great access to genome-wide methodologies and international collaboration. If I could be better organised I would spend two months in one block in Boston but in the current phase of my life with one child still at high school, this option is not possible. The Broad Institute gives me a safe haven in an exciting environment, a place to exchange ideas and rapid access to the newest technology and provides more challenges than if I stayed all time in Helsinki. Americans have that wonderful driving spirit. They come with a mug of coffee to your office and tell you, listen, is this or that a good idea? The energetic exchange of ideas is much better developed in the United States than in Europe.
Could you import some of the US enthusiasm and eagerness?
I have tried hard.
I think to some extent. There are some changes being observed at Biomedicum Helsinki and the new generation of European scientists are hopefully more outgoing and willing to break old department boundaries and hierarchic faculty systems. We need to open European academic culture, to build up more flexible structures and to make the environment really attractive intellectually for young scientists. We can do that and I want to contribute to that. However, in the end I returned because Finland is my home country and I want to live there. I returned because I love the European lifestyle. Once European, always European.
Let’s talk a bit about a revolutionising event in Europe: the establishment of the European Council. You are one of the members of the ERC’s Council.
The ERC is a wonderful new concept. We are trying to create a European Community science funding system similar to US funding organisations like NIH or NSF. Applicants do not need to form networks, or make concerted efforts. Money will be given for five years to individual investigators, the stars of Europe, starting with young investigators. Hopefully we can even attract some top scientists back to Europe.
What will your job be in the ERC in the next years?
This year we have met six times. Our task is to establish our credibility in the eyes of scientists and European decision makers, we need to design a strategy to evaluate grant applications and select the best projects in a transparent and efficient way to guarantee that the best investigators get their funds.
There was the issue of political influence about the ERC‘s funding decisions.
There‘s no doubt that the politicians within EC countries have their own agenda concerning research funding. It does not necessarily completely overlap with the views of the scientists. Until now we have successfully operated within the rules of science and excellence, avoiding any political thinking. ERC should only recognise excellence, as in sports. Only the best teams win their games. The ERC should fund the world champion league within science like in sports.
After all your jobs, is there any time left for family, husband – also a genome scientist – and hobbies?
Believe it or not: in my spare time I like being extremely lazy, really extremely lazy! I love to sleep excessively and to spend free time with the family. We have an old fisherman‘s house on an island in the Finnish archipelago between Finland and Sweden where we spend lazy extended weekends and summer vacations, watch the grass grow and listen to the music of the sea, I love it!
Interview: Karin Hollricher