# Bruce Lahn

Bruce Lahn is a Chinese-born American geneticist. Lahn came to the U.S. from China to continue his education in the late 1980s. He is the William B. Graham professor of Human Genetics at the University of Chicago. He is also the founder of the Center for Stem Cell Biology and Tissue Engineering at Sun Yat-sen University in Guangzhou, China. Lahn currently serves as the chief scientist of VectorBuilder, Inc.
Lahn's honors include the TR100 Award from Technology Review magazine, the Merrill Lynch Forum Global Innovation Award, the Burroughs Wellcome Career Award, and a Searle Scholarship. He was also named to the 40-Under-40 list by Crain’s Chicago Business magazine, Forbes China 100 Most Influential Chinese Worldwide, and PharmaVoice 100 Top Industry Leaders. Lahn received his B.A. in General Biology from Harvard University and his Ph.D. from the Massachusetts Institute of Technology in the lab of David C. Page. From 2000 to 2012, Lahn was a Howard Hughes Medical Institute Investigator.
His previous research specialized in human genetics and evolutionary genetics, especially human sex chromosome evolution and the genetic basis that underlies the evolutionary expansion of the human brain. Lahn's current research interests include stem cell biology, epigenetics and biotechnology.

## Biography

Bruce Lahn is a Chinese-born American scientist. He is the founder and Chief Scientist of VectorBuilder, a global leader in gene delivery solutions. In the past he has studied human genetics and evolutionary genetics. His main objective with previous studies was to study the evolution of human sex chromosomes and the underlying basis for the growth of the human brain. Lahn is currently doing a wide spread of stem cell research as well as working with epigenetics. Lahn's previous research has led to the hypothesis that the Neanderthals contributed to evolution of the human brain's size. Lahn is currently working to contribute a better understanding of the widespread use of stem cells to the science world.

## Contributions to science

Lahn's research covers several areas including human genetics, evolutionary biology, sex chromosome biology, and stem cell biology.

### Stem cell biology

Lahn’s team showed that the neural stem cell gene Nestin is essential in neurogenesis. He and his colleagues at Sun Yat-sen University explored the use of suicide genes to control tumorigenesis in stem-cell therapy, and the potential of stem Leydig cells in treating testicular dysfunctions. By transplanting embryonic stem cells into blastocyst embryos, his group created chimeric animals between two divergent mammals, Apodemus and Mus, showcasing for the first time that evolutionarily divergent species still possessed highly compatible developmental programs. It also suggested the feasibility of growing organs from human stem cells in animal bodies for human transplantation, which has become an active area of research today.

### Molecular evolution

Using molecular evolution analysis, Lahn's team discovered a strong correlation between background mutation rate in mammals and fixation rate of nonsynonymous substitutions that alter protein sequences. It supports the controversial idea that mutation rate can itself evolve, namely, mutation rates in different genes of a species can be tweaked by natural selection toward different optimal levels, with low mutation rates adopted in genes unlikely to benefit from nonsynonymous substitutions, while high mutation rates adopted in rapidly evolving genes likely to benefit from nonsynonymous substitutions. Lahn’s group developed a methodology combining phylogenetic analysis with protein structural analysis to examine the coevolution of interacting amino acid residues within proteins, which detected strong signals of interacting-residue coevolution in mammalian proteomes and revealed how physicochemical properties of the interactions impact this coevolution.

### Human evolutionary genetics

Lahn worked on several topics in human and primate evolutionary genetics. His group found that SEMG2, encoding a major structural component of semen, experienced faster evolution in primate species of high female promiscuity, showcasing the importance of sexual selection in driving the evolution of reproductive genes. Lahn’s team observed accelerated evolution of nervous system genes in primates and especially the human lineage, which may underlie the expanded cognitive capacity in humans. They showed that two brain size genes, ASPM and Microcephalin (MCPH1), whose null mutations lead to microcephaly (small head due to reduced brain size), experienced accelerated evolution in the primate lineage leading to humans, suggesting roles in the enlargement of the human brain. They further showed that in each of these two genes, a newly arisen haplotype (DNA sequence variant) underwent rapid selective sweep in recent human history because it was favored by strong positive selection. The sweep started about 5,800 years ago for ASPM and about 37,000 years ago for MCPH1, and reached high frequencies in some human populations today. They further showed that the selectively favored haplotype of MCPH1 bore a high degree of sequence difference from other variants of the gene, suggesting that it introgressed into humans from an archaic Homo species (Neanderthals being one possibility) through interbreeding with humans, and that this introgression might have contributed to human brain development. Later studies found some association of the positively selected haplotypes of ASPM and MCPH1 with tonal language and brain volume in humans, but association with mental abilities has not been found. The MCPH1 haplotype was not found in the individuals used to prepare the first draft of the Neanderthal genome, suggesting that it might have introgressed from a different archaic Homo lineage. Lahn's research provoked controversy due to the finding that the positively selected variants of ASPM and MCPH1 had spread to higher frequencies in some parts of the world than in others (for ASPM, it is higher in Europe and surrounding regions than other parts of the world; for MCPH1, it is higher outside sub-Saharan Africa than inside). Lahn emphasized the importance of scientific curiosity over political implications, and advocated the moral position that human genetic diversity should be embraced and celebrated as among humanity's great assets.

### Sex chromosome function and evolution

Working with David Page, Lahn uncovered many new genes on the human Y chromosome, and showed that human Y genes fall into two categories: widely expressed housekeeping genes with homologues on the X chromosome that escape X-inactivation, and genes expressed only in the testis and lacking X homologues. This showed that the human Y is not as gene poor as predicted by the degenerate Y hypothesis., as it retained important housekeeping genes that resisted degeneration and also acquired genes specializing in spermatogenesis. Their further analysis of Y genes with X homologues revealed the evolutionary history of the human sex chromosomes. It dates back to about 300 million years ago when a reptile-like ancestor of mammals acquired a new gene, SRY, on one of a pair of identical autosomes. This gene triggered male development, marking the emergence of sex chromosomes with the SRY-bearing chromosome became the Y while the other chromosome of the previous autosome pair became the X. It also marked the evolutionary switch from temperature-dependent sex-determination system still present in reptiles today to the XY chromosomal sex-determination system in mammals. When X and Y first emerged, they were matched in sequence just like between any pair of autosomes except for the SRY gene that was present on the Y but absent on the X. Over time, however, the Y degenerated in several episodes, each involving the sudden suppression of recombination (DNA exchange) across a large segment between X and the Y during male meiosis, likely due to inversion on the Y, which subsequently led to genes in the affected region of the Y to decay, a process hypothesized to be driven by Muller’s ratchet that operates on nonrecombining regions of the genome. The X maintained its function because it could still recombine in females. This eventually led to highly divergent sequence and function between the human X and Y chromosomes seen today.

### Biotechnology

Lahn worked on gene delivery technologies as the chief scientist of VectorBuilder. He led the creation of Vector Design Studio, an online software platform from VectorBuilder for the intuitive design of gene delivery vectors, allowing researchers with limited molecular biology background to gain access to complex vectors. He is also the architect of VectorBee, a desktop genetic engineering software for viewing, editing and analyzing DNA and protein sequences. Lahn's group developed the miniVec system of miniaturized plasmid backbone to enhance plasmid function, manufacturability and clinical safety. His team reported that nearly half of the plasmids constructed in laboratories around the world contained design or sequence errors, sparking discussions in the life sciences community on the need for community-wide standards to uphold the quality of lab-made plasmids that are a workhorse tool in research and medicine.