Dr. Hoeijmakers comes to us all the way from Rotterdam in the Netherlands, the country known for its tulips, windmills, clogs, bicycles and excellent biological research. Dr. Hoeijmakers’ lab is located at Erasmus University and focuses on DNA repair. Dr. Hoeijmakers received his PhD in 1982 for his work on trypanosomes, which are single cell eukaryotes that look like small worms under the microscope, are transmitted by the tse-tse fly, grow as parasites in your blood and cause sleeping sickness in Africa. After completing his PhD, Dr. Hoeijmakers did his postdoctoral studies at Erasmus University with a focus on DNA damage repair and genome stability in mammals. This work led to his discovery and articulation of the nucleotide excision repair (NER) pathway, a pathway in which a mutated or damaged nucleotide is removed from the DNA before continued transcription. Transcription is the process in which DNA is converted into RNA before the RNA is then translated into protein. Mutations in genes involved in the NER pathway result in several very rare (literally 1 in a million) human diseases including xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy (TTD). These diseases continue to be studied in his own lab, where he has pioneered the creation of the most accurate mouse models of these diseases to date (1, 2, 3, 4, 5). Dr. Hoeijmakers has received several notable scientific honors including knighthood from the Order of the Netherlands Lion.
Dr. Hoeijmakers’ talk at the Buck Institute focused on the current mouse models for NER pathway mutations. NER mice recapitulate many of the hallmark features of these diseases in humans including extremely small size, brittle hair, arrested development, and severe neurological abnormalities. Patients with advanced stages of these diseases are unable to walk or speak, lose their hearing and vision, and frequently die before their teenage years. The creation of NER mice is a critical step for understanding the mechanisms behind these very rare diseases. When studying NER mice, the researchers noticed that they also showed many symptoms associated with premature aging, making these mice potentially valuable models for studying aging. A result that supports this aging concept is that the mutant NER mice can perform tasks they learned when young, but have much more difficulty learning new tasks when they get old. This is similar in humans with NER mutations, who can easily do a task that they learned when young, but have much more difficulty mastering a newer task. In fact, research using NER mouse models revealed that their symptoms also resemble to a significant extent those of Alzheimer’s disease, a very common form dementia for which unfortunately no medication or manner of prevention exists despite enormous research efforts worldwide. It is likely that the mouse models for these rare disorders will be useful for understanding aspects of age-related diseases such as Alzheimer’s. The most startling result observed from NER mutant mice was their drastic phenotypic improvements when placed on a calorie restriction (limited food intake) diet. NER mice on calorie restriction lived much longer, had drastically increased energy, retained their ability to walk, and on a molecular level, showed much less DNA damage. These initial studies give hope to those families with NER diseased children, but also offer insight into potential treatments for age-associated symptoms in older individuals. These studies indicate that nutrients and amount of food intake may be viable treatments for both serious genetic diseases and common age-associated maladies.
Q: The children that you work with have very debilitating diseases, do you find it difficult to do research on such devastating diseases and interact with the patient’s families?
JH: I’m very much motivated after seeing how these children and their families function and how much they struggle. It is very inspirational to see the families and how well they cope with these diseases. I feel that right now we are reaching the stage where we have accurate mouse models, and we can begin to understand what is going on in these children. We are getting closer to the stage where we can give advice to the families about how to manage these diseases. For the first time while studying these diseases, I am optimistic about the future progress and the help we can soon offer these families.
Q: Are there any treatments available for these children?
JH: Not yet, and although the studies in mice are promising, we need to do additional studies before we can start offering treatment and management advice to the parents of these children. The advice now would be not to force the children to eat more then they want. Since these children are so small, our first instinctive response is to try to feed them as much as possible. This intuitive response is precisely not what we should do.
Q: We frequently hear the term calorie restriction, could you explain how a human might practice calorie restriction?
JH: Calorie restriction means you have a healthy diet, but you restrict the amount that you eat. In this case, what we did is we simply gave the animals only 70% of what an animal with free access to food would eat. This results in the animal feeling hungry during the day. In humans, this is also the case. It would be beneficial if there was a pill to make one feel “full” and eliminate the sensation of being hungry between meals. What calorie restriction does on a molecular level is to make the cell and organism invest more energy in maintenance instead of growth…so focusing on DNA maintenance pathways instead of growth.
Q: Were the calorie restricted mice smaller than their freely fed littermates, and what effects do you think calorie restriction will have on the children affected by these diseases?
JH: Yes, the calorie restriction mice are smaller and lean, and their metabolism is changed. The calorie restriction mice when taken off calorie restriction will catch-up in size to the normal mice. If an organism has free access to food, then it invests energy in growing and reproduction. But if food is restricted, then the animal invests in maintenance, and there is no incentive to invest in future growth and reproduction if food and hence energy conditions are not favorable. We must remember an animal’s top priority is to survive and maintain itself, and then wait for more favorable conditions for growth and reproduction. For the children, I expect that calorie restriction will cause them to be leaner, but that their neurological decline will be strongly delayed and their overall condition will be improved.
Q: Do you practice calorie restriction yourself?
JH: I try. Every night I sit down to dinner and say tomorrow I will start….
Q: Is it possible that calorie restriction, by restricting growth, gives the cells time to repair before replicating and thus not perpetuating any of the mutations?
JH: It may be part of the process. In the mice though, the pathways are so severely affected that they can’t compensate by simply using another DNA repair pathway. However I think that calorie restriction acts on a wide range of processes, and this is something we are still working on. We are not able to evaluate if the overall level of DNA damage is directly reduced at the molecular level, however we see indirect evidence of less DNA damage due to increased transcription of long genes when compared to the non-calorie restriction disease model animals. This increase in transcription indicates that the DNA damage that was previously halting transcription is being resolved in the calorie restriction treated animals.
Q: You have been to many prestigious scientific conferences, what are your favorite countries that you have visited?
JH: One country I always love visiting is Japan due to their hospitality. I am treated like a king. I also recently went to Saudi Arabia to attend a science conference for women. I was very inspired and impressed by the number of woman scientists and their high intellectual level, especially in a country that is not known for women in science. I am very much in favor of having all minds included and collaborating together; we will need this to solve the current questions in science.
Q: When you are not in the lab, what do you do for fun? The Netherlands is known for its expanses of bicycle paths?
JH: My children are a very important part of my life, and I spend my free time with them. I don’t have much time for hobbies, movies or TV. Science really is my hobby and my job. However I do like to ride my bike when I have the chance on our countries extensive amount of bike paths, and to work each day.
For more about Dr. Hoeijmakers, check out his faculty profile on the Erasmus MC website.